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Sample records for intracellular serotonin modulates

  1. Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation.

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    Nils Paulmann

    2009-10-01

    Full Text Available While serotonin (5-HT co-localization with insulin in granules of pancreatic beta-cells was demonstrated more than three decades ago, its physiological role in the etiology of diabetes is still unclear. We combined biochemical and electrophysiological analyses of mice selectively deficient in peripheral tryptophan hydroxylase (Tph1-/- and 5-HT to show that intracellular 5-HT regulates insulin secretion. We found that these mice are diabetic and have an impaired insulin secretion due to the lack of 5-HT in the pancreas. The pharmacological restoration of peripheral 5-HT levels rescued the impaired insulin secretion in vivo. These findings were further evidenced by patch clamp experiments with isolated Tph1-/- beta-cells, which clearly showed that the secretory defect is downstream of Ca(2+-signaling and can be rescued by direct intracellular application of 5-HT via the clamp pipette. In elucidating the underlying mechanism further, we demonstrate the covalent coupling of 5-HT by transglutaminases during insulin exocytosis to two key players in insulin secretion, the small GTPases Rab3a and Rab27a. This renders them constitutively active in a receptor-independent signaling mechanism we have recently termed serotonylation. Concordantly, an inhibition of such activating serotonylation in beta-cells abates insulin secretion. We also observed inactivation of serotonylated Rab3a by enhanced proteasomal degradation, which is in line with the inactivation of other serotonylated GTPases. Our results demonstrate that 5-HT regulates insulin secretion by serotonylation of GTPases within pancreatic beta-cells and suggest that intracellular 5-HT functions in various microenvironments via this mechanism in concert with the known receptor-mediated signaling.

  2. Serotonin: Modulator of a Drive to Withdraw

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    Tops, Mattie; Russo, Sascha; Boksem, Maarten A. S.; Tucker, Don M.

    2009-01-01

    Serotonin is a fundamental neuromodulator in both vertebrate and invertebrate nervous systems, with a suspected role in many human mental disorders. Yet, because of the complexity of serotonergic function, researchers have been unable to agree on a general theory. One function suggested for serotonin systems is the avoidance of threat. We propose…

  3. Modulation for emergent networks: serotonin and dopamine.

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    Weng, Juyang; Paslaski, Stephen; Daly, James; VanDam, Courtland; Brown, Jacob

    2013-05-01

    In autonomous learning, value-sensitive experiences can improve the efficiency of learning. A learning network needs be motivated so that the limited computational resources and the limited lifetime are devoted to events that are of high value for the agent to compete in its environment. The neuromodulatory system of the brain is mainly responsible for developing such a motivation system. Although reinforcement learning has been extensively studied, many existing models are symbolic whose internal nodes or modules have preset meanings. Neural networks have been used to automatically generate internal emergent representations. However, modeling an emergent motivational system for neural networks is still a great challenge. By emergent, we mean that the internal representations emerge autonomously through interactions with the external environments. This work proposes a generic emergent modulatory system for emergent networks, which includes two subsystems - the serotonin system and the dopamine system. The former signals a large class of stimuli that are intrinsically aversive (e.g., stress or pain). The latter signals a large class of stimuli that are intrinsically appetitive (e.g., pleasure or sweet). We experimented with this motivational system for two settings. The first is a visual recognition setting to investigate how such a system can learn through interactions with a teacher, who does not directly give answers, but only punishments and rewards. The second is a setting for wandering in the presence of a friend and a foe. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Intracellular signal modulation by nanomaterials.

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    Hussain, Salik; Garantziotis, Stavros; Rodrigues-Lima, Fernando; Dupret, Jean-Marie; Baeza-Squiban, Armelle; Boland, Sonja

    2014-01-01

    A thorough understanding of the interactions of nanomaterials with biological systems and the resulting activation of signal transduction pathways is essential for the development of safe and consumer friendly nanotechnology. Here we present an overview of signaling pathways induced by nanomaterial exposures and describe the possible correlation of their physicochemical characteristics with biological outcomes. In addition to the hierarchical oxidative stress model and a review of the intrinsic and cell-mediated mechanisms of reactive oxygen species (ROS) generating capacities of nanomaterials, we also discuss other oxidative stress dependent and independent cellular signaling pathways. Induction of the inflammasome, calcium signaling, and endoplasmic reticulum stress are reviewed. Furthermore, the uptake mechanisms can be of crucial importance for the cytotoxicity of nanomaterials and membrane-dependent signaling pathways have also been shown to be responsible for cellular effects of nanomaterials. Epigenetic regulation by nanomaterials, effects of nanoparticle-protein interactions on cell signaling pathways, and the induction of various cell death modalities by nanomaterials are described. We describe the common trigger mechanisms shared by various nanomaterials to induce cell death pathways and describe the interplay of different modalities in orchestrating the final outcome after nanomaterial exposures. A better understanding of signal modulations induced by nanomaterials is not only essential for the synthesis and design of safer nanomaterials but will also help to discover potential nanomedical applications of these materials. Several biomedical applications based on the different signaling pathways induced by nanomaterials are already proposed and will certainly gain a great deal of attraction in the near future.

  5. Characterization of intracellular regions in the human serotonin transporter for phosphorylation sites

    DEFF Research Database (Denmark)

    Sørensen, Lena; Strømgaard, Kristian; Kristensen, Anders S

    2014-01-01

    In the central nervous system, synaptic levels of the monoamine neurotransmitter serotonin are mainly controlled by the serotonin transporter (SERT), and drugs used in the treatment of various psychiatric diseases have SERT as primary target. SERT is a phosphoprotein that undergoes phosphorylation....../dephosphorylation during transporter regulation by multiple pathways. In particular, activation and/or inhibition of kinases including PKC, PKG, p38MAPK, and CaMKII modulate SERT function and trafficking. The molecular mechanisms by which kinase activity is linked to SERT regulation are poorly understood, including...

  6. Serotonin storage pools in basophil leukemia and mast cells: characterization of two types of serotonin binding protein and radioautographic analysis of the intracellular distribution of [3H]serotonin

    International Nuclear Information System (INIS)

    Tamir, H.; Theoharides, T.C.; Gershon, M.D.; Askenase, P.W.

    1982-01-01

    The binding of serotonin to protein(s) derived from rat basophil leukemia (RBL) cells and mast cells was studied. Two types of serotonin binding protein in RBL cells was found. These proteins differed from one another in molecular weight and eluted in separate peaks from sephadex G-200 columns. Peak I protein (KD = 1.9 x 10 -6 M) was a glycoprotein that bound to concanavalin A (Con A); Peak II protein (KD 1 = 4.5 x 10 - 8 M; KD 2 = 3.9 x 10 -6 M) did not bind to Con A. Moreover, binding of [ 3 H]serotonin to protein of Peak I was sensitive to inhibition by reserpine, while binding of [ 3 H]serotonin to protein of Peak II resisted inhibition by that drug. Other differences between the two types of binding protein were found, the most significant of which was the far more vigorous conditions of homogenization required to extract Peak I than Peak II protein. Electron microscope radioautographic analysis of the intracellular distribution of [ 3 H] serotonin taken up in vitro by RBL cells or in vivo by murine mast cells indicated that essentially all of the labeled amine was located in cytoplasmic granules.No evidence for a pool in the cytosol was found and all granules were capable of becoming labeled. The presence of two types of intracellular serotonin binding proteins in these cells may indicate that there are two intracellular storage compartments for the amine. Both may be intragranular, but Peak I protein may be associated with the granular membrane while Peak II protein may be more free within the granular core. Different storage proteins may help to explain the differential release of amines from mast cell granules

  7. Serotonin modulates immune function in T cells from HIV-seropositive subjects

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    Eugen-Olsen, J; Afzelius, P; Andresen, L

    1997-01-01

    We have shown earlier increased intracellular levels of cAMP in peripheral lymphocytes from HIV-seropositive subjects and that a chemically induced decrease in this level increases cell proliferation and cytotoxicity. Others have shown that serotonin indirectly decreases intracellular cAMP levels...

  8. Modulation of defensive reflex conditioning in snails by serotonin

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    Andrianov, Vyatcheslav V.; Bogodvid, Tatiana K.; Deryabina, Irina B.; Golovchenko, Aleksandra N.; Muranova, Lyudmila N.; Tagirova, Roza R.; Vinarskaya, Aliya K.; Gainutdinov, Khalil L.

    2015-01-01

    Highlights Daily injection of serotonin before a training session accelerated defensive reflex conditioning in snails.Daily injection of 5-hydroxytryptophan before a training session in snails with a deficiency of serotonin induced by the “neurotoxic” analog of serotonin 5,7-dihydroxytryptamine, restored the ability of snails to learn.After injection of the “neurotoxic” analogs of serotonin 5,6- and 5,7-dihydroxytryptamine as well as serotonin, depolarization of the membrane and decrease of the threshold potential of premotor interneurons was observed. We studied the role of serotonin in the mechanisms of learning in terrestrial snails. To produce a serotonin deficit, the “neurotoxic” analogs of serotonin, 5,6- or 5,7-dihydroxytryptamine (5,6/5,7-DHT) were used. Injection of 5,6/5,7-DHT was found to disrupt defensive reflex conditioning. Within 2 weeks of neurotoxin application, the ability to learn had recovered. Daily injection of serotonin before a training session accelerated defensive reflex conditioning and daily injections of 5-HTP in snails with a deficiency of serotonin induced by 5,7-DHT restored the snail's ability to learn. We discovered that injections of the neurotoxins 5,6/5,7-DHT as well as serotonin, caused a decrease in the resting and threshold potentials of the premotor interneurons LPa3 and RPa3. PMID:26557063

  9. Nutrient-induced glucagon like peptide-1 release is modulated by serotonin.

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    Ripken, Dina; van der Wielen, Nikkie; Wortelboer, Heleen M; Meijerink, Jocelijn; Witkamp, Renger F; Hendriks, Henk F J

    2016-06-01

    Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis for the current study was that nutrient-induced GLP-1 release from EECs is modulated by serotonin through a process involving serotonin receptor interaction. This was studied by assessing the effects of serotonin reuptake inhibition by fluoxetine on nutrient-induced GLP-1, PYY and CCK release from isolated pig intestinal segments. Next, serotonin-induced GLP-1 release was studied in enteroendocrine STC-1 cells, where effects of serotonin receptor inhibition were studied using specific and non-specific antagonists. Casein (1% w/v), safflower oil (3.35% w/v), sucrose (50mM) and rebaudioside A (12.5mM) stimulated GLP-1 release from intestinal segments, whereas casein only stimulated PYY and CCK release. Combining nutrients with fluoxetine further increased nutrient-induced GLP-1, PYY and CCK release. Serotonin release from intestinal tissue segments was stimulated by casein and safflower oil while sucrose and rebaudioside A had no effect. The combination with fluoxetine (0.155μM) further enhanced casein and safflower oil induced-serotonin release. Exposure of ileal tissue segments to serotonin (30μM) stimulated GLP-1 release whereas it did not induce PYY and CCK release. Serotonin (30 and 100μM) also stimulated GLP-1 release from STC-1 cells, which was inhibited by the non-specific 5HT receptor antagonist asenapine (1 and 10μM). These data suggest that nutrient-induced GLP-1 release is modulated by serotonin through a receptor mediated process. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Modulation of the intrinsic properties of motoneurons by serotonin

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    Perrier, Jean-François; Rasmussen, Hanne Borger; Christensen, Rasmus Kordt

    2013-01-01

    Serotonin (5-HT) is one of the main transmitters in the nervous system. Serotonergic neurons in the raphe nuclei in the brainstem innervate most parts of the central nervous system including motoneurons in the spinal cord and brainstem. This review will focus on the modulatory role that 5-HT exerts...... a sustained depolarization and an amplification of synaptic inputs. Under pathological conditions, such as after a spinal cord injury, the promotion of persistent inward currents by serotonin and/or the overexpression of autoactive serotonergic receptors may contribute to motoneuronal excitability, muscle...

  11. Inter- and intracellular relationship of substance P-containing neurons with serotonin and GABA in the dorsal raphe nucleus: combination of autoradiographic and immunocytochemical techniques

    International Nuclear Information System (INIS)

    Magoul, R.; Onteniente, B.; Oblin, A.; Calas, A.

    1986-01-01

    Double-labeling experiments were performed at the electron microscopic level in the dorsal raphe nucleus of rat, in order to study the inter- and intracellular relationship of substance P with gamma-aminobutyric acid (GABA) and serotonin. Autoradiography for either [ 3 H]serotonin or [ 3 H]GABA was coupled, on the same tissue section, with peroxidase-antiperoxidase immunocytochemistry for substance P in colchicine-treated animals. Intercellular relationships were represented by synaptic contacts made by [ 3 H]serotonin-labeled terminals on substance P-containing somata and dendrites, and by substance P-containing terminals on [ 3 H]GABA-labeled cells. Intracellular relationships were suggested by the occurrence of the peptide within [ 3 H]serotonin-containing and [ 3 H]GABA-containing cell bodies and fibers. Doubly labeled varicosities of the two kinds were also observed in the supraependymal plexus adjacent to the dorsal raphe nucleus. The results demonstrated that, in addition to reciprocal synaptic interactions made by substance P with serotonin and GABA, the dorsal raphe nucleus is the site of intracellular relationships between the peptide and either the amine or the amino acid

  12. Developmental exposure to fluoxetine modulates the serotonin system in hypothalamus.

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    Cecilia Berg

    Full Text Available The selective serotonin reuptake inhibitor (SSRI fluoxetine (FLU, Prozac® is commonly prescribed for depression in pregnant women. This results in SSRI exposure of the developing fetus. However, there are knowledge gaps regarding the impact of SSRI exposure during development. Given the role of serotonin in brain development and its cross-talk with sex hormone function, we investigated effects of developmental exposure to pharmacologically relevant concentrations of FLU (3 and 30 nM (measured on brain neurotransmitter levels, gonadal differentiation, aromatase activity in brain and gonads, and the thyroid system, using the Xenopus tropicalis model. Tadpoles were chronically exposed (8 weeks until metamorphosis. At metamorphosis brains were cryosectioned and levels of serotonin, dopamine, norepinephrine, and their metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were measured in discrete regions (telencephalon, hypothalamus and the reticular formation of the cryosections using high-performance liquid chromatography. Exposure to 30 nM FLU increased the concentration of 5-hydroxyindoleacetic acid in hypothalamus compared with controls. FLU exposure did not affect survival, time to metamorphosis, thyroid histology, gonadal sex differentiation, or aromatase activity implying that the effect on the serotonergic neurotransmitter system in the hypothalamus region was specific. The FLU concentration that impacted the serotonin system is lower than the concentration measured in umbilical cord serum, suggesting that the serotonin system of the developing brain is highly sensitive to in utero exposure to FLU. To our knowledge this is the first study showing effects of developmental FLU exposure on brain neurochemistry. Given that SSRIs are present in the aquatic environment the current results warrant further investigation into the neurobehavioral effects of SSRIs in aquatic wildlife.

  13. Modulation of rat blood phagocyte activity by serotonin

    Czech Academy of Sciences Publication Activity Database

    Okénková, Kateřina; Lojek, Antonín; Kubala, Lukáš; Číž, Milan

    2007-01-01

    Roč. 101, č. 14 (2007), s245-s246 E-ISSN 1213-7103. [Mezioborová česko-slovenská toxikologická konference /12./. Praha, 11.06.2007-13.06.2007] R&D Projects: GA ČR(CZ) GA524/04/0897 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : phagocytes * serotonin * reactive oxygen species Subject RIV: BO - Biophysics

  14. Prion protein modulates glucose homeostasis by altering intracellular iron.

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    Ashok, Ajay; Singh, Neena

    2018-04-26

    The prion protein (PrP C ), a mainly neuronal protein, is known to modulate glucose homeostasis in mouse models. We explored the underlying mechanism in mouse models and the human pancreatic β-cell line 1.1B4. We report expression of PrP C on mouse pancreatic β-cells, where it promoted uptake of iron through divalent-metal-transporters. Accordingly, pancreatic iron stores in PrP knockout mice (PrP -/- ) were significantly lower than wild type (PrP +/+ ) controls. Silencing of PrP C in 1.1B4 cells resulted in significant depletion of intracellular (IC) iron, and remarkably, upregulation of glucose transporter GLUT2 and insulin. Iron overloading, on the other hand, resulted in downregulation of GLUT2 and insulin in a PrP C -dependent manner. Similar observations were noted in the brain, liver, and neuroretina of iron overloaded PrP +/+ but not PrP -/- mice, indicating PrP C -mediated modulation of insulin and glucose homeostasis through iron. Peripheral challenge with glucose and insulin revealed blunting of the response in iron-overloaded PrP +/+ relative to PrP -/- mice, suggesting that PrP C -mediated modulation of IC iron influences both secretion and sensitivity of peripheral organs to insulin. These observations have implications for Alzheimer's disease and diabetic retinopathy, known complications of type-2-diabetes associated with brain and ocular iron-dyshomeostasis.

  15. cGMP-dependent protein kinase Iα associates with the antidepressant-sensitive serotonin transporter and dictates rapid modulation of serotonin uptake

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    Steiner Jennifer A

    2009-08-01

    Full Text Available Abstract Background The Na+/Cl--dependent serotonin (5-hydroxytryptamine, 5-HT transporter (SERT is a critical element in neuronal 5-HT signaling, being responsible for the efficient elimination of 5-HT after release. SERTs are not only targets for exogenous addictive and therapeutic agents but also can be modulated by endogenous, receptor-linked signaling pathways. We have shown that neuronal A3 adenosine receptor activation leads to enhanced presynaptic 5-HT transport in vitro and an increased rate of SERT-mediated 5-HT clearance in vivo. SERT stimulation by A3 adenosine receptors derives from an elevation of cGMP and subsequent activation of both cGMP-dependent protein kinase (PKG and p38 mitogen-activated protein kinase. PKG activators such as 8-Br-cGMP are known to lead to transporter phosphorylation, though how this modification supports SERT regulation is unclear. Results In this report, we explore the kinase isoform specificity underlying the rapid stimulation of SERT activity by PKG activators. Using immortalized, rat serotonergic raphe neurons (RN46A previously shown to support 8-Br-cGMP stimulation of SERT surface trafficking, we document expression of PKGI, and to a lower extent, PKGII. Quantitative analysis of staining profiles using permeabilized or nonpermeabilized conditions reveals that SERT colocalizes with PKGI in both intracellular and cell surface domains of RN46A cell bodies, and exhibits a more restricted, intracellular pattern of colocalization in neuritic processes. In the same cells, SERT demonstrates a lack of colocalization with PKGII in either intracellular or surface membranes. In keeping with the ability of the membrane permeant kinase inhibitor DT-2 to block 8-Br-cGMP stimulation of SERT, we found that DT-2 treatment eliminated cGMP-dependent kinase activity in PKGI-immunoreactive extracts resolved by liquid chromatography. Similarly, treatment of SERT-transfected HeLa cells with small interfering RNAs targeting

  16. Antidepressant effects of insulin in streptozotocin induced diabetic mice: Modulation of brain serotonin system.

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    Gupta, Deepali; Kurhe, Yeshwant; Radhakrishnan, Mahesh

    2014-04-22

    Diabetes is a persistent metabolic disorder, which often leads to depression as a result of the impaired neurotransmitter function. Insulin is believed to have antidepressant effects in depression associated with diabetes; however, the mechanism underlying the postulated effect is poorly understood. In the present study, it is hypothesized that insulin mediates an antidepressant effect in streptozotocin (STZ) induced diabetes in mice through modulation of the serotonin system in the brain. Therefore, the current study investigated the antidepressant effect of insulin in STZ induced diabetes in mice and insulin mediated modulation in the brain serotonin system. In addition, the possible pathways that lead to altered serotonin levels as a result of insulin administration were examined. Experimentally, Swiss albino mice of either sex were rendered diabetic by a single intraperitoneal (i.p.) injection of STZ. After one week, diabetic mice received a single dose of either insulin or saline or escitalopram for 14days. Thereafter, behavioral studies were conducted to test the behavioral despair effects using forced swim test (FST) and tail suspension test (TST), followed by biochemical estimations of serotonin concentrations and monoamine oxidase (MAO) activity in the whole brain content. The results demonstrated that, STZ treated diabetic mice exhibited an increased duration of immobility in FST and TST as compared to non-diabetic mice, while insulin treatment significantly reversed the effect. Biochemical assays revealed that administration of insulin attenuated STZ treated diabetes induced neurochemical alterations as indicated by elevated serotonin levels and decreased MAO-A and MAO-B activities in the brain. Collectively, the data indicate that insulin exhibits antidepressant effects in depression associated with STZ induced diabetes in mice through the elevation of the brain serotonin levels. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. The mechanical environment modulates intracellular calcium oscillation activities of myofibroblasts.

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    Charles Godbout

    Full Text Available Myofibroblast contraction is fundamental in the excessive tissue remodeling that is characteristic of fibrotic tissue contractures. Tissue remodeling during development of fibrosis leads to gradually increasing stiffness of the extracellular matrix. We propose that this increased stiffness positively feeds back on the contractile activities of myofibroblasts. We have previously shown that cycles of contraction directly correlate with periodic intracellular calcium oscillations in cultured myofibroblasts. We analyze cytosolic calcium dynamics using fluorescent calcium indicators to evaluate the possible impact of mechanical stress on myofibroblast contractile activity. To modulate extracellular mechanics, we seeded primary rat subcutaneous myofibroblasts on silicone substrates and into collagen gels of different elastic modulus. We modulated cell stress by cell growth on differently adhesive culture substrates, by restricting cell spreading area on micro-printed adhesive islands, and depolymerizing actin with Cytochalasin D. In general, calcium oscillation frequencies in myofibroblasts increased with increasing mechanical challenge. These results provide new insight on how changing mechanical conditions for myofibroblasts are encoded in calcium oscillations and possibly explain how reparative cells adapt their contractile behavior to the stresses occurring in normal and pathological tissue repair.

  18. Regulating prefrontal cortex activation: an emerging role for the 5-HT₂A serotonin receptor in the modulation of emotion-based actions?

    Science.gov (United States)

    Aznar, Susana; Klein, Anders B

    2013-12-01

    The prefrontal cortex (PFC) is involved in mediating important higher-order cognitive processes such as decision making, prompting thereby our actions. At the same time, PFC activation is strongly influenced by emotional reactions through its functional interaction with the amygdala and the striatal circuitry, areas involved in emotion and reward processing. The PFC, however, is able to modulate amygdala reactivity via a feedback loop to this area. A role for serotonin in adjusting for this circuitry of cognitive regulation of emotion has long been suggested based primarily on the positive pharmacological effect of elevating serotonin levels in anxiety regulation. Recent animal and human functional magnetic resonance studies have pointed to a specific involvement of the 5-hydroxytryptamine (5-HT)2A serotonin receptor in the PFC feedback regulatory projection onto the amygdala. This receptor is highly expressed in the prefrontal cortex areas, playing an important role in modulating cortical activity and neural oscillations (brain waves). This makes it an interesting potential pharmacological target for the treatment of neuropsychiatric modes characterized by lack of inhibitory control of emotion-based actions, such as addiction and other impulse-related behaviors. In this review, we give an overview of the 5-HT2A receptor distribution (neuronal, intracellular, and anatomical) along with its functional and physiological effect on PFC activation, and how that relates to more recent findings of a regulatory effect of the PFC on the emotional control of our actions.

  19. Serotonin and Serotonin Transporters in the Adrenal Medulla: A Potential Hub for Modulation of the Sympathetic Stress Response.

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    Brindley, Rebecca L; Bauer, Mary Beth; Blakely, Randy D; Currie, Kevin P M

    2017-05-17

    Serotonin (5-HT) is an important neurotransmitter in the central nervous system where it modulates circuits involved in mood, cognition, movement, arousal, and autonomic function. The 5-HT transporter (SERT; SLC6A4) is a key regulator of 5-HT signaling, and genetic variations in SERT are associated with various disorders including depression, anxiety, and autism. This review focuses on the role of SERT in the sympathetic nervous system. Autonomic/sympathetic dysfunction is evident in patients with depression, anxiety, and other diseases linked to serotonergic signaling. Experimentally, loss of SERT function (SERT knockout mice or chronic pharmacological block) has been reported to augment the sympathetic stress response. Alterations to serotonergic signaling in the CNS and thus central drive to the peripheral sympathetic nervous system are presumed to underlie this augmentation. Although less widely recognized, SERT is robustly expressed in chromaffin cells of the adrenal medulla, the neuroendocrine arm of the sympathetic nervous system. Adrenal chromaffin cells do not synthesize 5-HT but accumulate small amounts by SERT-mediated uptake. Recent evidence demonstrated that 5-HT 1A receptors inhibit catecholamine secretion from adrenal chromaffin cells via an atypical mechanism that does not involve modulation of cellular excitability or voltage-gated Ca 2+ channels. This raises the possibility that the adrenal medulla is a previously unrecognized peripheral hub for serotonergic control of the sympathetic stress response. As a framework for future investigation, a model is proposed in which stress-evoked adrenal catecholamine secretion is fine-tuned by SERT-modulated autocrine 5-HT signaling.

  20. Thalamic synaptic transmission of sensory information modulated by synergistic interaction of adenosine and serotonin.

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    Yang, Ya-Chin; Hu, Chun-Chang; Huang, Chen-Syuan; Chou, Pei-Yu

    2014-03-01

    The thalamic synapses relay peripheral sensory information to the cortex, and constitute an important part of the thalamocortical network that generates oscillatory activities responsible for different vigilance (sleep and wakefulness) states. However, the modulation of thalamic synaptic transmission by potential sleep regulators, especially by combination of regulators in physiological scenarios, is not fully characterized. We found that somnogen adenosine itself acts similar to wake-promoting serotonin, both decreasing synaptic strength as well as short-term depression, at the retinothalamic synapse. We then combined the two modulators considering the coexistence of them in the hypnagogic (sleep-onset) state. Adenosine plus serotonin results in robust synergistic inhibition of synaptic strength and dramatic transformation of short-term synaptic depression to facilitation. These synaptic effects are not achievable with a single modulator, and are consistent with a high signal-to-noise ratio but a low level of signal transmission through the thalamus appropriate for slow-wave sleep. This study for the first time demonstrates that the sleep-regulatory modulators may work differently when present in combination than present singly in terms of shaping information flow in the thalamocortical network. The major synaptic characters such as the strength and short-term plasticity can be profoundly altered by combination of modulators based on physiological considerations. © 2013 International Society for Neurochemistry.

  1. Intracellular loop 5 is important for the transport mechanism and molecular pharmacology of the human serotonin transporter

    DEFF Research Database (Denmark)

    Said, Saida; Neubauer, Henrik Amtoft; Müller, Heidi Kaastrup

    2015-01-01

    The serotonin transporter (SERT) belongs to a family of transport proteins called the neurotransmitter:sodium symporters. The specialized members of this family transport different neurotransmitters across the cell membrane, thereby regulating signaling between neurons. Most of these transporters...

  2. Intracellular calcium modulation of voltage-gated sodium channels in ventricular myocytes

    NARCIS (Netherlands)

    Casini, Simona; Verkerk, Arie O.; van Borren, Marcel M. G. J.; van Ginneken, Antoni C. G.; Veldkamp, Marieke W.; de Bakker, Jacques M. T.; Tan, Hanno L.

    2009-01-01

    AIMS: Cardiac voltage-gated sodium channels control action potential (AP) upstroke and cell excitability. Intracellular calcium (Ca(i)(2+)) regulates AP properties by modulating various ion channels. Whether Ca(i)(2+) modulates sodium channels in ventricular myocytes, is unresolved. We studied

  3. Serotonin, dopamine and noradrenaline adjust actions of myelinated afferents via modulation of presynaptic inhibition in the mouse spinal cord.

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    David L García-Ramírez

    Full Text Available Gain control of primary afferent neurotransmission at their intraspinal terminals occurs by several mechanisms including primary afferent depolarization (PAD. PAD produces presynaptic inhibition via a reduction in transmitter release. While it is known that descending monoaminergic pathways complexly regulate sensory processing, the extent these actions include modulation of afferent-evoked PAD remains uncertain. We investigated the effects of serotonin (5HT, dopamine (DA and noradrenaline (NA on afferent transmission and PAD. Responses were evoked by stimulation of myelinated hindlimb cutaneous and muscle afferents in the isolated neonatal mouse spinal cord. Monosynaptic responses were examined in the deep dorsal horn either as population excitatory synaptic responses (recorded as extracellular field potentials; EFPs or intracellular excitatory postsynaptic currents (EPSCs. The magnitude of PAD generated intraspinally was estimated from electrotonically back-propagating dorsal root potentials (DRPs recorded on lumbar dorsal roots. 5HT depressed the DRP by 76%. Monosynaptic actions were similarly depressed by 5HT (EFPs 54%; EPSCs 75% but with a slower time course. This suggests that depression of monosynaptic EFPs and DRPs occurs by independent mechanisms. DA and NA had similar depressant actions on DRPs but weaker effects on EFPs. IC50 values for DRP depression were 0.6, 0.8 and 1.0 µM for 5HT, DA and NA, respectively. Depression of DRPs by monoamines was nearly-identical in both muscle and cutaneous afferent-evoked responses, supporting a global modulation of the multimodal afferents stimulated. 5HT, DA and NA produced no change in the compound antidromic potentials evoked by intraspinal microstimulation indicating that depression of the DRP is unrelated to direct changes in the excitability of intraspinal afferent fibers, but due to metabotropic receptor activation. In summary, both myelinated afferent-evoked DRPs and monosynaptic

  4. Intestinal Serotonin Transporter Inhibition by Toll-Like Receptor 2 Activation. A Feedback Modulation.

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    Eva Latorre

    Full Text Available TLR2 is a microbiota recognition receptor that has been described to contribute to intestinal homeostasis and to ameliorate inflammatory intestinal injury. In this context, serotonin (5-HT has shown to be an essential intestinal physiological neuromodulator that is also involved in intestinal inflammatory diseases. Since the interaction between TLR2 activation and the intestinal serotoninergic system remains non-investigated, our main aim was to analyze the effect of TLR2 on intestinal serotonin transporter (SERT activity and expression and the intracellular pathways involved. Caco-2/TC7 cells were used to analyze SERT and TLR2 molecular expression and SERT activity by measuring 5-HT uptake. The results showed that apical TLR2 activation inhibits SERT activity in Caco-2/TC7 cells mainly by reducing SERT protein level either in the plasma membrane, after short-term TLR2 activation or in both the plasma membrane and cell lysate, after long-term activation. cAMP/PKA pathway appears to mediate short-term inhibitory effect of TLR2 on SERT; however, p38 MAPK pathway has been shown to be involved in both short- and long-term TLR2 effect. Reciprocally, 5-HT long-term treatment yielded TLR2 down regulation in Caco-2/TC7 cells. Finally, results from in vivo showed an augmented intestinal SERT expression in mice Tlr2-/-, thus confirming our inhibitory effect of TLR2 on intestinal SERT in vitro. The present work infers that TLR2 may act in intestinal pathophysiology, not only by its inherent innate immune role, but also by regulating the intestinal serotoninergic system.

  5. Can a Selective Serotonin Reuptake Inhibitor Act as a Glutamatergic Modulator?

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    Marcos Emilio Frizzo, PhD

    2017-01-01

    Full Text Available Sertraline (Zoloft and fluoxetine (Prozac are selective serotonin reuptake inhibitors whose antidepressant mechanism of action is classically attributed to an elevation of the extracellular levels of serotonin in the synaptic cleft. However, the biological effects of these drugs seem to be more complex than their traditionally described mechanism of action. Among their actions is the inhibition of different types of Na+ and K+ channels, as well as of glutamate uptake activity. The clearance of extracellular glutamate is essential to maintain the central nervous system within physiological conditions, and this excitatory neurotransmitter is removed from the synaptic cleft by astrocyte transporters. This transport depends upon a hyperpolarized membrane potential in astrocytes that is mainly maintained by Kir4.1 K+ channels. The impairment of the Kir4.1 channel activity reduces driving force for the glutamate transporter, resulting in an accumulation of extracellular glutamate. It has been shown that sertraline and fluoxetine inhibit Kir4.1 K+ channels. Recently, we demonstrated that sertraline reduces glutamate uptake in human platelets, which contain a high-affinity Na+-dependent glutamate uptake system, with kinetic and pharmacological properties similar to astrocytes in the central nervous system. Considering these similarities between human platelets and astrocytes, one might ask if sertraline could potentially reduce glutamate clearance in the synaptic cleft and consequently modulate glutamatergic transmission. This possibility merits investigation, since it may provide additional information regarding the mechanism of action and perhaps the side effects of these antidepressants.

  6. Molecular analysis of the interaction between the intracellular loops of the human serotonin receptor type 6 (5-HT6) and the α subunit of GS protein

    International Nuclear Information System (INIS)

    Kang, Hatan; Lee, Won Kyu; Choi, Yun Hui; Vukoti, Krishna Moorthy; Bang, Won Gi; Yu, Yeon Gyu

    2005-01-01

    The serotonin type 6 (5-HT 6 ) receptor is a G-protein coupled receptor (GPCR) coupled to a stimulatory G-protein (G S ). To identify the structural basis for the interaction of the 5-HT 6 receptor with the G S protein, we have dissected the interaction between GST-fusion proteins containing the second intracellular loop (iL2), the third intracellular loop (iL3), or the C-terminal tail of the 5-HT 6 receptor and the α subunit of G S (Gα S ). The direct interaction of iL3 and Gα S was demonstrated by co-immunoprecipitation. Furthermore, the kinetic parameters of the interaction between iL3 and Gα S were measured by surface plasmon resonance, and the apparent dissociation constant was determined to be 0.9 x 10 -6 M. In contrast, the second intracellular loop and C-terminal tail regions showed negligible affinity to Gα S . The critical residues within the iL3 region for the interaction with Gα S were identified as conserved positively charged residues near the C-terminus of iL3 by measuring the cellular levels of cAMP produced in response to 5-HT stimulation of cells transfected with 5-HT 6 receptor mutants

  7. Efficiency of immunotoxin cytotoxicity is modulated by the intracellular itinerary.

    Directory of Open Access Journals (Sweden)

    Lori L Tortorella

    Full Text Available Pseudomonas exotoxin-based immunotoxins, including LMB-2 (antiTac(F(v-PE38, are proposed to traffic to the trans-Golgi network (TGN and move by a retrograde pathway to the endoplasmic reticulum, where they undergo translocation to the cytoplasm, a step that is essential for cytotoxicity. The retrograde transport pathways used by LMB-2 are not completely understood, so it is unclear if transit through specific organelles is critical for maximal cytotoxic activity. In this study, we used Chinese hamster ovary (CHO cell lines that express chimeric constructs of CD25, the Tac antigen, attached to the cytoplasmic domain of the TGN-targeted transmembrane proteins, TGN38 and furin. These chimeras are both targeted to the TGN, but the itineraries they follow are quite different. LMB-2 was incubated with the two cell lines, and the efficiency of cell killing was determined using cell viability and cytotoxicity assays. LMB-2 that is targeted through the endocytic recycling compartment to the TGN via Tac-TGN38 kills the cells more efficiently than immunotoxins delivered through the late endosomes by Tac-furin. Although the processing to the 37 kDa active fragment was more efficient in Tac-furin cells than in Tac-TGN38 cells, this was not associated with enhanced cytotoxicity - presumably because the toxin was also degraded more rapidly in these cells. These data indicate that trafficking through specific organelles is an important factor modulating toxicity by LMB-2.

  8. Serotonin transporter genotype modulates subgenual response to fearful faces using an incidental task.

    Science.gov (United States)

    O'Nions, Elizabeth J P; Dolan, Raymond J; Roiser, Jonathan P

    2011-11-01

    This study assessed the impact of serotonin transporter genotype (5-HTTLPR) on regional responses to emotional faces in the amygdala and subgenual cingulate cortex (sgACC), while subjects performed a gender discrimination task. Although we found no evidence for greater amygdala reactivity or reduced amygdala-sgACC coupling in short variant 5-HTTLPR homozygotes (s/s), we observed an interaction between genotype and emotion in sgACC. Only long variant homozygotes (la/la) exhibited subgenual deactivation to fearful versus neutral faces, whereas the effect in s/s subjects was in the other direction. This absence of subgenual deactivation in s/s subjects parallels a recent finding in depressed subjects [Grimm, S., Boesiger, P., Beck, J., Schuepbach, D., Bermpohl, F., Walter, M., et al. Altered negative BOLD responses in the default-mode network during emotion processing in depressed subjects. Neuropsychopharmacology, 34, 932-943, 2009]. Taken together, the findings suggest that subgenual cingulate activity may play an important role in regulating the impact of aversive stimuli, potentially conferring greater resilience to the effects of aversive stimuli in la/la subjects. Using dynamic causal modeling of functional magnetic resonance imaging data, we explored the effects of genotype on effective connectivity and emotion-specific changes in coupling across a network of regions implicated in social processing. Viewing fearful faces enhanced bidirectional excitatory coupling between the amygdala and the fusiform gyrus, and increased the inhibitory influence of the amygdala over the sgACC, although this modulation of coupling did not differ between the genotype groups. The findings are discussed in relation to the role of sgACC and serotonin in moderating responses to aversive stimuli [Dayan, P., & Huys, Q. J., Serotonin, inhibition, and negative mood. PLoS Comput Biol, 4, e4, 2008; Mayberg, H. S., Liotti, M., Brannan, S. K., McGinnis, S., Mahurin, R. K., Jerabek, P. A., et

  9. Estrous cycle modulation of extracellular serotonin in mediobasal hypothalamus: role of the serotonin transporter and terminal autoreceptors.

    Science.gov (United States)

    Maswood, S; Truitt, W; Hotema, M; Caldarola-Pastuszka, M; Uphouse, L

    1999-06-12

    In vivo microdialysis was used to examine extracellular serotonin (5-HT) in the mediobasal hypothalamus (MBH) of male and female Fischer (CDF-344) rats. Females from the stages of diestrus, proestrus, and estrus were used. Additionally, ovariectomized rats, primed subcutaneously (s.c.) with estradiol benzoate or estradiol benzoate plus progesterone were examined. Extracellular 5-HT in the MBH varied with stage of the estrous cycle and with the light/dark cycle. Proestrous females had the highest microdialysate concentrations of 5-HT during the light portion of the light/dark cycle and lowest concentrations during the dark portion of the cycle. Diestrous females had the highest levels during the dark portion of the cycle, while males and estrous females showed little change between light and dark portions of the cycle. In ovariectomized rats, there was no effect of 2.5 microg or 25 microg estradiol benzoate (s.c.) on extracellular 5-HT; but the addition of 500 microg progesterone, 48 h after estrogen priming, reduced microdialysate 5-HT near the threshold for detection. In intact females and in males, reverse perfusion with 3 microM fluoxetine, a selective serotonin reuptake inhibitor (SSRI), or 2 microM methiothepin, a 5-HT receptor antagonist, increased microdialysate concentrations of 5-HT. Estrous females and males showed nearly a 4-fold increase in microdialysate 5-HT in response to fluoxetine while smaller responses were seen in diestrous and proestrous rats. In contrast, proestrous rats showed the largest response to methiothepin. Estrous females showed a delayed response to methiothepin, but there was no methiothepin-induced increase in extracellular 5-HT in males. These findings are discussed in reference to the suggestion that extracellular 5-HT in the MBH is regulated in a manner that is gender and estrous cycle dependent. The 5-HT terminal autoreceptor may exert a greater role in proestrous females; the serotonin transporter appears to play a more active

  10. Nutrient-induced glucagon like peptide-1 release is modulated by serotonin

    NARCIS (Netherlands)

    Ripken, Dina; Wielen, van der Nikkie; Wortelboer, Heleen M.; Meijerink, Jocelijn; Witkamp, Renger F.; Hendriks, Henk F.J.

    2016-01-01

    Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis

  11. Nutrient-induced glucagon like peptide-1 release is modulated by serotonin

    NARCIS (Netherlands)

    Ripken, D.; Wielen, N. van der; Wortelboer, H.M.; Meijerink, J.; Witkamp, R.F.; Hendriks, H.F.J.

    2016-01-01

    Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis

  12. Modulation of [3H]-glutamate binding by serotonin in the rat hippocampus: An autoradiographic study

    International Nuclear Information System (INIS)

    Mennini, T.; Miari, A.

    1991-01-01

    Serotonin (5-HT) added in vitro increased [ 3 H]-glutamate specific binding in the rat hippocampus, reaching statistical significance in layers rich in N-Methyl-D-Aspartate sensitive glutamate receptors. This effect was explained by a significant increase in the apparent affinity of [ 3 H]-glutamate when 5-HT is added in vitro. Two days after lesion of serotonergic afferents to the hippocampus with 5,7- Dihydroxytryptamine [ 3 H]-glutamate binding was significantly decreased in the CA3 region and stratum lacunosum moleculare of the hippocampus, this reduction being reversed by in vitro addition of 10 μM 5-HT. The decrease observed is due to a significant reduction of quisqualate-insensitive (radiatum CA3) and kainate receptors (strata oriens, radiatum, pyramidal of CA3). Five days after lesion [ 3 H]-glutamate binding increased significantly in the CA3 region of the hippocampus but was not different from sham animals in the other hippocampal layers. Two weeks after lesion [ 3 H]-glutamate binding to quisqualate-insensitive receptors was increased in all the hippocampal layers, while kainate and quisqualate-sensitive receptors were not affected. These data are consistent with the possibility that 5-HT is a direct positive modulator of glutamate receptor subtypes

  13. Bilobalide modulates serotonin-controlled behaviors in the nematode Caenorhabditis elegans

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    Luo Yuan

    2009-06-01

    Full Text Available Abstract Background Dysfunctions in the serotonergic system have been implicated in several neurological disorders such as depression. Elderly individuals who have been diagnosed with clinical depression show elevated cases of neurodegenerative diseases. This has led to suggestions that modulating the serotonin (5-HT system could provide an alternative method to current therapies for alleviating these pathologies. The neuroprotective effects of bilobalide in vitro have been documented. We aim to determine whether bilobalide affects the 5-HT system in the nematode C. elegans. The wild type worms, as well as well-characterized 5-HT mutants, were fed with bilobalide in a range of concentrations, and several 5-HT controlled behaviors were tested. Results We observed that bilobalide significantly inhibited 5-HT-controlled egg-laying behavior in a dose-dependent manner, which was blocked in the 5-HT receptor mutants (ser-4, mod-1, but not in the 5-HT transporter (mod-5 or synthesis (tph-1 mutants. Bilobalide also potentiated a 5-HT-controlled, experience-dependent locomotory behavior, termed the enhanced slowing response in the wild type animals. However, this effect was fully blocked in 5-HT receptor mod-1 and dopamine defective cat-2 mutants, but only partially blocked in ser-4 mutants. We also demonstrated that acetylcholine transmission was inhibited in a transgenic C. elegans strain that constitutively expresses Aβ, and bilobalide did not significantly affect this inhibition. Conclusion These results suggest that bilobalide may modulate specific 5-HT receptor subtypes, which involves interplay with dopamine transmission. Additional studies for the function of bilobalide in neurotransmitter systems could aid in our understanding of its neuroprotective properties.

  14. Serotonin syndrome

    Science.gov (United States)

    Hyperserotonemia; Serotonergic syndrome; Serotonin toxicity; SSRI - serotonin syndrome; MAO - serotonin syndrome ... brain area. For example, you can develop this syndrome if you take migraine medicines called triptans together ...

  15. Intra- and Interhemispheric Propagation of Electrophysiological Synchronous Activity and Its Modulation by Serotonin in the Cingulate Cortex of Juvenile Mice.

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    Víctor Rovira

    Full Text Available Disinhibition of the cortex (e.g., by GABA -receptor blockade generates synchronous and oscillatory electrophysiological activity that propagates along the cortex. We have studied, in brain slices of the cingulate cortex of mice (postnatal age 14-20 days, the propagation along layer 2/3 as well as the interhemispheric propagation through the corpus callosum of synchronous discharges recorded extracellularly and evoked in the presence of 10 μM bicuculline by electrical stimulation of layer 1. The latency of the responses obtained at the same distance from the stimulus electrode was longer in anterior cingulate cortex (ACC: 39.53 ± 2.83 ms, n = 7 than in retrosplenial cortex slices (RSC: 21.99 ± 2.75 ms, n = 5; p<0.05, which is equivalent to a lower propagation velocity in the dorso-ventral direction in ACC than in RSC slices (43.0 mm/s vs 72.9 mm/s. We studied the modulation of this propagation by serotonin. Serotonin significantly increased the latency of the intracortical synchronous discharges (18.9% in the ipsilateral hemisphere and 40.2% in the contralateral hemisphere, and also increased the interhemispheric propagation time by 86.4%. These actions of serotonin were mimicked by the activation of either 5-HT1B or 5-HT2A receptors, but not by the activation of the 5-HT1A subtype. These findings provide further knowledge about the propagation of synchronic electrical activity in the cerebral cortex, including its modulation by serotonin, and suggest the presence of deep differences between the ACC and RSC in the structure of the local cortical microcircuits underlying the propagation of synchronous discharges.

  16. Do serotonin(1-7) receptors modulate short and long-term memory?

    Science.gov (United States)

    Meneses, A

    2007-05-01

    Evidence from invertebrates to human studies indicates that serotonin (5-hydroxytryptamine; 5-HT) system modulates short- (STM) and long-term memory (LTM). This work is primarily focused on analyzing the contribution of 5-HT, cholinergic and glutamatergic receptors as well as protein synthesis to STM and LTM of an autoshaping learning task. It was observed that the inhibition of hippocampal protein synthesis or new mRNA did not produce a significant effect on autoshaping STM performance but it did impair LTM. Both non-contingent protein inhibition and 5-HT depletion showed no effects. It was basically the non-selective 5-HT receptor antagonist cyproheptadine, which facilitated STM. However, the blockade of glutamatergic and cholinergic transmission impaired STM. In contrast, the selective 5-HT(1B) receptor antagonist SB-224289 facilitated both STM and LTM. Selective receptor antagonists for the 5-HT(1A) (WAY100635), 5-HT(1D) (GR127935), 5-HT(2A) (MDL100907), 5-HT(2C/2B) (SB-200646), 5-HT(3) (ondansetron) or 5-HT(4) (GR125487), 5-HT(6) (Ro 04-6790, SB-399885 and SB-35713) or 5-HT(7) (SB-269970) did not impact STM. Nevertheless, WAY100635, MDL100907, SB-200646, GR125487, Ro 04-6790, SB-399885 or SB-357134 facilitated LTM. Notably, some of these changes shown to be independent of food-intake. Concomitantly, these data indicate that '5-HT tone via 5-HT(1B) receptors' might function in a serial manner from STM to LTM, whereas working in parallel using 5-HT(1A), 5-HT(2A), 5-HT(2B/2C), 5-HT(4), or 5-HT(6) receptors.

  17. Subsecond Sensory Modulation of Serotonin Levels in a Primary Sensory Area and Its Relation to Ongoing Communication Behavior in a Weakly Electric Fish.

    Science.gov (United States)

    Fotowat, Haleh; Harvey-Girard, Erik; Cheer, Joseph F; Krahe, Rüdiger; Maler, Leonard

    2016-01-01

    Serotonergic neurons of the raphe nuclei of vertebrates project to most regions of the brain and are known to significantly affect sensory processing. The subsecond dynamics of sensory modulation of serotonin levels and its relation to behavior, however, remain unknown. We used fast-scan cyclic voltammetry to measure serotonin release in the electrosensory system of weakly electric fish, Apteronotus leptorhynchus . These fish use an electric organ to generate a quasi-sinusoidal electric field for communicating with conspecifics. In response to conspecific signals, they frequently produce signal modulations called chirps. We measured changes in serotonin concentration in the hindbrain electrosensory lobe (ELL) with a resolution of 0.1 s concurrently with chirping behavior evoked by mimics of conspecific electric signals. We show that serotonin release can occur phase locked to stimulus onset as well as spontaneously in the ELL region responsible for processing these signals. Intense auditory stimuli, on the other hand, do not modulate serotonin levels in this region, suggesting modality specificity. We found no significant correlation between serotonin release and chirp production on a trial-by-trial basis. However, on average, in the trials where the fish chirped, there was a reduction in serotonin release in response to stimuli mimicking similar-sized same-sex conspecifics. We hypothesize that the serotonergic system is part of an intricate sensory-motor loop: serotonin release in a sensory area is triggered by sensory input, giving rise to motor output, which can in turn affect serotonin release at the timescale of the ongoing sensory experience and in a context-dependent manner.

  18. Comparison of P2X and TRPV1 receptors in ganglia or primary culture of trigeminal neurons and their modulation by NGF or serotonin

    Directory of Open Access Journals (Sweden)

    Giniatullin Rashid

    2006-03-01

    Full Text Available Abstract Background Cultured sensory neurons are a common experimental model to elucidate the molecular mechanisms of pain transduction typically involving activation of ATP-sensitive P2X or capsaicin-sensitive TRPV1 receptors. This applies also to trigeminal ganglion neurons that convey pain inputs from head tissues. Little is, however, known about the plasticity of these receptors on trigeminal neurons in culture, grown without adding the neurotrophin NGF which per se is a powerful algogen. The characteristics of such receptors after short-term culture were compared with those of ganglia. Furthermore, their modulation by chronically-applied serotonin or NGF was investigated. Results Rat or mouse neurons in culture mainly belonged to small and medium diameter neurons as observed in sections of trigeminal ganglia. Real time RT-PCR, Western blot analysis and immunocytochemistry showed upregulation of P2X3 and TRPV1 receptors after 1–4 days in culture (together with their more frequent co-localization, while P2X2 ones were unchanged. TRPV1 immunoreactivity was, however, lower in mouse ganglia and cultures. Intracellular Ca2+ imaging and whole-cell patch clamping showed functional P2X and TRPV1 receptors. Neurons exhibited a range of responses to the P2X agonist α, β-methylene-adenosine-5'-triphosphate indicating the presence of homomeric P2X3 receptors (selectively antagonized by A-317491 and heteromeric P2X2/3 receptors. The latter were observed in 16 % mouse neurons only. Despite upregulation of receptors in culture, neurons retained the potential for further enhancement of P2X3 receptors by 24 h NGF treatment. At this time point TRPV1 receptors had lost the facilitation observed after acute NGF application. Conversely, chronically-applied serotonin selectively upregulated TRPV1 receptors rather than P2X3 receptors. Conclusion Comparing ganglia and cultures offered the advantage of understanding early adaptive changes of nociception

  19. Serotonin receptors expressed in Drosophila mushroom bodies differentially modulate larval locomotion.

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    Bryon Silva

    Full Text Available Drosophila melanogaster has been successfully used as a simple model to study the cellular and molecular mechanisms underlying behaviors, including the generation of motor programs. Thus, it has been shown that, as in vertebrates, CNS biogenic amines (BA including serotonin (5HT participate in motor control in Drosophila. Several evidence show that BA systems innervate an important association area in the insect brain previously associated to the planning and/or execution of motor programs, the Mushroom Bodies (MB. The main objective of this work is to evaluate the contribution of 5HT and its receptors expressed in MB to motor behavior in fly larva. Locomotion was evaluated using an automated tracking system, in Drosophila larvae (3(rd-instar exposed to drugs that affect the serotonergic neuronal transmission: alpha-methyl-L-dopa, MDMA and fluoxetine. In addition, animals expressing mutations in the 5HT biosynthetic enzymes or in any of the previously identified receptors for this amine (5HT1AR, 5HT1BR, 5HT2R and 5HT7R were evaluated in their locomotion. Finally, RNAi directed to the Drosophila 5HT receptor transcripts were expressed in MB and the effect of this manipulation on motor behavior was assessed. Data obtained in the mutants and in animals exposed to the serotonergic drugs, suggest that 5HT systems are important regulators of motor programs in fly larvae. Studies carried out in animals pan-neuronally expressing the RNAi for each of the serotonergic receptors, support this idea and further suggest that CNS 5HT pathways play a role in motor control. Moreover, animals expressing an RNAi for 5HT1BR, 5HT2R and 5HT7R in MB show increased motor behavior, while no effect is observed when the RNAi for 5HT1AR is expressed in this region. Thus, our data suggest that CNS 5HT systems are involved in motor control, and that 5HT receptors expressed in MB differentially modulate motor programs in fly larvae.

  20. Intracellular calcium levels determine differential modulation of allosteric interactions within G protein-coupled receptor heteromers.

    Science.gov (United States)

    Navarro, Gemma; Aguinaga, David; Moreno, Estefania; Hradsky, Johannes; Reddy, Pasham P; Cortés, Antoni; Mallol, Josefa; Casadó, Vicent; Mikhaylova, Marina; Kreutz, Michael R; Lluís, Carme; Canela, Enric I; McCormick, Peter J; Ferré, Sergi

    2014-11-20

    The pharmacological significance of the adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromer is well established and it is being considered as an important target for the treatment of Parkinson’s disease and other neuropsychiatric disorders. However, the physiological factors that control its distinctive biochemical properties are still unknown. We demonstrate that different intracellular Ca2+ levels exert a differential modulation of A2AR-D2R heteromer-mediated adenylyl-cyclase and MAPK signaling in striatal cells. This depends on the ability of low and high Ca2+ levels to promote a selective interaction of the heteromer with the neuronal Ca2+-binding proteins NCS-1 and calneuron-1, respectively. These Ca2+-binding proteins differentially modulate allosteric interactions within the A2AR-D2R heteromer, which constitutes a unique cellular device that integrates extracellular (adenosine and dopamine) and intracellular (Ca+2) signals to produce a specific functional response.

  1. Serotonin modulates the oxidative burst of human phagocytes via various mechanisms

    Czech Academy of Sciences Publication Activity Database

    Číž, Milan; Komrsková, Daniela; Prachařová, Lucie; Okénková, Kateřina; Čížová, Hana; Moravcová, Aneta; Jančinová, V.; Petríková, M.; Lojek, Antonín; Nosál, R.

    2007-01-01

    Roč. 18, č. 18 (2007), s. 583-590 ISSN 0953-7104 R&D Projects: GA ČR(CZ) GA524/04/0897 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : antioxidants * chemiluminescence * serotonin Subject RIV: BO - Biophysics Impact factor: 1.915, year: 2007

  2. Spatiotemporal brain dynamics of emotional face processing modulations induced by the serotonin 1A/2A receptor agonist psilocybin.

    Science.gov (United States)

    Bernasconi, Fosco; Schmidt, André; Pokorny, Thomas; Kometer, Michael; Seifritz, Erich; Vollenweider, Franz X

    2014-12-01

    Emotional face processing is critically modulated by the serotonergic system. For instance, emotional face processing is impaired by acute psilocybin administration, a serotonin (5-HT) 1A and 2A receptor agonist. However, the spatiotemporal brain mechanisms underlying these modulations are poorly understood. Here, we investigated the spatiotemporal brain dynamics underlying psilocybin-induced modulations during emotional face processing. Electrical neuroimaging analyses were applied to visual evoked potentials in response to emotional faces, following psilocybin and placebo administration. Our results indicate a first time period of strength (i.e., Global Field Power) modulation over the 168-189 ms poststimulus interval, induced by psilocybin. A second time period of strength modulation was identified over the 211-242 ms poststimulus interval. Source estimations over these 2 time periods further revealed decreased activity in response to both neutral and fearful faces within limbic areas, including amygdala and parahippocampal gyrus, and the right temporal cortex over the 168-189 ms interval, and reduced activity in response to happy faces within limbic and right temporo-occipital brain areas over the 211-242 ms interval. Our results indicate a selective and temporally dissociable effect of psilocybin on the neuronal correlates of emotional face processing, consistent with a modulation of the top-down control. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Intracellular pH homeostasis and serotonin-induced pH changes in Calliphora salivary glands: the contribution of V-ATPase and carbonic anhydrase.

    Science.gov (United States)

    Schewe, Bettina; Schmälzlin, Elmar; Walz, Bernd

    2008-03-01

    Blowfly salivary gland cells have a vacuolar-type H(+)-ATPase (V-ATPase) in their apical membrane that energizes secretion of a KCl-rich saliva upon stimulation with serotonin (5-hydroxytryptamine, 5-HT). We have used BCECF to study microfluometrically whether V-ATPase and carbonic anhydrase (CA) are involved in intracellular pH (pH(i)) regulation, and we have localized CA activity by histochemistry. We show: (1) mean pH(i) in salivary gland cells is 7.5+/-0.3 pH units (N=96), higher than that expected from passive H(+) distribution; (2) low 5-HT concentrations (0.3-3 nmol l(-1)) induce a dose-dependent acidification of up to 0.2 pH units, with 5-HT concentrations >10 nmol l(-1), causing monophasic or multiphasic pH changes; (3) the acidifying effect of 5-HT is mimicked by bath application of cAMP, forskolin or IBMX; (4) salivary gland cells exhibit CA activity; (5) CA inhibition with acetazolamide and V-ATPase inhibition with concanamycin A lead to a slow acidification of steady-state pH(i); (6) 5-HT stimuli in the presence of acetazolamide induce an alkalinization that can be decreased by simultaneous application of the V-ATPase inhibitor concanamycin A; (7) concanamycin A removes alkali-going components from multiphasic 5-HT-induced pH changes; (8) NHE activity and a Cl(-)-dependent process are involved in generating 5-HT-induced pH changes; (9) the salivary glands probably contain a Na(+)-driven amino acid transporter. We conclude that V-ATPase and CA contribute to steady-state pH(i) regulation and 5-HT-induced outward H(+) pumping does not cause an alkalinization of pH(i) because of cytosolic H(+) accumulation attributable to stimulated cellular respiration and AE activity, masking the alkalizing effect of V-ATPase-mediated acid extrusion.

  4. Serotonin transporter genotype modulates social reward and punishment in rhesus macaques.

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    Karli K Watson

    Full Text Available Serotonin signaling influences social behavior in both human and nonhuman primates. In humans, variation upstream of the promoter region of the serotonin transporter gene (5-HTTLPR has recently been shown to influence both behavioral measures of social anxiety and amygdala response to social threats. Here we show that length polymorphisms in 5-HTTLPR predict social reward and punishment in rhesus macaques, a species in which 5-HTTLPR variation is analogous to that of humans.In contrast to monkeys with two copies of the long allele (L/L, monkeys with one copy of the short allele of this gene (S/L spent less time gazing at face than non-face images, less time looking in the eye region of faces, and had larger pupil diameters when gazing at photos of a high versus low status male macaques. Moreover, in a novel primed gambling task, presentation of photos of high status male macaques promoted risk-aversion in S/L monkeys but promoted risk-seeking in L/L monkeys. Finally, as measured by a "pay-per-view" task, S/L monkeys required juice payment to view photos of high status males, whereas L/L monkeys sacrificed fluid to see the same photos.These data indicate that genetic variation in serotonin function contributes to social reward and punishment in rhesus macaques, and thus shapes social behavior in humans and rhesus macaques alike.

  5. Serotonin Modulation of Prefronto-Hippocampal Rhythms in Health and Disease.

    Science.gov (United States)

    Puig, M Victoria; Gener, Thomas

    2015-07-15

    There is mounting evidence that most cognitive functions depend upon the coordinated activity of neuronal networks often located far from each other in the brain. Ensembles of neurons synchronize their activity, generating oscillations at different frequencies that may encode behavior by allowing an efficient communication between brain areas. The serotonin system, by virtue of the widespread arborisation of serotonergic neurons, is in an excellent position to exert strong modulatory actions on brain rhythms. These include specific oscillatory activities in the prefrontal cortex and the hippocampus, two brain areas essential for many higher-order cognitive functions. Psychiatric patients show abnormal oscillatory activities in these areas, notably patients with schizophrenia who display psychotic symptoms as well as affective and cognitive impairments. Synchronization of neural activity between the prefrontal cortex and the hippocampus seems to be important for cognition and, in fact, reduced prefronto-hippocampal synchrony has been observed in a genetic mouse model of schizophrenia. Here, we review recent advances in the field of neuromodulation of brain rhythms by serotonin, focusing on the actions of serotonin in the prefrontal cortex and the hippocampus. Considering that the serotonergic system plays a crucial role in cognition and mood and is a target of many psychiatric treatments, it is surprising that this field of research is still in its infancy. In that regard, we point to future investigations that are much needed in this field.

  6. Salmonella modulation of host cell gene expression promotes its intracellular growth.

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    Sebastian Hannemann

    Full Text Available Salmonella Typhimurium has evolved a complex functional interface with its host cell largely determined by two type III secretion systems (T3SS, which through the delivery of bacterial effector proteins modulate a variety of cellular processes. We show here that Salmonella Typhimurium infection of epithelial cells results in a profound transcriptional reprogramming that changes over time. This response is triggered by Salmonella T3SS effector proteins, which stimulate unique signal transduction pathways leading to STAT3 activation. We found that the Salmonella-stimulated changes in host cell gene expression are required for the formation of its specialized vesicular compartment that is permissive for its intracellular replication. This study uncovers a cell-autonomous process required for Salmonella pathogenesis potentially opening up new avenues for the development of anti-infective strategies that target relevant host pathways.

  7. Salmonella modulation of host cell gene expression promotes its intracellular growth.

    Science.gov (United States)

    Hannemann, Sebastian; Gao, Beile; Galán, Jorge E

    2013-01-01

    Salmonella Typhimurium has evolved a complex functional interface with its host cell largely determined by two type III secretion systems (T3SS), which through the delivery of bacterial effector proteins modulate a variety of cellular processes. We show here that Salmonella Typhimurium infection of epithelial cells results in a profound transcriptional reprogramming that changes over time. This response is triggered by Salmonella T3SS effector proteins, which stimulate unique signal transduction pathways leading to STAT3 activation. We found that the Salmonella-stimulated changes in host cell gene expression are required for the formation of its specialized vesicular compartment that is permissive for its intracellular replication. This study uncovers a cell-autonomous process required for Salmonella pathogenesis potentially opening up new avenues for the development of anti-infective strategies that target relevant host pathways.

  8. Integrating Protein Engineering and Bioorthogonal Click Conjugation for Extracellular Vesicle Modulation and Intracellular Delivery.

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    Ming Wang

    Full Text Available Exosomes are small, cell-secreted vesicles that transfer proteins and genetic information between cells. This intercellular transmission regulates many physiological and pathological processes. Therefore, exosomes have emerged as novel biomarkers for disease diagnosis and as nanocarriers for drug delivery. Here, we report an easy-to-adapt and highly versatile methodology to modulate exosome composition and conjugate exosomes for intracellular delivery. Our strategy combines the metabolic labeling of newly synthesized proteins or glycan/glycoproteins of exosome-secreting cells with active azides and bioorthogonal click conjugation to modify and functionalize the exosomes. The azide-integrated can be conjugated to a variety of small molecules and proteins and can efficiently deliver conjugates into cells. The metabolic engineering of exosomes diversifies the chemistry of exosomes and expands the functions that can be introduced into exosomes, providing novel, powerful tools to study the roles of exosomes in biology and expand the biomedical potential of exosomes.

  9. Intracellular Trafficking Modulation by Ginsenoside Rg3 Inhibits Brucella abortus Uptake and Intracellular Survival within RAW 264.7 Cells.

    Science.gov (United States)

    Huy, Tran Xuan Ngoc; Reyes, Alisha Wehdnesday Bernardo; Hop, Huynh Tan; Arayan, Lauren Togonon; Min, WonGi; Lee, Hu Jang; Rhee, Man Hee; Chang, Hong Hee; Kim, Suk

    2017-03-28

    Ginsenoside Rg3, a saponin extracted from ginseng, has various pharmacological and biological activities; however, its effects against Brucella infection are still unclear. Herein, the inhibitory effects of ginsenoside Rg3 against intracellular parasitic Brucella infection were evaluated through bacterial infection, adherence assays, and LAMP-1 colocalization, as well as immunoblotting and FACS for detecting MAPK signaling proteins and F-actin polymerization, respectively. The internalization, intracellular growth, and adherence of Brucella abortus in Rg3-treated RAW 264.7 cells were significantly decreased compared with the Rg3-untreated control. Furthermore, an apparent reduction of F-actin content and intensity of F-actin fluorescence in Rg3-treated cells was observed compared with B. abortus -infected cells without treatment by flow cytometry analysis and confocal microscopy, respectively. In addition, treating cells with Rg3 decreased the phosphorylation of MAPK signaling proteins such as ERK 1/2 and p38 compared with untreated cells. Moreover, the colocalization of B. abortus -containing phagosomes with LAMP-1 was markedly increased in Rg3-treated cells. These findings suggest that ginsenoside Rg3 inhibits B. abortus infection in mammalian cells and can be used as an alternative approach in the treatment of brucellosis.

  10. Nano hydroxyapatite-blasted titanium surface affects pre-osteoblast morphology by modulating critical intracellular pathways.

    Science.gov (United States)

    Bezerra, Fábio; Ferreira, Marcel R; Fontes, Giselle N; da Costa Fernandes, Célio Jr; Andia, Denise C; Cruz, Nilson C; da Silva, Rodrigo A; Zambuzzi, Willian F

    2017-08-01

    Although, intracellular signaling pathways are proposed to predict the quality of cell-surface relationship, this study addressed pre-osteoblast behavior in response to nano hydroxyapatite (HA)-blasted titanium (Ti) surface by exploring critical intracellular pathways and pre-osteoblast morphological change. Physicochemical properties were evaluated by atomic force microscopy (AFM) and wettability considering water contact angle of three differently texturized Ti surfaces: Machined (Mac), Dual acid-etching (DAE), and nano hydroxyapatite-blasted (nHA). The results revealed critical differences in surface topography, impacting the water contact angle and later the osteoblast performance. In order to evaluate the effect of those topographical characteristics on biological responses, we have seeded pre-osteoblast cells on the Ti discs for up to 4 h and subjected the cultures to biological analysis. First, we have observed pre-osteoblasts morphological changes resulting from the interaction with the Ti texturized surfaces whereas the cells cultured on nHA presented a more advanced spreading process when compared with the cells cultured on the other surfaces. These results argued us for analyzing the molecular machinery and thus, we have shown that nHA promoted a lower Bax/Bcl2 ratio, suggesting an interesting anti-apoptotic effect, maybe explained by the fact that HA is a natural element present in bone composition. Thereafter, we investigated the potential effect of those surfaces on promoting pre-osteoblast adhesion and survival signaling by performing crystal violet and immunoblotting approaches, respectively. Our results showed that nHA promoted a higher pre-osteoblast adhesion supported by up-modulating FAK and Src activations, both signaling transducers involved during eukaryotic cell adhesion. Also, we have shown Ras-Erk stimulation by the all evaluated surfaces. Finally, we showed that all Ti-texturing surfaces were able to promote osteoblast differentiation

  11. Affective startle modulation : psychopharmacological studies on the roles of CRF and serotonin in the regulation of emotions

    NARCIS (Netherlands)

    Bijlsma, E.Y.

    2010-01-01

    Major depression and anxiety disorders are the most prevalent psychiatric disorders. The high co-morbidity and strong overlap in symptoms suggest that neurobiological mechanisms may also overlap. Two neuromodulators have received much attention. First, serotonin: Selective serotonin reuptake

  12. Affective neural responses modulated by serotonin transporter genotype in clinical anxiety and depression.

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    Desmond J Oathes

    Full Text Available Serotonin transporter gene variants are known to interact with stressful life experiences to increase chances of developing affective symptoms, and these same variants have been shown to influence amygdala reactivity to affective stimuli in non-psychiatric populations. The impact of these gene variants on affective neurocircuitry in anxiety and mood disorders has been studied less extensively. Utilizing a triallelic assay (5-HTTLPR and rs25531 to assess genetic variation linked with altered serotonin signaling, this fMRI study investigated genetic influences on amygdala and anterior insula activity in 50 generalized anxiety disorder patients, 26 of whom also met DSM-IV criteria for social anxiety disorder and/or major depressive disorder, and 39 healthy comparison subjects. A Group x Genotype interaction was observed for both the amygdala and anterior insula in a paradigm designed to elicit responses in these brain areas during the anticipation of and response to aversive pictures. Patients who are S/L(G carriers showed less activity than their L(A/L(A counterparts in both regions and less activity than S/L(G healthy comparison subjects in the amygdala. Moreover, patients with greater insula responses reported higher levels of intolerance of uncertainty, an association that was particularly pronounced for patients with two LA alleles. A genotype effect was not established in healthy controls. These findings link the serotonin transporter gene to affective circuitry findings in anxiety and depression psychopathology and further suggest that its impact on patients may be different from effects typically observed in healthy populations.

  13. Rescuing cholinergic neurons from apoptotic degeneration by targeting of serotonin modulator- and apolipoprotein E-conjugated liposomes to the hippocampus

    Directory of Open Access Journals (Sweden)

    Kuo YC

    2016-12-01

    Full Text Available Yung-Chih Kuo, Yin-Jung Lee Department of Chemical Engineering, National Chung Cheng University, Chia-Yi, Taiwan, Republic of China Abstract: β-Amyloid (Aβ-targeting liposomes (LIP with surface serotonin modulator (SM and apolipoprotein E (ApoE were utilized to facilitate the delivery of nerve growth factor (NGF across the blood–brain barrier (BBB for neuroprotection in the hippocampus. The therapeutic efficacy of SM- and ApoE-grafted LIP carrying NGF (NGF-SM-ApoE-LIP was assessed by an in vitro Alzheimer’s disease (AD model of degenerated SK-N-MC cells and an in vivo AD model of Aβ-insulted Wistar rats. The experimental evidences revealed that the modified SM and ApoE on the surface of LIP increased the permeation of NGF across the BBB without serious damage to structural integrity of tight junction. When compared with free NGF, NGF-SM-ApoE-LIP upregulated the expression of phosphorylated neurotrophic tyrosine kinase receptor type 1 on cholinergic neurons and significantly improved their survival. In addition, NGF-SM-ApoE-LIP could reduce the secretion of acetylcholinesterase and malondialdehyde and rescue hippocampal neurons from apoptosis in rat brains. The synergistic effect of SM and ApoE is promising in the induction of NGF to inhibit the neurotoxicity of Aβ and NGF-SM-ApoE-LIP can be a potent antiapoptotic pharmacotherapy for clinical care of patients with AD. Keywords: Alzheimer’s disease, blood–brain barrier, serotonin modulator, apolipoprotein E, nerve growth factor, liposome

  14. The Effect of WNK4 on the Na+-Cl- Cotransporter Is Modulated by Intracellular Chloride.

    Science.gov (United States)

    Bazúa-Valenti, Silvana; Chávez-Canales, María; Rojas-Vega, Lorena; González-Rodríguez, Xochiquetzal; Vázquez, Norma; Rodríguez-Gama, Alejandro; Argaiz, Eduardo R; Melo, Zesergio; Plata, Consuelo; Ellison, David H; García-Valdés, Jesús; Hadchouel, Juliette; Gamba, Gerardo

    2015-08-01

    It is widely recognized that the phenotype of familial hyperkalemic hypertension is mainly a consequence of increased activity of the renal Na(+)-Cl(-) cotransporter (NCC) because of altered regulation by with no-lysine-kinase 1 (WNK1) or WNK4. The effect of WNK4 on NCC, however, has been controversial because both inhibition and activation have been reported. It has been recently shown that the long isoform of WNK1 (L-WNK1) is a chloride-sensitive kinase activated by a low Cl(-) concentration. Therefore, we hypothesized that WNK4 effects on NCC could be modulated by intracellular chloride concentration ([Cl(-)]i), and we tested this hypothesis in oocytes injected with NCC cRNA with or without WNK4 cRNA. At baseline in oocytes, [Cl(-)]i was near 50 mM, autophosphorylation of WNK4 was undetectable, and NCC activity was either decreased or unaffected by WNK4. A reduction of [Cl(-)]i, either by low chloride hypotonic stress or coinjection of oocytes with the solute carrier family 26 (anion exchanger)-member 9 (SLC26A9) cRNA, promoted WNK4 autophosphorylation and increased NCC-dependent Na(+) transport in a WNK4-dependent manner. Substitution of the leucine with phenylalanine at residue 322 of WNK4, homologous to the chloride-binding pocket in L-WNK1, converted WNK4 into a constitutively autophosphorylated kinase that activated NCC, even without chloride depletion. Elimination of the catalytic activity (D321A or D321K-K186D) or the autophosphorylation site (S335A) in mutant WNK4-L322F abrogated the positive effect on NCC. These observations suggest that WNK4 can exert differential effects on NCC, depending on the intracellular chloride concentration. Copyright © 2015 by the American Society of Nephrology.

  15. Variation in the serotonin transporter gene modulates selective attention to threat.

    Science.gov (United States)

    Osinsky, Roman; Reuter, Martin; Küpper, Yvonne; Schmitz, Anja; Kozyra, Eva; Alexander, Nina; Hennig, Jürgen

    2008-08-01

    The 5-HTTLPR is an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene. Prior research has revealed associations between the short-allele variant of this polymorphism, enhanced self-reported negative emotionality, and hypersensitivity of fear relevant neural circuits. In a sample of 50 healthy women we examined the role of 5-HTTLPR for cognitive-affective processing of phylogenetical fear-relevant stimuli (spiders) in a dot probe task. In contrast to homozygote long-allele carriers (ll), participants carrying at least 1 short allele (ss and sl) selectively shifted attention toward pictures of spiders, when these were presented for a duration of 2,000 ms. These results argue for an involvement of 5-HTTLPR in cognitive processing of threatening stimuli and thus, underpin its general role for individual differences in negative affect.

  16. Modulation of the consolidation and reconsolidation of fear memory by three different serotonin receptors in hippocampus.

    Science.gov (United States)

    Schmidt, S D; Furini, C R G; Zinn, C G; Cavalcante, L E; Ferreira, F F; Behling, J A K; Myskiw, J C; Izquierdo, I

    2017-07-01

    The process of memory formation is complex and highly dynamic. During learning, the newly acquired information is found in a fragile and labile state. Through a process known as consolidation, which requires specific mechanisms such as protein synthesis, the memory trace is stored and stabilized. It is known that when a consolidated memory is recalled, it again becomes labile and sensitive to disruption. To be maintained, this memory must undergo an additional process of restabilization called reconsolidation, which requires another phase of protein synthesis. Memory consolidation has been studied for more than a century, while the molecular mechanisms underlying the memory reconsolidation are starting to be elucidated. For this, is essential compare the participation of important neurotransmitters and its receptors in both processes in brain regions that play a central role in the fear response learning. With focus on serotonin (5-HT), a well characterized neurotransmitter that has been strongly implicated in learning and memory, we investigated, in the CA1 region of the dorsal hippocampus, whether the latest discovered serotonergic receptors, 5-HT 5A , 5-HT 6 and 5-HT 7 , are involved in the consolidation and reconsolidation of contextual fear conditioning (CFC) memory. For this, male rats with cannulae implanted in the CA1 region received immediately after the training or reactivation session, or 3h post-reactivation of the CFC, infusions of agonists or antagonists of the 5-HT 5A , 5-HT 6 and 5-HT 7 receptors. After 24h, animals were subjected to a 3-min retention test. The results indicated that in the CA1 region of the hippocampus the 5-HT 5A , 5-HT 6 and 5-HT 7 serotonin receptors participate in the reconsolidation of the CFC memory 3h post-reactivation. Additionally, the results suggest that the 5-HT 6 and 5-HT 7 receptors also participate in the consolidation of the CFC memory. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Improvement of dizocilpine-induced social recognition deficits in mice by brexpiprazole, a novel serotonin-dopamine activity modulator.

    Science.gov (United States)

    Yoshimi, Noriko; Futamura, Takashi; Hashimoto, Kenji

    2015-03-01

    Cognitive impairment, including impaired social cognition, is largely responsible for the deterioration in social life suffered by patients with psychiatric disorders, such as schizophrenia and major depressive disorder (MDD). Brexpiprazole (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one), a novel serotonin-dopamine activity modulator, was developed to offer efficacious and tolerable therapy for different psychiatric disorders, including schizophrenia and adjunctive treatment of MDD. In this study, we investigated whether brexpiprazole could improve social recognition deficits (one of social cognition deficits) in mice, after administration of the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine). Dosing with dizocilpine (0.1mg/kg) induced significant impairment of social recognition in mice. Brexpiprazole (0.01, 0.03, 0.1mg/kg, p.o.) significantly ameliorated dizocilpine-induced social recognition deficits, without sedation or a reduction of exploratory behavior. In addition, brexpiprazole alone had no effect on social recognition in untreated control mice. By contrast, neither risperidone (0.03mg/kg, p.o.) nor olanzapine (0.03mg/kg, p.o.) altered dizocilpine-induced social recognition deficits. Finally, the effect of brexpiprazole on dizocilpine-induced social recognition deficits was antagonized by WAY-100,635, a selective serotonin 5-HT1A antagonist. These results suggest that brexpiprazole could improve dizocilpine-induced social recognition deficits via 5-HT1A receptor activation in mice. Therefore, brexpiprazole may confer a beneficial effect on social cognition deficits in patients with psychiatric disorders. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  18. Serotonin inputs to the dorsal BNST modulate anxiety in a 5-HT1A receptor dependent manner

    Science.gov (United States)

    Garcia-Garcia, Alvaro L.; Canetta, Sarah; Stujenske, Joseph M.; Burghardt, Nesha S.; Ansorge, Mark S.; Dranovsky, Alex; Leonardo, E. David

    2017-01-01

    Serotonin (5-HT) neurons project from the raphe nuclei throughout the brain where they act to maintain homeostasis. Here, we study 5-HT inputs into the bed nucleus of the stria terminalis (BNST), a major subdivision of the extended amygdala that has been proposed to regulate responses to anxiogenic environments in humans and rodents. While the dorsal part of the BNST (dBNST) receives dense 5-HT innervation, whether and how 5-HT in the dBNST normally modulates anxiety remains unclear. Using optogenetics, we demonstrate that activation of 5-HT terminals in the dBNST reduces anxiety in a highly anxiogenic environment. Further analysis revealed that optogenetic inhibition of 5-HT inputs into the dBNST increases anxiety in a less anxiogenic environment. We found that 5-HT predominantly hyperpolarizes dBNST neurons, reducing their activity in a manner that can be blocked by a 5-HT1A antagonist. Finally, we demonstrate that activation of 5-HT1A receptors in the dBNST is necessary for the anxiolytic effect observed following optogenetic stimulation of 5-HT inputs into the dBNST. These data reveal that 5-HT release in the dBNST modulates anxiety-like behavior via 5-HT1A receptors under naturalistic conditions. PMID:28761080

  19. Serotonin inputs to the dorsal BNST modulate anxiety in a 5-HT1A receptor-dependent manner.

    Science.gov (United States)

    Garcia-Garcia, A L; Canetta, S; Stujenske, J M; Burghardt, N S; Ansorge, M S; Dranovsky, A; Leonardo, E D

    2017-08-01

    Serotonin (5-HT) neurons project from the raphe nuclei throughout the brain where they act to maintain homeostasis. Here, we study 5-HT inputs into the bed nucleus of the stria terminalis (BNST), a major subdivision of the extended amygdala that has been proposed to regulate responses to anxiogenic environments in humans and rodents. While the dorsal part of the BNST (dBNST) receives dense 5-HT innervation, whether and how 5-HT in the dBNST normally modulates anxiety remains unclear. Using optogenetics, we demonstrate that activation of 5-HT terminals in the dBNST reduces anxiety in a highly anxiogenic environment. Further analysis revealed that optogenetic inhibition of 5-HT inputs into the dBNST increases anxiety in a less anxiogenic environment. We found that 5-HT predominantly hyperpolarizes dBNST neurons, reducing their activity in a manner that can be blocked by a 5-HT 1A antagonist. Finally, we demonstrate that activation of 5-HT 1A receptors in the dBNST is necessary for the anxiolytic effect observed following optogenetic stimulation of 5-HT inputs into the dBNST. These data reveal that 5-HT release in the dBNST modulates anxiety-like behavior via 5-HT 1A receptors under naturalistic conditions.Molecular Psychiatry advance online publication, 1 August 2017; doi:10.1038/mp.2017.165.

  20. Brain Aromatase Modulates Serotonergic Neuron by Regulating Serotonin Levels in Zebrafish Embryos and Larvae

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    Zulvikar Syambani Ulhaq

    2018-05-01

    Full Text Available Teleost fish are known to express two isoforms of P450 aromatase, a key enzyme for estrogen synthesis. One of the isoforms, brain aromatase (AroB, cyp19a1b, is highly expressed during early development of zebrafish, thereby suggesting its role in brain development. On the other hand, early development of serotonergic neuron, one of the major monoamine neurons, is considered to play an important role in neurogenesis. Therefore, in this study, we investigated the role of AroB in development of serotonergic neuron by testing the effects of (1 estradiol (E2 exposure and (2 morpholino (MO-mediated AroB knockdown. When embryos were exposed to E2, the effects were biphasic. The low dose of E2 (0.005 µM significantly increased serotonin (5-HT positive area at 48 hour post-fertilization (hpf detected by immunohistochemistry and relative mRNA levels of tryptophan hydroxylase isoforms (tph1a, tph1b, and tph2 at 96 hpf measured by semi-quantitative PCR. To test the effects on serotonin transmission, heart rate and thigmotaxis, an indicator of anxiety, were analyzed. The low dose also significantly increased heart rate at 48 hpf and decreased thigmotaxis. The high dose of E2 (1 µM exhibited opposite effects in all parameters. The effects of both low and high doses were reversed by addition of estrogen receptor (ER blocker, ICI 182,780, thereby suggesting that the effects were mediated through ER. When AroB MO was injected to fertilized eggs, 5-HT-positive area was significantly decreased, while the significant decrease in relative tph mRNA levels was found only with tph2 but not with two other isoforms. AroB MO also decreased heart rate and increased thigmotaxis. All the effects were rescued by co-injection with AroB mRNA and by exposure to E2. Taken together, this study demonstrates the role of brain aromatase in development of serotonergic neuron in zebrafish embryos and larvae, implying that brain-formed estrogen is an important factor to

  1. Modulation of Human Serotonin Transporter Expression by 5-HTTLPR in Colon Cells

    Directory of Open Access Journals (Sweden)

    Tewin Tencomnao

    2011-10-01

    Full Text Available Serotonin (5-HT is a monoamine neurotransmitter and plays important roles in several of the human body’s systems. Known as a primary target for psychoactive drug development, the 5-HT transporter (5-HTT, SERT plays a critical role in the regulation of serotonergic function by reuptaking 5-HT. The allelic variation of 5-HTT expression is caused by functional gene promoter polymorphism with two principal variant alleles, 5-HTT gene-linked polymorphic region (5-HTTLPR. It has been demonstrated that 5-HTTLPR is associated with numerous neuropsychiatric disorders. The functional roles of 5-HTTLPR have been reported in human choriocarcinoma (JAR, lymphoblast and raphe cells. To date, the significance of 5-HTTLPR in gastrointestinal tract-derived cells has never been elucidated. Thus, the impact of 5-HTTLPR on 5-HTT transcription was studied in SW480 human colon carcinoma cells, which were shown to express 5-HTT. We found 42-bp fragment in long (L allele as compared to short (S allele, and this allelic difference resulted in 2-fold higher transcriptional efficiency of L allele (P < 0.05 as demonstrated using a functional reporter gene assay. Nevertheless, the transcriptional effect of estrogen and glucocorticoid on 5-HTT expression via 5-HTTLPR was not found in this cell line. Our study was the first to demonstrate the molecular role of this allelic variation in gastrointestinal tract cells.

  2. Modulation of the platelet serotonin transporter by thermal balneotherapy: a study in healthy subjects.

    Science.gov (United States)

    Baroni, S; Marazziti, D; Consoli, G; Picchetti, M; Catena-Dell'Osso, M; Galassi, A

    2012-05-01

    Although the beneficial effects of balneotherapy have been recognized since a long time, a few information is available on the biological mechanisms underlying them and the subjective feelings of increased well-being and mood. The links between the serotonin (5-HT) system and mood prompted us to investigate the 5-HT platelet transporter (SERT), which is considered a reliable, peripheral marker of the same structure present in presynaptic neurons, in 30 healthy volunteers before (t0) and 30 minutes after (t1) thermal balneotherapy with ozonized water, as compared with a similar group who underwent a bath in non-mineral water. MATERIALS AN METHODS: The SERT was evaluated by means of the specific binding of 3H-paroxetine (3H-Par) to platelet membranes. Equilibrium-saturation binding data, the maximal binding capacity (Bmax) and the dissociation constant (Kd), were obtained by means of the Scatchard analysis. The results showed that, while Bmax values did not change in both groups, the Kd values decreased significantly at t1 only in those subjects who bathed in ozonized water. The results of this study, while showing a decrease of the dissociation constant (Kd) which is the inverse of affinity constant, of 3H-Par binding to SERT in all subjects after balneotherapy and not in those bathing in normal water, suggest that SERT modifications may be related to a specific effect of ozonized water and, perhaps, also to the increased sense of well-being.

  3. Light therapy modulates serotonin levels and blood flow in women with headache. A preliminary study.

    Science.gov (United States)

    Tomaz de Magalhães, Miriam; Núñez, Silvia Cristina; Kato, Ilka Tiemy; Ribeiro, Martha Simões

    2016-01-01

    In this study, we looked at the possible effects of low-level laser therapy (LLLT) on blood flow velocity, and serotonin (5-HT) and cholinesterase levels in patients with chronic headache associated with temporomandibular disorders (TMD). LLLT has been clinically applied over the past years with positive results in analgesia and without the report of any side effects. The understanding of biological mechanisms of action may improve clinical results and facilitate its indication. Ten patients presenting headache associated with TMD completed the study. An 830-nm infrared diode laser with power of 100 mW, exposure time of 34 s, and energy of 3.4 J was applied on the tender points of masseter and temporal muscle. Blood flow velocity was determined via ultrasound Doppler velocimetry before and after laser irradiation. The whole blood 5-HT and cholinesterase levels were evaluated three days before, immediately, and three days after laser irradiation. Pain score after treatment decreased to a score of 5.8 corresponding to 64% of pain reduction (P  0.05). Our findings indicated that LLLT regulates blood flow in the temporal artery after irradiation and might control 5-HT levels in patients suffering with tension-type headache associated to TMD contributing to pain relief. © 2016 by the Society for Experimental Biology and Medicine.

  4. Serotonin Receptors in Hippocampus

    Science.gov (United States)

    Berumen, Laura Cristina; Rodríguez, Angelina; Miledi, Ricardo; García-Alcocer, Guadalupe

    2012-01-01

    Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system. PMID:22629209

  5. Modulation of Acid-sensing Ion Channel 1a by Intracellular pH and Its Role in Ischemic Stroke.

    Science.gov (United States)

    Li, Ming-Hua; Leng, Tian-Dong; Feng, Xue-Chao; Yang, Tao; Simon, Roger P; Xiong, Zhi-Gang

    2016-08-26

    An important contributor to brain ischemia is known to be extracellular acidosis, which activates acid-sensing ion channels (ASICs), a family of proton-gated sodium channels. Lines of evidence suggest that targeting ASICs may lead to novel therapeutic strategies for stroke. Investigations of the role of ASICs in ischemic brain injury have naturally focused on the role of extracellular pH in ASIC activation. By contrast, intracellular pH (pHi) has received little attention. This is a significant gap in our understanding because the ASIC response to extracellular pH is modulated by pHi, and activation of ASICs by extracellular protons is paradoxically enhanced by intracellular alkalosis. Our previous studies show that acidosis-induced cell injury in in vitro models is attenuated by intracellular acidification. However, whether pHi affects ischemic brain injury in vivo is completely unknown. Furthermore, whereas ASICs in native neurons are composed of different subunits characterized by distinct electrophysiological/pharmacological properties, the subunit-dependent modulation of ASIC activity by pHi has not been investigated. Using a combination of in vitro and in vivo ischemic brain injury models, electrophysiological, biochemical, and molecular biological approaches, we show that the intracellular alkalizing agent quinine potentiates, whereas the intracellular acidifying agent propionate inhibits, oxygen-glucose deprivation-induced cell injury in vitro and brain ischemia-induced infarct volume in vivo Moreover, we find that the potentiation of ASICs by quinine depends on the presence of the ASIC1a, ASIC2a subunits, but not ASIC1b, ASIC3 subunits. Furthermore, we have determined the amino acids in ASIC1a that are involved in the modulation of ASICs by pHi. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Characterization of prejunctional serotonin receptors modulating [3H]acetylcholine release in the human detrusor.

    Science.gov (United States)

    D'Agostino, Gianluigi; Condino, Anna M; Gallinari, Paola; Franceschetti, Gian P; Tonini, Marcello

    2006-01-01

    Bladder overactivity (OAB) is a chronic and debilitating lower urinary tract (LUT) disorder that affects millions of individuals worldwide. LUT symptoms associated with OAB, such as urgency and urinary incontinence, cause a hygienic and social concern to patients, but their current pharmacological treatment is largely inadequate due to the lack of uroselectivity. Although OAB etiology remains multifactorial and poorly understood, increasing evidence indicates that serotonin [5-hydroxytryptamine (5-HT)] is an endogenous substance involved in the control of micturition at central and peripheral sites. In this study, we demonstrated the presence of three distinct 5-HT receptors localized at parasympathetic nerve terminals of the human bladder by measuring electrically evoked tritiated acetylcholine release in isolated detrusor strips. These prejunctional receptors, involved in both positive and negative feedback mechanisms regulating cholinergic transmission, have been characterized by means of three highly selective 5-HT antagonists for 5-HT(4), 5-HT(7), and 5-HT(1A) receptors, namely GR113808A ([1-[2-[(-methylsulphonyl) amino] ethyl]4-piperinidyl]methyl1-methyl-1H-indole-3-carboxylate succinate), SB269970 [(R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulfonyl)phenol hydrochloride], and WAY100635 [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)-cyclohexane-carboxamide trichloride]. Under these conditions, we confirmed the facilitatory role of 5-HT(4) heteroreceptors on acetylcholine release and revealed for the first time the occurrence of 5-HT(7) and 5-HT(1A) heteroreceptors with a facilitatory and an inhibitory action, respectively. Our findings strengthen the novel concept for the use of recently patented selective 5-HT agonists and antagonists for the control of OAB dysfunctions associated with inflammatory conditions, although their therapeutic efficacy needs to be explored in the clinical setting.

  7. The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity.

    Science.gov (United States)

    Kraehenmann, Rainer; Schmidt, André; Friston, Karl; Preller, Katrin H; Seifritz, Erich; Vollenweider, Franz X

    2016-01-01

    Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybin's effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. We therefore analyzed our previous fMRI data using dynamic causal modeling and used Bayesian model selection to infer how psilocybin modulated effective connectivity within the visual-limbic-prefrontal network during threat processing. First, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. Second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. These findings may have important implications for the treatment of mood and anxiety disorders.

  8. The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity

    Directory of Open Access Journals (Sweden)

    Rainer Kraehenmann

    2016-01-01

    Full Text Available Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybin's effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. We therefore analyzed our previous fMRI data using dynamic causal modeling and used Bayesian model selection to infer how psilocybin modulated effective connectivity within the visual–limbic–prefrontal network during threat processing. First, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. Second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. These findings may have important implications for the treatment of mood and anxiety disorders.

  9. Serotonin-mediated modulation of Na+/K+ pump current in rat hippocampal CA1 pyramidal neurons.

    Science.gov (United States)

    Zhang, Li Nan; Su, Su Wen; Guo, Fang; Guo, Hui Cai; Shi, Xiao Lu; Li, Wen Ya; Liu, Xu; Wang, Yong Li

    2012-01-19

    The aim of this study was to investigate whether serotonin (5-hydroxytryptamine, 5-HT) can modulate Na+/K+ pump in rat hippocampal CA1 pyramidal neurons. 5-HT (0.1, 1 mM) showed Na+/K+ pump current (Ip) densities of 0.40 ± 0.04, 0.34 ± 0.03 pA/pF contrast to 0.63 ± 0.04 pA/pF of the control of 0.5 mM strophanthidin (Str), demonstrating 5-HT-induced inhibition of Ip in a dose-dependent manner in hippocampal CA1 pyramidal neurons. The effect was partly attenuated by ondasetron, a 5-HT3 receptor (5-HT3R) antagonist, not by WAY100635, a 5-HT1AR antagonist, while 1-(3-Chlorophenyl) biguanide hydrochloride (m-CPBG), a 5-HT3R specific agonist, mimicked the effect of 5-HT on Ip. 5-HT inhibits neuronal Na+/K+ pump activity via 5-HT3R in rat hippocampal CA1 pyramidal neurons. This discloses novel mechanisms for the function of 5-HT in learning and memory, which may be a useful target to benefit these patients with cognitive disorder.

  10. The serotonin transporter polymorphism (5-HTTLPR) and cortisol stress responsiveness: preliminary evidence for a modulating role for sleep quality.

    Science.gov (United States)

    van Dalfsen, Jens H; Markus, C Rob

    2018-05-23

    The short (S) allele of a functional polymorphism (5-HTTLPR) within the promoter region of the serotonin transporter gene (SLC6A4) is found to predispose the risk for stress-related affective disorders relative to the long (L) allele. Evidence suggests that elevated stress reactivity of the hypothalamic-pituitary-adrenal (HPA) axis might underlie this association although there is little understanding about the origin of inconsistent findings. Since inadequate sleep is commonly known to promote HPA stress reactivity, it might well play an important modulating role. The present study tested this hypothesis by investigating whether sleep quality moderates the relationship between 5-HTTLPR and cortisol stress responsiveness. From a large 5-HTTLPR database (n = 771), a sample of healthy male and female participants homozygous for either the 5-HTTLPR S-allele (n = 25) or L-allele (n = 25) were assessed for sleep quality and salivary cortisol secretion during acute laboratory stress. Diminished sleep quality was found to exclusively potentiate cortisol stress reactivity in the homozygous L-allele genotype. Accounting for this 5-HTTLPR-dependent influence enhanced the predictive value of 5-HTTLPR on cortisol stress responsiveness, revealing greater HPA reactivity in S-allele relative to L-allele carriers. Current findings suggest that variations in sleep quality may serve as a confounding factor in the search for genetic differences in stress sensitivity and related affective disorders.

  11. The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity

    OpenAIRE

    Kraehenmann, Rainer; Schmidt, André; Friston, Karl; Preller, Katrin H; Seifritz, Erich; Vollenweider, Franz X

    2016-01-01

    Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybin's effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. We therefore analyzed our previous fMRI dat...

  12. Medium pH in submerged cultivation modulates differences in the intracellular protein profile of Fusarium oxysporum.

    Science.gov (United States)

    da Rosa-Garzon, Nathália Gonsales; Laure, Hélen Julie; Souza-Motta, Cristina Maria de; Rosa, José César; Cabral, Hamilton

    2017-08-09

    Fusarium oxysporum is a filamentous fungus that damages a wide range of plants and thus causes severe crop losses. In fungal pathogens, the genes and proteins involved in virulence are known to be controlled by environmental pH. Here, we report the influence of culture-medium pH (5, 6, 7, and 8) on the production of degradative enzymes involved in the pathogenesis of F. oxysporum URM 7401 and on the 2D-electrophoresis profile of intracellular proteins in this fungus. F. oxysporum URM 7401 was grown in acidic, neutral, and alkaline culture media in a submerged bioprocess. After 96 hr, the crude extract was processed to enzyme activity assays, while the intracellular proteins were obtained from mycelium and analyzed using 2D electrophoresis and mass spectrometry. We note that the diversity of secreted enzymes was changed quantitatively in different culture-medium pH. Also, the highest accumulated biomass and the intracellular protein profile of F. oxysporum URM 7401 indicate an increase in metabolism in neutral-alkaline conditions. The differential profiles of secreted enzymes and intracellular proteins under the evaluated conditions indicate that the global protein content in F. oxysporum URM 7401 is modulated by extracellular pH.

  13. Latency modulation of collicular neurons induced by electric stimulation of the auditory cortex in Hipposideros pratti: In vivo intracellular recording.

    Directory of Open Access Journals (Sweden)

    Kang Peng

    Full Text Available In the auditory pathway, the inferior colliculus (IC receives and integrates excitatory and inhibitory inputs from the lower auditory nuclei, contralateral IC, and auditory cortex (AC, and then uploads these inputs to the thalamus and cortex. Meanwhile, the AC modulates the sound signal processing of IC neurons, including their latency (i.e., first-spike latency. Excitatory and inhibitory corticofugal projections to the IC may shorten and prolong the latency of IC neurons, respectively. However, the synaptic mechanisms underlying the corticofugal latency modulation of IC neurons remain unclear. Thus, this study probed these mechanisms via in vivo intracellular recording and acoustic and focal electric stimulation. The AC latency modulation of IC neurons is possibly mediated by pre-spike depolarization duration, pre-spike hyperpolarization duration, and spike onset time. This study suggests an effective strategy for the timing sequence determination of auditory information uploaded to the thalamus and cortex.

  14. Amphetamine Action at the Cocaine- and Antidepressant-Sensitive Serotonin Transporter Is Modulated by αCaMKII

    DEFF Research Database (Denmark)

    Steinkellner, Thomas; Montgomery, Therese R; Hofmaier, Tina

    2015-01-01

    Serotonergic neurotransmission is terminated by reuptake of extracellular serotonin (5-HT) by the high-affinity serotonin transporter (SERT). Selective 5-HT reuptake inhibitors (SSRIs) such as fluoxetine or escitalopram inhibit SERT and are currently the principal treatment for depression and anx...... and efflux at monoamine transporters are asymmetric processes that can be targeted separately. Ultimately, this may provide a molecular mechanism for putative drug developments to treat amphetamine addiction....

  15. Brain serotonin and dopamine modulators, perceptual responses and endurance performance during exercise in the heat following creatine supplementation

    Directory of Open Access Journals (Sweden)

    Kilduff Liam P

    2008-09-01

    Full Text Available Abstract Background The present experiment examined the responses of peripheral modulators and indices of brain serotonin (5-HT and dopamine (DA function and their association with perception of effort during prolonged exercise in the heat after creatine (Cr supplementation. Methods Twenty one endurance-trained males performed, in a double-blind fashion, two constant-load exercise tests to exhaustion at 63 ± 5% V˙ MathType@MTEF@5@5@+=feaagaart1ev2aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi=xH8viVGI8Gi=hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY=rqGqVepae9pg0db9vqaiVgFr0xfr=xfr=xc9adbaqaaeGaciGaaiaabeqaaeqabiWaaaGcbaGafeOvayLbaiaaaaa@2D11@O2 max in the heat (ambient temperature: 30.3 ± 0.5 °C, relative humidity: 70 ± 2% before and after 7 days of Cr (20 g·d-1 Cr + 140 g·d-1 glucose polymer or placebo (Plc (160 g·d-1 glucose polymer supplementation. Results 3-way interaction has shown that Cr supplementation reduced rectal temperature, heart rate, ratings of perceived leg fatigue (P P P P > 0.05; Cr group, n = 11: 47.0 ± 4.7 min vs. 49.7 ± 7.5 min, P > 0.05. However, after dividing the participants into "responders" and "non-responders" to Cr, based on their intramuscular Cr uptake, performance was higher in the "responders" relative to "non-responders" group (51.7 ± 7.4 min vs.47.3 ± 4.9 min, p Conclusion although Cr influenced key modulators of brain 5-HT and DA function and reduced various thermophysiological parameters which all may have contributed to the reduced effort perception during exercise in the heat, performance was improved only in the "responders" to Cr supplementation. The present results may also suggest the demanding of the pre-experimental identification of the participants into "responders" and "non-responders" to Cr supplementation before performing the main experimentation. Otherwise, the possibility of the type II error may be enhanced.

  16. Modulating intracellular acidification by regulating the incubation time of proton caged compounds.

    Science.gov (United States)

    Carbone, Marilena; Sabbatella, Gianfranco; Antonaroli, Simonetta; Orlando, Viviana; Biagioni, Stefano; Nucara, Alessandro

    2016-09-01

    A proton caged compound, the 1-(2-nitrophenyl)- ethylhexadecyl sulfonate (HDNS), was dosed into HEK-293 at different incubation times. Samples were irradiated with filtered UV light for inducing photolysis of the HDNS and then probed by infrared spectroscopy. The intracellular acidification reaction can be followed by monitoring the consequent CO2 peak intensity variation. The total CO2 produced is similar for all the samples, hence it is only a function of the initial HDNS concentration. The way it is achieved, though, is different for the different incubation times and follows kinetics, which results in a combination of a linear CO2 increase and a steep CO2 increase followed by a decay. This is interpreted in terms of confinement of the HDNS into intracellular vesicles of variable average size and sensitive to UV light when they reach critical dimensions.

  17. Modulation of Connexin-36 Gap Junction Channels by Intracellular pH and Magnesium Ions.

    Science.gov (United States)

    Rimkute, Lina; Kraujalis, Tadas; Snipas, Mindaugas; Palacios-Prado, Nicolas; Jotautis, Vaidas; Skeberdis, Vytenis A; Bukauskas, Feliksas F

    2018-01-01

    Connexin-36 (Cx36) protein forms gap junction (GJ) channels in pancreatic beta cells and is also the main Cx isoform forming electrical synapses in the adult mammalian brain. Cx36 GJs can be regulated by intracellular pH (pH i ) and cytosolic magnesium ion concentration ([Mg 2+ ] i ), which can vary significantly under various physiological and pathological conditions. However, the combined effect and relationship of these two factors over Cx36-dependent coupling have not been previously studied in detail. Our experimental results in HeLa cells expressing Cx36 show that changes in both pH i and [Mg 2+ ] i affect junctional conductance (g j ) in an interdependent manner; in other words, intracellular acidification cause increase or decay in g j depending on whether [Mg 2+ ] i is high or low, respectively, and intracellular alkalization cause reduction in g j independently of [Mg 2+ ] i . Our experimental and modelling data support the hypothesis that Cx36 GJ channels contain two separate gating mechanisms, and both are differentially sensitive to changes in pH i and [Mg 2+ ] i . Using recombinant Cx36 we found that two glutamate residues in the N-terminus could be partly responsible for the observed interrelated effect of pH i and [Mg 2+ ] i . Mutation of glutamate at position 8 attenuated the stimulatory effect of intracellular acidification at high [Mg 2+ ] i , while mutation at position 12 and double mutation at both positions reversed stimulatory effect to inhibition. Moreover, Cx36 * E8Q lost the initial increase of g j at low [Mg 2+ ] i and double mutation lost the sensitivity to high [Mg 2+ ] i . These results suggest that E8 and E12 are involved in regulation of Cx36 GJ channels by Mg 2+ and H + ions.

  18. Identification of key amino acid residues modulating intracellular and in vitro microcin E492 amyloid formation

    Directory of Open Access Journals (Sweden)

    Paulina eAguilera

    2016-01-01

    Full Text Available Microcin E492 (MccE492 is a pore-forming bacteriocin produced and exported by Klebsiella pneumoniae RYC492. Besides its antibacterial activity, excreted MccE492 can form amyloid fibrils in vivo as well as in vitro. It has been proposed that bacterial amyloids can be functional playing a biological role, and in the particular case of MccE492 it would control the antibacterial activity. MccE492 amyloid fibril’s morphology and formation kinetics in vitro have been well characterized, however it is not known which amino acid residues determine its amyloidogenic propensity, nor if it forms intracellular amyloid inclusions as has been reported for other bacterial amyloids. In this work we found the conditions in which MccE492 forms intracellular amyloids in E. coli cells, that were visualized as round-shaped inclusion bodies recognized by two amyloidophillic probes, 2-4´-methylaminophenyl benzothiazole and thioflavin-S. We used this property to perform a flow cytometry-based assay to evaluate the aggregation propensity of MccE492 mutants, that were designed using an in silico prediction of putative aggregation hotspots. We established that the predicted amino acid residues 54-63, effectively act as a pro-amyloidogenic stretch. As in the case of other amyloidogenic proteins, this region presented two gatekeeper residues (P57 and P59, which disfavor both intracellular and in vitro MccE492 amyloid formation, preventing an uncontrolled aggregation. Mutants in each of these gatekeeper residues showed faster in vitro aggregation and bactericidal inactivation kinetics, and the two mutants were accumulated as dense amyloid inclusions in more than 80% of E. coli cells expressing these variants. In contrast, the MccE492 mutant lacking residues 54-63 showed a significantly lower intracellular aggregation propensity and slower in vitro polymerization kinetics. Electron microscopy analysis of the amyloids formed in vitro by these mutants revealed that, although

  19. The Pseudomonas aeruginosa Chp Chemosensory System Regulates Intracellular cAMP Levels by Modulating Adenylate Cyclase Activity

    Science.gov (United States)

    Fulcher, Nanette B.; Holliday, Phillip M.; Klem, Erich; Cann, Martin J.; Wolfgang, Matthew C.

    2010-01-01

    Summary Multiple virulence systems in the opportunistic pathogen Pseudomonas aeruginosa are regulated by the second messenger signaling molecule adenosine 3’, 5’-cyclic monophosphate (cAMP). Production of cAMP by the putative adenylate cyclase enzyme CyaB represents a critical control point for virulence gene regulation. To identify regulators of CyaB, we screened a transposon insertion library for mutants with reduced intracellular cAMP. The majority of insertions resulting in reduced cAMP mapped to the Chp gene cluster encoding a putative chemotaxis-like chemosensory system. Further genetic analysis of the Chp system revealed that it has both positive and negative effects on intracellular cAMP and that it regulates cAMP levels by modulating CyaB activity. The Chp system was previously implicated in the production and function of type IV pili (TFP). Given that cAMP and the cAMP-dependent transcriptional regulator Vfr control TFP biogenesis gene expression, we explored the relationship between cAMP, the Chp system and TFP regulation. We discovered that the Chp system controls TFP production through modulation of cAMP while control of TFP-dependent twitching motility is cAMP-independent. Overall, our data define a novel function for a chemotaxis-like system in controlling cAMP production and establish a regulatory link between the Chp system, TFP and other cAMP-dependent virulence systems. PMID:20345659

  20. Modulation of intracellular calcium waves and triggered activities by mitochondrial ca flux in mouse cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Zhenghang Zhao

    Full Text Available Recent studies have suggested that mitochondria may play important roles in the Ca(2+ homeostasis of cardiac myocytes. However, it is still unclear if mitochondrial Ca(2+ flux can regulate the generation of Ca(2+ waves (CaWs and triggered activities in cardiac myocytes. In the present study, intracellular/cytosolic Ca(2+ (Cai (2+ was imaged in Fluo-4-AM loaded mouse ventricular myocytes. Spontaneous sarcoplasmic reticulum (SR Ca(2+ release and CaWs were induced in the presence of high (4 mM external Ca(2+ (Cao (2+. The protonophore carbonyl cyanide p-(trifluoromethoxyphenylhydrazone (FCCP reversibly raised basal Cai (2+ levels even after depletion of SR Ca(2+ in the absence of Cao (2+ , suggesting Ca(2+ release from mitochondria. FCCP at 0.01 - 0.1 µM partially depolarized the mitochondrial membrane potential (Δψ m and increased the frequency and amplitude of CaWs in a dose-dependent manner. Simultaneous recording of cell membrane potentials showed the augmentation of delayed afterdepolarization amplitudes and frequencies, and induction of triggered action potentials. The effect of FCCP on CaWs was mimicked by antimycin A (an electron transport chain inhibitor disrupting Δψ m or Ru360 (a mitochondrial Ca(2+ uniporter inhibitor, but not by oligomycin (an ATP synthase inhibitor or iodoacetic acid (a glycolytic inhibitor, excluding the contribution of intracellular ATP levels. The effects of FCCP on CaWs were counteracted by the mitochondrial permeability transition pore blocker cyclosporine A, or the mitochondrial Ca(2+ uniporter activator kaempferol. Our results suggest that mitochondrial Ca(2+ release and uptake exquisitely control the local Ca(2+ level in the micro-domain near SR ryanodine receptors and play an important role in regulation of intracellular CaWs and arrhythmogenesis.

  1. Intracellular Ca2+ release mediates cationic but not anionic poly(amidoamine) (PAMAM) dendrimer-induced tight junction modulation.

    Science.gov (United States)

    Avaritt, Brittany R; Swaan, Peter W

    2014-09-01

    Poly(amidoamine) (PAMAM) dendrimers show great promise for utilization as oral drug delivery vehicles. These polymers are capable of traversing epithelial barriers, and have been shown to translocate by both transcellular and paracellular routes. While many proof-of-concept studies have shown that PAMAM dendrimers improve intestinal transport, little information exists on the mechanisms of paracellular transport, specifically dendrimer-induced tight junction modulation. Using anionic G3.5 and cationic G4 PAMAM dendrimers with known absorption enhancers, we investigated tight junction modulation in Caco-2 monolayers by visualization and mannitol permeability and compared dendrimer-mediated tight junction modulation to that of established permeation enhancers. [(14)C]-Mannitol permeability in the presence and absence of phospholipase C-dependent signaling pathway inhibitors was also examined and indicated that this pathway may mediate dendrimer-induced changes in permeability. Differences between G3.5 and G4 in tight junction protein staining and permeability with inhibitors were evident, suggesting divergent mechanisms were responsible for tight junction modulation. These dissimilarities are further intimated by the intracellular calcium release caused by G4 but not G3.5. Based on our results, it is apparent that the underlying mechanisms of dendrimer permeability are complex, and the complexities are likely a result of the density and sign of the surface charges of PAMAM dendrimers. The results of this study will have implications on the future use of PAMAM dendrimers for oral drug delivery.

  2. Modulation of Olfactory Bulb Network Activity by Serotonin: Synchronous Inhibition of Mitral Cells Mediated by Spatially Localized GABAergic Microcircuits

    Science.gov (United States)

    Schmidt, Loren J.; Strowbridge, Ben W.

    2014-01-01

    Although inhibition has often been proposed as a central mechanism for coordinating activity in the olfactory system, relatively little is known about how activation of different inhibitory local circuit pathways can generate coincident inhibition of principal cells. We used serotonin (5-HT) as a pharmacological tool to induce spiking in ensembles…

  3. Altered expression and modulation of activity-regulated cytoskeletal associated protein (Arc) in serotonin transporter knockout rats.

    NARCIS (Netherlands)

    Molteni, R.; Calabrese, F.; Maj, P.F.; Olivier, J.D.A.; Racagni, G.; Ellenbroek, A.A.; Riva, M.A.

    2009-01-01

    A gene variant in the human serotonin transporter (SERT) can increase the vulnerability to mood disorders. SERT knockout animals show similarities to the human condition and represent an important tool to investigate the mechanisms underlying the pathologic condition in humans. Along this line of

  4. Modulation of Tryptophan and Serotonin Metabolism as a Biochemical Basis of the Behavioral Effects of Use and Withdrawal of Androgenic-Anabolic Steroids and Other Image- and Performance-Enhancing Agents

    Directory of Open Access Journals (Sweden)

    Abdulla A-B Badawy

    2018-02-01

    Full Text Available Modulation of tryptophan (Trp metabolism may underpin the behavioral effects of androgenic-anabolic steroids (AAS and associated image and performance enhancers. Euphoria, arousal, and decreased anxiety observed with moderate use and exercise may involve enhanced cerebral serotonin synthesis and function by increased release of albumin-bound Trp and estrogen-mediated liver Trp 2,3-dioxygenase (TDO inhibition and enhancement of serotonin function. Aggression, anxiety, depression, personality disorders, and psychosis, observed on withdrawal of AAS or with use of large doses, can be caused by decreased serotonin synthesis due to TDO induction on withdrawal, excess Trp inhibiting the 2 enzymes of serotonin synthesis, and increased cerebral levels of neuroactive kynurenines. Exercise and excessive protein and branched-chain amino acid intakes may aggravate the effects of large AAS dosage. The hypothesis is testable in humans and experimental animals by measuring parameters of Trp metabolism and disposition and related metabolic processes.

  5. Connexin43 hemichannels contributes to the disassembly of cell junctions through modulation of intracellular oxidative status

    Directory of Open Access Journals (Sweden)

    Yuan Chi

    2016-10-01

    Full Text Available Connexin (Cx hemichannels regulate many cellular processes with little information available regarding their mechanisms. Given that many pathological factors that activate hemichannels also disrupts the integrity of cellular junctions, we speculated a potential participation of hemichannels in the regulation of cell junctions. Here we tested this hypothesis. Exposure of renal tubular epithelial cells to Ca2+-free medium led to disassembly of tight and adherens junctions, as indicated by the reduced level of ZO-1 and cadherin, disorganization of F-actin, and severe drop in transepithelial electric resistance. These changes were preceded by an activation of Cx43 hemichannels, as revealed by extracellular efflux of ATP and intracellular influx of Lucifer Yellow. Inhibition of hemichannels with chemical inhibitors or Cx43 siRNA greatly attenuated the disassembly of cell junctions. Further analysis using fetal fibroblasts derived from Cx43 wide-type (Cx43+/+, heterozygous (Cx43+/- and knockout (Cx43-/- littermates showed that Cx43-positive cells (Cx43+/+ exhibited more dramatic changes in cell shape, F-actin, and cadherin in response to Ca2+ depletion, as compared to Cx43-null cells (Cx43-/-. Consistently, these cells had higher level of protein carbonyl modification and phosphorylation, and much stronger activation of P38 and JNK. Hemichannel opening led to extracellular loss of the major antioxidant glutathione (GSH. Supplement of cells with exogenous GSH or inhibition of oxidative sensitive kinases largely prevented the above-mentioned changes. Taken together, our study indicates that Cx43 hemichannels promote the disassembly of cell junctions through regulation of intracellular oxidative status.

  6. HBV core protein allosteric modulators differentially alter cccDNA biosynthesis from de novo infection and intracellular amplification pathways

    Science.gov (United States)

    Guo, Fang; Zhao, Qiong; Cheng, Junjun; Qi, Yonghe; Su, Qing; Wei, Lai; Li, Wenhui; Chang, Jinhong

    2017-01-01

    Hepatitis B virus (HBV) core protein assembles viral pre-genomic (pg) RNA and DNA polymerase into nucleocapsids for reverse transcriptional DNA replication to take place. Several chemotypes of small molecules, including heteroaryldihydropyrimidines (HAPs) and sulfamoylbenzamides (SBAs), have been discovered to allosterically modulate core protein structure and consequentially alter the kinetics and pathway of core protein assembly, resulting in formation of irregularly-shaped core protein aggregates or “empty” capsids devoid of pre-genomic RNA and viral DNA polymerase. Interestingly, in addition to inhibiting nucleocapsid assembly and subsequent viral genome replication, we have now demonstrated that HAPs and SBAs differentially modulate the biosynthesis of covalently closed circular (ccc) DNA from de novo infection and intracellular amplification pathways by inducing disassembly of nucleocapsids derived from virions as well as double-stranded DNA-containing progeny nucleocapsids in the cytoplasm. Specifically, the mistimed cuing of nucleocapsid uncoating prevents cccDNA formation during de novo infection of hepatocytes, while transiently accelerating cccDNA synthesis from cytoplasmic progeny nucleocapsids. Our studies indicate that elongation of positive-stranded DNA induces structural changes of nucleocapsids, which confers ability of mature nucleocapsids to bind CpAMs and triggers its disassembly. Understanding the molecular mechanism underlying the dual effects of the core protein allosteric modulators on nucleocapsid assembly and disassembly will facilitate the discovery of novel core protein-targeting antiviral agents that can more efficiently suppress cccDNA synthesis and cure chronic hepatitis B. PMID:28945802

  7. HBV core protein allosteric modulators differentially alter cccDNA biosynthesis from de novo infection and intracellular amplification pathways.

    Science.gov (United States)

    Guo, Fang; Zhao, Qiong; Sheraz, Muhammad; Cheng, Junjun; Qi, Yonghe; Su, Qing; Cuconati, Andrea; Wei, Lai; Du, Yanming; Li, Wenhui; Chang, Jinhong; Guo, Ju-Tao

    2017-09-01

    Hepatitis B virus (HBV) core protein assembles viral pre-genomic (pg) RNA and DNA polymerase into nucleocapsids for reverse transcriptional DNA replication to take place. Several chemotypes of small molecules, including heteroaryldihydropyrimidines (HAPs) and sulfamoylbenzamides (SBAs), have been discovered to allosterically modulate core protein structure and consequentially alter the kinetics and pathway of core protein assembly, resulting in formation of irregularly-shaped core protein aggregates or "empty" capsids devoid of pre-genomic RNA and viral DNA polymerase. Interestingly, in addition to inhibiting nucleocapsid assembly and subsequent viral genome replication, we have now demonstrated that HAPs and SBAs differentially modulate the biosynthesis of covalently closed circular (ccc) DNA from de novo infection and intracellular amplification pathways by inducing disassembly of nucleocapsids derived from virions as well as double-stranded DNA-containing progeny nucleocapsids in the cytoplasm. Specifically, the mistimed cuing of nucleocapsid uncoating prevents cccDNA formation during de novo infection of hepatocytes, while transiently accelerating cccDNA synthesis from cytoplasmic progeny nucleocapsids. Our studies indicate that elongation of positive-stranded DNA induces structural changes of nucleocapsids, which confers ability of mature nucleocapsids to bind CpAMs and triggers its disassembly. Understanding the molecular mechanism underlying the dual effects of the core protein allosteric modulators on nucleocapsid assembly and disassembly will facilitate the discovery of novel core protein-targeting antiviral agents that can more efficiently suppress cccDNA synthesis and cure chronic hepatitis B.

  8. HBV core protein allosteric modulators differentially alter cccDNA biosynthesis from de novo infection and intracellular amplification pathways.

    Directory of Open Access Journals (Sweden)

    Fang Guo

    2017-09-01

    Full Text Available Hepatitis B virus (HBV core protein assembles viral pre-genomic (pg RNA and DNA polymerase into nucleocapsids for reverse transcriptional DNA replication to take place. Several chemotypes of small molecules, including heteroaryldihydropyrimidines (HAPs and sulfamoylbenzamides (SBAs, have been discovered to allosterically modulate core protein structure and consequentially alter the kinetics and pathway of core protein assembly, resulting in formation of irregularly-shaped core protein aggregates or "empty" capsids devoid of pre-genomic RNA and viral DNA polymerase. Interestingly, in addition to inhibiting nucleocapsid assembly and subsequent viral genome replication, we have now demonstrated that HAPs and SBAs differentially modulate the biosynthesis of covalently closed circular (ccc DNA from de novo infection and intracellular amplification pathways by inducing disassembly of nucleocapsids derived from virions as well as double-stranded DNA-containing progeny nucleocapsids in the cytoplasm. Specifically, the mistimed cuing of nucleocapsid uncoating prevents cccDNA formation during de novo infection of hepatocytes, while transiently accelerating cccDNA synthesis from cytoplasmic progeny nucleocapsids. Our studies indicate that elongation of positive-stranded DNA induces structural changes of nucleocapsids, which confers ability of mature nucleocapsids to bind CpAMs and triggers its disassembly. Understanding the molecular mechanism underlying the dual effects of the core protein allosteric modulators on nucleocapsid assembly and disassembly will facilitate the discovery of novel core protein-targeting antiviral agents that can more efficiently suppress cccDNA synthesis and cure chronic hepatitis B.

  9. Serotonin Test

    Science.gov (United States)

    ... microscope. (For more, see the article on Anatomic Pathology .) See More Common Questions See Less Common Questions ... tumor. Accessed December 2010. Vorvick, L. (Updated 2009 March 14). Serum serotonin level. MedlinePlus Medical Encyclopedia [On- ...

  10. Intracellular calcium modulates basolateral K(+)-permeability in frog skin epithelium

    DEFF Research Database (Denmark)

    Brodin, Birger; Rytved, K A; Nielsen, R

    1994-01-01

    Cytosolic calcium ([Ca2+]i) has been suggested as a key modulator in the regulation of active sodium transport across electrically "tight" (high resistance) epithelia. In this study we investigated the effects of calcium on cellular electrophysiological parameters in a classical model tissue, the...

  11. Intracellular Diagnostics: Hunting for the Mode of Action of Redox-Modulating Selenium Compounds in Selected Model Systems

    Directory of Open Access Journals (Sweden)

    Dominika Mániková

    2014-08-01

    Full Text Available Redox-modulating compounds derived from natural sources, such as redox active secondary metabolites, are currently of considerable interest in the field of chemoprevention, drug and phytoprotectant development. Unfortunately, the exact and occasionally even selective activity of such products, and the underlying (bio-chemical causes thereof, are often only poorly understood. A combination of the nematode- and yeast-based assays provides a powerful platform to investigate a possible biological activity of a new compound and also to explore the “redox link” which may exist between its activity on the one side and its chemistry on the other. Here, we will demonstrate the usefulness of this platform for screening several selenium and tellurium compounds for their activity and action. We will also show how the nematode-based assay can be used to obtain information on compound uptake and distribution inside a multicellular organism, whilst the yeast-based system can be employed to explore possible intracellular mechanisms via chemogenetic screening and intracellular diagnostics. Whilst none of these simple and easy-to-use assays can ultimately substitute for in-depth studies in human cells and animals, these methods nonetheless provide a first glimpse on the possible biological activities of new compounds and offer direction for more complicated future investigations. They may also uncover some rather unpleasant biochemical actions of certain compounds, such as the ability of the trace element supplement selenite to induce DNA strand breaks.

  12. Bee venom induces apoptosis through intracellular Ca2+ -modulated intrinsic death pathway in human bladder cancer cells.

    Science.gov (United States)

    Ip, Siu-Wan; Chu, Yung-Lin; Yu, Chun-Shu; Chen, Po-Yuan; Ho, Heng-Chien; Yang, Jai-Sing; Huang, Hui-Ying; Chueh, Fu-Shin; Lai, Tung-Yuan; Chung, Jing-Gung

    2012-01-01

    To focus on bee venom-induced apoptosis in human bladder cancer TSGH-8301 cells and to investigate its signaling pathway to ascertain whether intracellular calcium iron (Ca(2+)) is involved in this effect. Bee venom-induced cytotoxic effects, productions of reactive oxygen species and Ca(2+) and the level of mitochondrial membrane potential (ΔΨm) were analyzed by flow cytometry. Apoptosis-associated proteins were examined by Western blot analysis and confocal laser microscopy. Bee venom-induced cell morphological changes and decreased cell viability through the induction of apoptosis in TSGH-8301 cell were found. Bee venom promoted the protein levels of Bax, caspase-9, caspase-3 and endonuclease G. The enhancements of endoplasmic reticulum stress-related protein levels were shown in bee venom-provoked apoptosis of TSGH-8301 cells. Bee venom promoted the activities of caspase-3, caspase-8, and caspase-9, increased Ca(2+) release and decreased the level of ΔΨm. Co-localization of immunofluorescence analysis showed the releases of endonuclease G and apoptosis-inducing factor trafficking to nuclei for bee venom-mediated apoptosis. The images revealed evidence of nuclear condensation and formation of apoptotic bodies by 4',6-diamidino-2-phenylindole staining and DNA gel electrophoresis showed the DNA fragmentation in TSGH-8301 cells. Bee venom treatment induces both caspase-dependent and caspase-independent apoptotic death through intracellular Ca(2+) -modulated intrinsic death pathway in TSGH-8301 cells. © 2011 The Japanese Urological Association.

  13. Rationally Engineering Phototherapy Modules of Eosin-Conjugated Responsive Polymeric Nanocarriers via Intracellular Endocytic pH Gradients.

    Science.gov (United States)

    Liu, Guhuan; Hu, Jinming; Zhang, Guoying; Liu, Shiyong

    2015-07-15

    Spatiotemporal switching of respective phototherapy modes at the cellular level with minimum side effects and high therapeutic efficacy is a major challenge for cancer phototherapy. Herein we demonstrate how to address this issue by employing photosensitizer-conjugated pH-responsive block copolymers in combination with intracellular endocytic pH gradients. At neutral pH corresponding to extracellular and cytosol milieu, the copolymers self-assemble into micelles with prominently quenched fluorescence emission and low (1)O2 generation capability, favoring a highly efficient photothermal module. Under mildly acidic pH associated with endolysosomes, protonation-triggered micelle-to-unimer transition results in recovered emission and enhanced photodynamic (1)O2 efficiency, which synergistically actuates release of encapsulated drugs, endosomal escape, and photochemical internalization processes.

  14. A new Drosophila octopamine receptor responds to serotonin.

    Science.gov (United States)

    Qi, Yi-Xiang; Xu, Gang; Gu, Gui-Xiang; Mao, Fen; Ye, Gong-Yin; Liu, Weiwei; Huang, Jia

    2017-11-01

    As the counterparts of the vertebrate adrenergic transmitters, octopamine and tyramine are important physiological regulators in invertebrates. They control and modulate many physiological and behavioral functions in insects. In this study, we reported the pharmacological properties of a new α2-adrenergic-like octopamine receptor (CG18208) from Drosophila melanogaster, named DmOctα2R. This new receptor gene encodes two transcripts by alternative splicing. The long isoform DmOctα2R-L differs from the short isoform DmOctα2R-S by the presence of an additional 29 amino acids within the third intracellular loop. When heterologously expressed in mammalian cell lines, both receptors were activated by octopamine, tyramine, epinephrine and norepinephrine, resulting in the inhibition of cAMP production in a dose-dependent manner. The long form is more sensitive to the above ligands than the short form. The adrenergic agonists naphazoline, tolazoline and clonidine can stimulate DmOctα2R as full agonists. Surprisingly, serotonin and serotoninergic agonists can also activate DmOctα2R. Several tested adrenergic antagonists and serotonin antagonists blocked the action of octopamine or serotonin on DmOctα2R. The data presented here reported an adrenergic-like G protein-coupled receptor activated by serotonin, suggesting that the neurotransmission and neuromodulation in the nervous system could be more complex than previously thought. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Maternal obesity modulates intracellular lipid turnover in the human term placenta.

    Science.gov (United States)

    Hirschmugl, B; Desoye, G; Catalano, P; Klymiuk, I; Scharnagl, H; Payr, S; Kitzinger, E; Schliefsteiner, C; Lang, U; Wadsack, C; Hauguel-de Mouzon, S

    2017-02-01

    Obesity before pregnancy is associated with impaired metabolic status of the mother and the offspring later in life. These adverse effects have been attributed to epigenetic changes in utero, but little is known about the role of placental metabolism and its contribution to fetal development. We examined the impact of maternal pre-pregnancy obesity on the expression of genes involved in placental lipid metabolism in lean and obese women. Seventy-three lean and obese women with healthy pregnancy were recruited at term elective cesarean delivery. Metabolic parameters were measured on maternal venous blood samples. Expression of 88 genes involved in lipid metabolism was measured in whole placenta tissue. Proteins of genes differently expressed in response to maternal obesity were quantified, correlated with maternal parameters and immunolocalized in placenta sections. Isolated primary trophoblasts were used for in vitro assays. Triglyceride (TG) content was increased in placental tissue of obese (1.10, CI 1.04-1.24 mg g -1 , Pwomen. Among target genes examined, six showed positive correlation (Pobese vs lean women. CGI-58 protein levels correlated positively with maternal insulin levels and pre-pregnancy body mass index (R=0.63, Ptreatment of cultured trophoblast cells. Pre-gravid obesity significantly modifies the expression of placental genes related to transport and storage of neutral lipids. We propose that the upregulation of CGI-58, a master regulator of TG hydrolysis, contributes to the turnover of intracellular lipids in placenta of obese women, and is tightly regulated by metabolic factors of the mother.

  16. Edible bird's nest modulate intracellular molecular pathways of influenza A virus infected cells.

    Science.gov (United States)

    Haghani, Amin; Mehrbod, Parvaneh; Safi, Nikoo; Kadir, Fadzilah A'ini Abd; Omar, Abdul Rahman; Ideris, Aini

    2017-01-05

    Edible Bird's Nest (EBN) as a popular traditional Chinese medicine is believed to have health enhancing and antiviral activities against influenza A virus (IAV); however, the molecular mechanism behind therapeutic effects of EBN is not well characterized. In this study, EBNs that underwent different enzymatic preparation were tested against IAV infected cells. 50% cytotoxic concentration (CC 50 ) and 50% inhibitory concentration (IC 50 ) of the EBNs against IAV strain A/Puerto Rico/8/1934(H1N1) were determined by HA and MTT assays. Subsequently, the sialic acid content of the used EBNs were analyzed by fluorometric HPLC. Western Blotting and immunofluorescent staining were used to investigate the effects of EBNs on early endosomal trafficking and autophagy process of influenza virus. This study showed that post inoculations of EBNs after enzymatic preparations have the highest efficacy to inhibit IAV. While CC50 of the tested EBNs ranged from 27.5-32 mg/ml, the IC50 of these compounds ranged between 2.5-4.9 mg/ml. EBNs could inhibit IAV as efficient as commercial antiviral agents, such as amantadine and oseltamivir with different mechanisms of action against IAV. The antiviral activity of these EBNs correlated with the content of N-acetyl neuraminic acid. EBNs could affect early endosomal trafficking of the virus by reducing Rab5 and RhoA GTPase proteins and also reoriented actin cytoskeleton of IAV infected cells. In addition, for the first time this study showed that EBNs can inhibit intracellular autophagy process of IAV life cycle as evidenced by reduction of LC3-II and increasing of lysosomal degradation. The results procured in this study support the potential of EBNs as supplementary medication or alternative to antiviral agents to inhibit influenza infections. Evidently, EBNs can be a promising antiviral agent; however, these natural compounds should be screened for their metabolites prior to usage as therapeutic approach.

  17. Modulation of intracellular calcium and proliferative activity of invertebrate and vertebrate cells by ethylene

    Directory of Open Access Journals (Sweden)

    Müller Werner EG

    2001-05-01

    Full Text Available Abstract Background Ethylene is a widely distributed alkene product which is formed enzymatically (e.g., in plants or by photochemical reactions (e.g., in the upper oceanic layers from dissolved organic carbon. This gaseous compound was recently found to induce in cells from the marine sponge Suberites domuncula, an increase in intracellular Ca2+ level ([Ca2+]i and an upregulation of the expression of two genes, the potential ethylene-responsive gene, SDERR, and a Ca2+/calmodulin-dependent protein kinase. Results Here we describe for the first time, that besides sponge cells, mammalian cell lines (mouse NIH-3T3 and human HeLa and SaOS-2 cells respond to ethylene, generated by ethephon, with an immediate and strong, transient increase in [Ca2+]i level, as demonstrated using Fura-2 imaging method. A rise of [Ca2+]i level was also found following exposure to ethylene gas of cells kept under pressure (SaOS-2 cells. The upregulation of [Ca2+]i was associated with an increase in the level of the cell cycle-associated Ki-67 antigen. In addition, we show that the effect of ethephon addition to S. domuncula cells depends on the presence of calcium in the extracellular milieu. Conclusion The results presented in this paper indicate that ethylene, previously known to act as a mediator (hormone in plants only, deserves also attention as a potential signaling molecule in higher vertebrates. Further studies are necessary to clarify the specificity and physiological significance of the effects induced by ethylene in mammalian cells.

  18. [Effect of serotonin-modulated anticonsolidation protein on formation of long-term memory in carps Cyprinus carpio in the model of active avoidance learning].

    Science.gov (United States)

    Garina, D V; Mekhtiev, A A

    2014-01-01

    Effect of serotonin-modulated anticonsolidation protein (SMAP) that has property of disturbing formation of memory trace in mammals and of learning and memory in teleost fish was studied in the model of active avoidance learning. The experiment was performed in three stages: (1) fry of carps Cyprinus carpio L. was injected intracerebrovenricularly with the SMAP protein at a dose of 0.3 μg/g; control individuals were administered with equal amount of the buffered saline for poikilothermic animals; (2) 24 h after the injection, fish were learnt during 8 sèances for 2 days the conditioned reflex of active avoidance; (3) 48 h after the learning the testing of the skill was performed. The administration of the protein was shown to lead to disturbance of reproduction of the skill in the fish: the latent time of the skill reproduction in experimental individuals exceeded that in control fish more than two times, while the number of individuals succeeding the task in the experimental group was non-significantly lower than in the control group. However, unlike mammals, injection of the SMAP protein in this model produced no effect on the process of learning in carps. Thus, there was first demonstrated the inhibiting effect of the SMAP protein whose concentration correlated positively with the content of the neurotransmitter serotonin in brain on consolidation of memory traces in teleost fish.

  19. In vitro neuroprotective potential of lichen metabolite fumarprotocetraric acid via intracellular redox modulation

    International Nuclear Information System (INIS)

    Fernández-Moriano, Carlos; Divakar, Pradeep Kumar; Crespo, Ana; Gómez-Serranillos, M. Pilar

    2017-01-01

    The lichen-forming fungi Cetraria islandica has been largely used in folk medicines, and it has recently showed promising in vitro antioxidant effects in glial-like cells. Current work aimed at investigating the neuroprotective potential of its major isolated secondary metabolite: the depsidone fumarprotocetraric acid (FUM). H 2 O 2 was used herein to induce oxidative stress (OS)-mediated cytotoxicity in two models of neurons and astrocytes cells (SH-SY5Y and U373-MG cell lines). We found that a pre-treatment with FUM significantly enhanced cell viability compared to H 2 O 2 -treated cells, and we selected the optimal concentrations in each model (1 and 25 μg/ml, respectively) for assessing its cytoprotective mechanisms. FUM, which exerted effective peroxyl radical scavenging effect in the chemical oxygen radical antioxidant capacity (ORAC) assay, alleviated the alterations in OS markers provoked by H 2 O 2 . It attenuated intracellular ROS formation, lipid peroxidation and GSH depletion. At mitochondrial level, FUM prevented from the dissipation of mitochondrial membrane potential and the increase in mitochondrial calcium, implying a protective role against oxidative damage in mitochondrial membrane. Similarly, FUM pre-treatment diminished H 2 O 2 -induced apoptosis, as evidenced by the reduction in caspase-3 activity and expression; inmunoblot analysis also revealed a decrease in Bax and an increase in Bcl-2 proteins levels. Furthermore, FUM up-regulated the expression of the antioxidant enzymes catalase, superoxide dismutase-1, and hemeoxigenase-1. These findings and the activation of Nrf2 binding activity in nuclear extracts suggest a plausible involvement of Nrf2 signaling pathway in the cytoprotection by FUM. In conclusion, FUM emerges as a potential drug candidate in the therapy of OS-related diseases, such as the neurodegenerative disorders. - Highlights: • FUM pre-treatment exerts significant cytoprotection against H 2 O 2 -mediated apoptosis. • ROS

  20. In vitro neuroprotective potential of lichen metabolite fumarprotocetraric acid via intracellular redox modulation

    Energy Technology Data Exchange (ETDEWEB)

    Fernández-Moriano, Carlos [Department of Pharmacology, Faculty of Pharmacy, University Complutense of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid (Spain); Divakar, Pradeep Kumar; Crespo, Ana [Department of Plant Biology II, Faculty of Pharmacy, University Complutense of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid (Spain); Gómez-Serranillos, M. Pilar, E-mail: pserra@ucm.es [Department of Pharmacology, Faculty of Pharmacy, University Complutense of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid (Spain)

    2017-02-01

    The lichen-forming fungi Cetraria islandica has been largely used in folk medicines, and it has recently showed promising in vitro antioxidant effects in glial-like cells. Current work aimed at investigating the neuroprotective potential of its major isolated secondary metabolite: the depsidone fumarprotocetraric acid (FUM). H{sub 2}O{sub 2} was used herein to induce oxidative stress (OS)-mediated cytotoxicity in two models of neurons and astrocytes cells (SH-SY5Y and U373-MG cell lines). We found that a pre-treatment with FUM significantly enhanced cell viability compared to H{sub 2}O{sub 2}-treated cells, and we selected the optimal concentrations in each model (1 and 25 μg/ml, respectively) for assessing its cytoprotective mechanisms. FUM, which exerted effective peroxyl radical scavenging effect in the chemical oxygen radical antioxidant capacity (ORAC) assay, alleviated the alterations in OS markers provoked by H{sub 2}O{sub 2}. It attenuated intracellular ROS formation, lipid peroxidation and GSH depletion. At mitochondrial level, FUM prevented from the dissipation of mitochondrial membrane potential and the increase in mitochondrial calcium, implying a protective role against oxidative damage in mitochondrial membrane. Similarly, FUM pre-treatment diminished H{sub 2}O{sub 2}-induced apoptosis, as evidenced by the reduction in caspase-3 activity and expression; inmunoblot analysis also revealed a decrease in Bax and an increase in Bcl-2 proteins levels. Furthermore, FUM up-regulated the expression of the antioxidant enzymes catalase, superoxide dismutase-1, and hemeoxigenase-1. These findings and the activation of Nrf2 binding activity in nuclear extracts suggest a plausible involvement of Nrf2 signaling pathway in the cytoprotection by FUM. In conclusion, FUM emerges as a potential drug candidate in the therapy of OS-related diseases, such as the neurodegenerative disorders. - Highlights: • FUM pre-treatment exerts significant cytoprotection against H

  1. Modulation of intracellular protein degradation by SSB1-SIS1 chaperon system in yeast S. cerevisiae.

    Science.gov (United States)

    Ohba, M

    1997-06-09

    In prokaryotes, DnaK-DnaJ chaperon is involved in the protein degradation catalyzed by proteases La and ClpA/B complex as shown in E. coli. To extend this into eukaryotic cells, we examined the effects of hsp70 genes, SSA1 and SSB1, and DnaJ genes, SIS1 and YDJ1, on the growth of proteasome subunit mutants of the yeast S. cerevisiae. The results identified SSB1 and SIS1 as a pair of chaperon genes specifically involved in efficient protein turnover in the yeast, whose overexpression suppressed the growth defects caused by the proteasome mutations. Moreover, a single amino acid substitution in the putative peptide-binding site of SSB1 protein profoundly enhanced the suppression activity, indicating that the activity is mediated by the peptide-binding activity of this chaperon. Thus SSB1, with its partner DnaJ, SIS1, modulates the efficiency of protein turnover through its chaperon activity.

  2. Intracellular responses to frequency modulated tones in the dorsal cortex of the mouse inferior colliculus

    Directory of Open Access Journals (Sweden)

    Ruediger eGeis

    2013-01-01

    Full Text Available Frequency modulations occur in many natural sounds, including vocalizations. The neuronal response to frequency modulated (FM stimuli has been studied extensively in different brain areas, with an emphasis on the auditory cortex and the central nucleus of the inferior colliculus. Here, we measured the responses to FM sweeps in whole-cell recordings from neurons in the dorsal cortex of the mouse inferior colliculus. Both up- and downward logarithmic FM sweeps were presented at two different speeds to both the ipsi- and the contralateral ear. Based on the number of action potentials that were fired, between 10-24% of cells were selective for rate or direction of the FM sweeps. A somewhat lower percentage of cells, 6-21%, showed selectivity based on EPSP size. To study the mechanisms underlying the generation of FM selectivity, we compared FM responses with responses to simple tones in the same cells. We found that if pairs of neurons responded in a similar way to simple tones, they generally also responded in a similar way to FM sweeps. Further evidence that FM selectivity can be generated within the dorsal cortex was obtained by reconstructing FM sweeps from the response to simple tones using three different models. In about half of the direction selective neurons the selectivity was generated by spectrally asymmetric synaptic inhibition. In addition, evidence for direction selectivity based on the timing of excitatory responses was also obtained in some cells. No clear evidence for the local generation of rate selectivity was obtained. We conclude that FM direction selectivity can be generated within the dorsal cortex of the mouse inferior colliculus by multiple mechanisms.

  3. Neurotrophin-3 Regulates Synapse Development by Modulating TrkC-PTPσ Synaptic Adhesion and Intracellular Signaling Pathways.

    Science.gov (United States)

    Han, Kyung Ah; Woo, Doyeon; Kim, Seungjoon; Choii, Gayoung; Jeon, Sangmin; Won, Seoung Youn; Kim, Ho Min; Heo, Won Do; Um, Ji Won; Ko, Jaewon

    2016-04-27

    neurotrophin-3 (NT-3) modulates the synaptic adhesion pathway involving neurotrophin receptor tyrosine kinase C (TrkC) and presynaptic protein tyrosine phosphatase σ (PTPσ) in a bidirectional manner at excitatory synapses. NT-3 acts in concentration-independent manner to facilitate TrkC-mediated presynaptic differentiation, whereas it acts in a concentration-dependent manner to exert differential effects on TrkC-mediated organization of postsynaptic development. We further investigated TrkC extracellular ligand binding, intracellular signaling pathways, and kinase activity in NT-3-induced synapse development. Last, we found that interneuronal differences in TrkC levels regulate the synapse number. Overall, these results suggest that NT-3 functions as a positive modulator of synaptogenesis involving TrkC and PTPσ. Copyright © 2016 the authors 0270-6474/16/364817-16$15.00/0.

  4. Silver ions increase plasma membrane permeability through modulation of intracellular calcium levels in tobacco BY-2 cells.

    Science.gov (United States)

    Klíma, Petr; Laňková, Martina; Vandenbussche, Filip; Van Der Straeten, Dominique; Petrášek, Jan

    2018-05-01

    Silver ions increase plasma membrane permeability for water and small organic compounds through their stimulatory effect on plasma membrane calcium channels, with subsequent modulation of intracellular calcium levels and ion homeostasis. The action of silver ions at the plant plasma membrane is largely connected with the inhibition of ethylene signalling thanks to the ability of silver ion to replace the copper cofactor in the ethylene receptor. A link coupling the action of silver ions and cellular auxin efflux has been suggested earlier by their possible direct interaction with auxin efflux carriers or by influencing plasma membrane permeability. Using tobacco BY-2 cells, we demonstrate here that besides a dramatic increase of efflux of synthetic auxins 2,4-dichlorophenoxyacetic acid (2,4-D) and 1-naphthalene acetic acid (NAA), treatment with AgNO 3 resulted in enhanced efflux of the cytokinin trans-zeatin (tZ) as well as the auxin structural analogues tryptophan (Trp) and benzoic acid (BA). The application of AgNO 3 was accompanied by gradual water loss and plasmolysis. The observed effects were dependent on the availability of extracellular calcium ions (Ca 2+ ) as shown by comparison of transport assays in Ca 2+ -rich and Ca 2+ -free buffers and upon treatment with inhibitors of plasma membrane Ca 2+ -permeable channels Al 3+ and ruthenium red, both abolishing the effect of AgNO 3 . Confocal microscopy of Ca 2+ -sensitive fluorescence indicator Fluo-4FF, acetoxymethyl (AM) ester suggested that the extracellular Ca 2+ availability is necessary to trigger the response to silver ions and that the intracellular Ca 2+ pool alone is not sufficient for this effect. Altogether, our data suggest that in plant cells the effects of silver ions originate from the primal modification of the internal calcium levels, possibly by their interaction with Ca 2+ -permeable channels at the plasma membrane.

  5. Modulation of leak K(+) channel in hypoglossal motoneurons of rats by serotonin and/or variation of pH value.

    Science.gov (United States)

    Xu, Xue-Feng; Tsai, Hao-Jan; Li, Lin; Chen, Yi-Fan; Zhang, Cheng; Wang, Guang-Fa

    2009-08-25

    The cloned TWIK-related acid-sensitive K(+) channel (TASK-1) is sensitive to the pH changes within physiological pH range (pK~7.4). Recently, the native TASK-1-like channel was suggested to be the main contributor to the background (or leak) K(+) conductance in the motoneurons of the brain stem. Serotonin (5-HT) and variation of pH value in perfused solution could modulate these currents. Here we aimed to examine the properties and modulation of the currents by serotonin or variation of pH value in hypoglossal motoneurons of rats. Transverse slices were prepared from the brainstem of neonatal Sprague-Dawley rats (postnatal days 7-8). Hypoglossal motoneurons were used for the study. The leak K(+) current (TASK-1-like current) and hyperpolarization-activated cationic current (I(h)) were recorded with the whole-cell patch-clamp technique. The results showed that these currents were inhibited by acidified artificial cerebrospinal fluid (ACSF, pH 6.0) and activated by alkalized ACSF (pH 8.5). 5-HT (10 mumol/L) significantly inhibited both leak K(+) current and I(h) with depolarization of membrane potential and the occurrence of oscillation and/or spikes. Bath application of Ketanserine, an antagonist of 5-HT₂ receptor, reversed or reduced the inhibitory effect of acidified solution on leak K(+) current and I(h). The results suggest that 5-HT₂ receptors mediate the effects of acidified media on leak K(+) current and I(h) in hypoglossal motoneurons.

  6. Platelet activating factor enhances synaptic vesicle exocytosis via PKC, elevated intracellular calcium, and modulation of synapsin 1 dynamics and phosphorylation

    Directory of Open Access Journals (Sweden)

    Jennetta W Hammond

    2016-01-01

    Full Text Available Platelet activating factor (PAF is an inflammatory phospholipid signaling molecule implicated in synaptic plasticity, learning and memory and neurotoxicity during neuroinflammation. However, little is known about the intracellular mechanisms mediating PAF’s physiological or pathological effects on synaptic facilitation. We show here that PAF receptors are localized at the synapse. Using fluorescent reporters of presynaptic activity we show that a non-hydrolysable analogue of PAF (cPAF enhances synaptic vesicle release from individual presynaptic boutons by increasing the size or release of the readily releasable pool and the exocytosis rate of the total recycling pool. cPAF also activates previously silent boutons resulting in vesicle release from a larger number of terminals. The underlying mechanism involves elevated calcium within presynaptic boutons and protein kinase C (PKC activation. Furthermore, cPAF increases synapsin I phosphorylation at sites 1 and 3, and increases dispersion of synapsin I from the presynaptic compartment during stimulation, freeing synaptic vesicles for subsequent release. These findings provide a conceptual framework for how PAF, regardless of its cellular origin, can modulate synapses during normal and pathologic synaptic activity.

  7. Electrophysiological and biochemical studies of slow responses to serotonin and dopamine of snail identified neurons. Mediating role of the cyclic AMP

    International Nuclear Information System (INIS)

    Deterre, Philippe

    1983-01-01

    In this research thesis, the electrophysiological study of slow incoming currents induced in some identified neurons of the Helix aspersa snail by serotonin and dopamine shows that they are associated with a decrease of a potassium conductance involved in the modulation of the action potential duration. By means of enzymatic tests performed on a single cell, and of electrophysiological experiments, the author shows that the cyclic AMP is an intracellular mediator involved in the genesis of these slow responses. Moreover, the obtained results show that serotonin and dopamine act by binding to specific receptors, and that these receptors activate the adenylate-cyclase through a GTP binding protein [fr

  8. Macrophage ABCA2 deletion modulates intracellular cholesterol deposition, affects macrophage apoptosis, and decreases early atherosclerosis in LDL receptor knockout mice.

    Science.gov (United States)

    Calpe-Berdiel, Laura; Zhao, Ying; de Graauw, Marjo; Ye, Dan; van Santbrink, Peter J; Mommaas, A Mieke; Foks, Amanda; Bot, Martine; Meurs, Illiana; Kuiper, Johan; Mack, Jody T; Van Eck, Miranda; Tew, Kenneth D; van Berkel, Theo J C

    2012-08-01

    The ABCA2 transporter shares high structural homology to ABCA1, which is crucial for the removal of excess cholesterol from macrophages and, by extension, in atherosclerosis. It has been suggested that ABCA2 sequesters cholesterol inside the lysosomes, however, little is known of the macrophage-specific role of ABCA2 in regulating lipid homeostasis in vivo and in modulating susceptibility to atherosclerosis. Chimeras with dysfunctional macrophage ABCA2 were generated by transplantation of bone marrow from ABCA2 knockout (KO) mice into irradiated LDL receptor (LDLr) KO mice. Interestingly, lack of ABCA2 in macrophages resulted in a diminished lesion size in the aortic root (-24.5%) and descending thoracic aorta (-36.6%) associated with a 3-fold increase in apoptotic cells, as measured by both caspase 3 and TUNEL. Upon oxidized LDL exposure, macrophages from wildtype (WT) transplanted animals developed filipin-positive droplets in lysosomal-like compartments, corresponding to free cholesterol (FC) accumulation. In contrast, ABCA2-deficient macrophages displayed an abnormal diffuse distribution of FC over peripheral regions. The accumulation of neutral sterols in lipid droplets was increased in ABCA2-deficient macrophages, but primarily in cytoplasmic clusters and not in lysosomes. Importantly, apoptosis of oxLDL loaded macrophages lacking ABCA2 was increased 2.7-fold, probably as a consequence of the broad cellular distribution of FC. Lack of functional ABCA2 generates abnormalities in intracellular lipid distribution/trafficking in macrophages consistent with its lysosomal sequestering role, leading to an increased susceptibility to apoptosis in response to oxidized lipids and reduced atherosclerotic lesion development. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  9. Capture and retention of tritiated serotonin by the chick notochord

    International Nuclear Information System (INIS)

    Gerard, Anne; Gerard, Hubert; Dollander, Alexis

    1978-01-01

    The 3 day old chick notochord capacity to fix tritiated serotonin is maximal in its axis and in cephalic region. Observations permitting to find, the intracellular serotonin binding sites, contribute to an explanation of the capture mechanism and suggest a special direct role of the notochord on the monoaminergic neuron cytodifferentiation [fr

  10. Drosophila insulin-producing cells are differentially modulated by serotonin and octopamine receptors and affect social behavior.

    Directory of Open Access Journals (Sweden)

    Jiangnan Luo

    Full Text Available A set of 14 insulin-producing cells (IPCs in the Drosophila brain produces three insulin-like peptides (DILP2, 3 and 5. Activity in IPCs and release of DILPs is nutrient dependent and controlled by multiple factors such as fat body-derived proteins, neurotransmitters, and neuropeptides. Two monoamine receptors, the octopamine receptor OAMB and the serotonin receptor 5-HT1A, are expressed by the IPCs. These receptors may act antagonistically on adenylate cyclase. Here we investigate the action of the two receptors on activity in and output from the IPCs. Knockdown of OAMB by targeted RNAi led to elevated Dilp3 transcript levels in the brain, whereas 5-HT1A knockdown resulted in increases of Dilp2 and 5. OAMB-RNAi in IPCs leads to extended survival of starved flies and increased food intake, whereas 5-HT1A-RNAi produces the opposite phenotypes. However, knockdown of either OAMB or 5-HT1A in IPCs both lead to increased resistance to oxidative stress. In assays of carbohydrate levels we found that 5-HT1A knockdown in IPCs resulted in elevated hemolymph glucose, body glycogen and body trehalose levels, while no effects were seen after OAMB knockdown. We also found that manipulations of the two receptors in IPCs affected male aggressive behavior in different ways and 5-HT1A-RNAi reduced courtship latency. Our observations suggest that activation of 5-HT1A and OAMB signaling in IPCs generates differential effects on Dilp transcription, fly physiology, metabolism and social interactions. However the findings do not support an antagonistic action of the two monoamines and their receptors in this particular system.

  11. Drosophila insulin-producing cells are differentially modulated by serotonin and octopamine receptors and affect social behavior.

    Science.gov (United States)

    Luo, Jiangnan; Lushchak, Oleh V; Goergen, Philip; Williams, Michael J; Nässel, Dick R

    2014-01-01

    A set of 14 insulin-producing cells (IPCs) in the Drosophila brain produces three insulin-like peptides (DILP2, 3 and 5). Activity in IPCs and release of DILPs is nutrient dependent and controlled by multiple factors such as fat body-derived proteins, neurotransmitters, and neuropeptides. Two monoamine receptors, the octopamine receptor OAMB and the serotonin receptor 5-HT1A, are expressed by the IPCs. These receptors may act antagonistically on adenylate cyclase. Here we investigate the action of the two receptors on activity in and output from the IPCs. Knockdown of OAMB by targeted RNAi led to elevated Dilp3 transcript levels in the brain, whereas 5-HT1A knockdown resulted in increases of Dilp2 and 5. OAMB-RNAi in IPCs leads to extended survival of starved flies and increased food intake, whereas 5-HT1A-RNAi produces the opposite phenotypes. However, knockdown of either OAMB or 5-HT1A in IPCs both lead to increased resistance to oxidative stress. In assays of carbohydrate levels we found that 5-HT1A knockdown in IPCs resulted in elevated hemolymph glucose, body glycogen and body trehalose levels, while no effects were seen after OAMB knockdown. We also found that manipulations of the two receptors in IPCs affected male aggressive behavior in different ways and 5-HT1A-RNAi reduced courtship latency. Our observations suggest that activation of 5-HT1A and OAMB signaling in IPCs generates differential effects on Dilp transcription, fly physiology, metabolism and social interactions. However the findings do not support an antagonistic action of the two monoamines and their receptors in this particular system.

  12. Serotonin Signaling in Schistosoma mansoni: A Serotonin–Activated G Protein-Coupled Receptor Controls Parasite Movement

    Science.gov (United States)

    Rashid, Mohammed; Ribeiro, Paula

    2014-01-01

    Serotonin is an important neuroactive substance in all the parasitic helminths. In Schistosoma mansoni, serotonin is strongly myoexcitatory; it potentiates contraction of the body wall muscles and stimulates motor activity. This is considered to be a critical mechanism of motor control in the parasite, but the mode of action of serotonin is poorly understood. Here we provide the first molecular evidence of a functional serotonin receptor (Sm5HTR) in S. mansoni. The schistosome receptor belongs to the G protein-coupled receptor (GPCR) superfamily and is distantly related to serotonergic type 7 (5HT7) receptors from other species. Functional expression studies in transfected HEK 293 cells showed that Sm5HTR is a specific serotonin receptor and it signals through an increase in intracellular cAMP, consistent with a 5HT7 signaling mechanism. Immunolocalization studies with a specific anti-Sm5HTR antibody revealed that the receptor is abundantly distributed in the worm's nervous system, including the cerebral ganglia and main nerve cords of the central nervous system and the peripheral innervation of the body wall muscles and tegument. RNA interference (RNAi) was performed both in schistosomulae and adult worms to test whether the receptor is required for parasite motility. The RNAi-suppressed adults and larvae were markedly hypoactive compared to the corresponding controls and they were also resistant to exogenous serotonin treatment. These results show that Sm5HTR is at least one of the receptors responsible for the motor effects of serotonin in S. mansoni. The fact that Sm5HTR is expressed in nerve tissue further suggests that serotonin stimulates movement via this receptor by modulating neuronal output to the musculature. Together, the evidence identifies Sm5HTR as an important neuronal protein and a key component of the motor control apparatus in S. mansoni. PMID:24453972

  13. Lateral/Basolateral Amygdala Serotonin Type-2 Receptors Modulate Operant Self-administration of a Sweetened Ethanol Solution via Inhibition of Principal Neuron Activity

    Directory of Open Access Journals (Sweden)

    Brian eMccool

    2014-01-01

    Full Text Available The lateral/basolateral amygdala (BLA forms an integral part of the neural circuitry controlling innate anxiety and learned fear. More recently, BLA dependent modulation of self-administration behaviors suggests a much broader role in the regulation of reward evaluation. To test this, we employed a self-administration paradigm that procedurally segregates ‘seeking’ (exemplified as lever-press behaviors from consumption (drinking directed at a sweetened ethanol solution. Microinjection of the nonselective serotonin type-2 receptor agonist, alpha-methyl-5-hydroxytryptamine (-m5HT into the BLA reduced lever pressing behaviors in a dose-dependent fashion. This was associated with a significant reduction in the number of response-bouts expressed during non-reinforced sessions without altering the size of a bout or the rate of responding. Conversely, intra-BLA -m5HT only modestly effected consumption-related behaviors; the highest dose reduced the total time spent consuming a sweetened ethanol solution but did not inhibit the total number of licks, number of lick bouts, or amount of solution consumed during a session. In vitro neurophysiological characterization of BLA synaptic responses showed that -m5HT significantly reduced extracellular field potentials. This was blocked by the 5-HT2A/C antagonist ketanserin suggesting that 5-HT2-like receptors mediate the behavioral effect of -m5HT. During whole-cell patch current-clamp recordings, we subsequently found that -m5HT increased action potential threshold and hyperpolarized the resting membrane potential of BLA pyramidal neurons. Together, our findings show that the activation of BLA 5-HT2A/C receptors inhibits behaviors related to reward-seeking by suppressing BLA principal neuron activity. These data are consistent with the hypothesis that the BLA modulates reward-related behaviors and provides specific insight into BLA contributions during operant self-administration of a

  14. Lead perturbs epidermal growth factor (EGF) modulation of intracellular calcium metabolism in clonal rat osteoblastic (ROS 17/2.8) cells

    International Nuclear Information System (INIS)

    Long, G.J.; Rosen, J.F.

    1991-01-01

    EGF, a single chain polypeptide growth factor important for many cellular functions including glycolysis and protein phophorylation, is known to modulate calcium metabolism in several cell systems. It has been shown that EGF causes an increase in Ca 2+ influx and accumulation of inositol triphosphate, and probably exhibits many, if not all, of its effects via the calcium messenger system. Lead is known to interact with and perturb normal calcium signaling pathways; hence, the purpose of this work was to determine if lead perturbs EGF modulation of calcium metabolism in ROS 17/2.8 cells and if cell functions controlled by EGF were impaired. Cells were labelled with 45 Ca (1.87 mM Ca) for 20 hr in the presence of 5 μM Pb, 50 ng/ml EGF or μM Pb and 50 ng/ml EGF. Following an EGTA rinse, kinetic parameters were determined from 45 Ca efflux curves. Three kinetic compartments described the intracellular metabolism of 45 Ca. 5 μM Pb significantly altered the effect of EGF on intracellular calcium metabolism. Calcium distribution was shifted from the fast exchanging, quantitatively small calcium pools, S 1 and S 2 to the slow exchanging, quantitatively large S 2 . There was also a 50% increase in total cell calcium in cells treated with 5 μM Pb and 50 ng/ml EGF over cells treated with 50 ng/ml EGF alone. There was also a 25% decrease in the half-time for calcium exchange from S 3 to S 1 was also decreased. These data show that Pb impairs the normal modulation of intracellular calcium homeostasis by EGF and may therefore perturb functions that are modulated by EGF via the calcium messenger system

  15. Lens intracellular hydrostatic pressure is generated by the circulation of sodium and modulated by gap junction coupling

    Science.gov (United States)

    Gao, Junyuan; Sun, Xiurong; Moore, Leon C.; White, Thomas W.; Brink, Peter R.

    2011-01-01

    We recently modeled fluid flow through gap junction channels coupling the pigmented and nonpigmented layers of the ciliary body. The model suggested the channels could transport the secretion of aqueous humor, but flow would be driven by hydrostatic pressure rather than osmosis. The pressure required to drive fluid through a single layer of gap junctions might be just a few mmHg and difficult to measure. In the lens, however, there is a circulation of Na+ that may be coupled to intracellular fluid flow. Based on this hypothesis, the fluid would cross hundreds of layers of gap junctions, and this might require a large hydrostatic gradient. Therefore, we measured hydrostatic pressure as a function of distance from the center of the lens using an intracellular microelectrode-based pressure-sensing system. In wild-type mouse lenses, intracellular pressure varied from ∼330 mmHg at the center to zero at the surface. We have several knockout/knock-in mouse models with differing levels of expression of gap junction channels coupling lens fiber cells. Intracellular hydrostatic pressure in lenses from these mouse models varied inversely with the number of channels. When the lens’ circulation of Na+ was either blocked or reduced, intracellular hydrostatic pressure in central fiber cells was either eliminated or reduced proportionally. These data are consistent with our hypotheses: fluid circulates through the lens; the intracellular leg of fluid circulation is through gap junction channels and is driven by hydrostatic pressure; and the fluid flow is generated by membrane transport of sodium. PMID:21624945

  16. Modulation of Intracellular Quantum Dot to Fluorescent Protein Förster Resonance Energy Transfer via Customized Ligands and Spatial Control of Donor–Acceptor Assembly

    Directory of Open Access Journals (Sweden)

    Lauren D. Field

    2015-12-01

    Full Text Available Understanding how to controllably modulate the efficiency of energy transfer in Förster resonance energy transfer (FRET-based assemblies is critical to their implementation as sensing modalities. This is particularly true for sensing assemblies that are to be used as the basis for real time intracellular sensing of intracellular processes and events. We use a quantum dot (QD donor -mCherry acceptor platform that is engineered to self-assemble in situ wherein the protein acceptor is expressed via transient transfection and the QD donor is microinjected into the cell. QD-protein assembly is driven by metal-affinity interactions where a terminal polyhistidine tag on the protein binds to the QD surface. Using this system, we show the ability to modulate the efficiency of the donor–acceptor energy transfer process by controllably altering either the ligand coating on the QD surface or the precise location where the QD-protein assembly process occurs. Intracellularly, a short, zwitterionic ligand mediates more efficient FRET relative to longer ligand species that are based on the solubilizing polymer, poly(ethylene glycol. We further show that a greater FRET efficiency is achieved when the QD-protein assembly occurs free in the cytosol compared to when the mCherry acceptor is expressed tethered to the inner leaflet of the plasma membrane. In the latter case, the lower FRET efficiency is likely attributable to a lower expression level of the mCherry acceptor at the membrane combined with steric hindrance. Our work points to some of the design considerations that one must be mindful of when developing FRET-based sensing schemes for use in intracellular sensing.

  17. Rotavirus and Serotonin Cross-Talk in Diarrhoea

    Science.gov (United States)

    Nordgren, Johan; Karlsson, Thommie; Sharma, Sumit; Magnusson, Karl-Eric; Svensson, Lennart

    2016-01-01

    Rotavirus (RV) has been shown to infect and stimulate secretion of serotonin from human enterochromaffin (EC) cells and to infect EC cells in the small intestine of mice. It remains to identify which intracellularly expressed viral protein(s) is responsible for this novel property and to further establish the clinical role of serotonin in RV infection. First, we found that siRNA specifically silencing NSP4 (siRNANSP4) significantly attenuated secretion of serotonin from Rhesus rotavirus (RRV) infected EC tumor cells compared to siRNAVP4, siRNAVP6 and siRNAVP7. Second, intracellular calcium mobilization and diarrhoeal capacity from virulent and avirulent porcine viruses correlated with the capacity to release serotonin from EC tumor cells. Third, following administration of serotonin, all (10/10) infants, but no (0/8) adult mice, responded with diarrhoea. Finally, blocking of serotonin receptors using Ondansetron significantly attenuated murine RV (strain EDIM) diarrhoea in infant mice (2.9 vs 4.5 days). Ondansetron-treated mice (n = 11) had significantly (p serotonin receptor antagonist significantly (p serotonin from human EC tumor cells and that serotonin participates in RV diarrhoea, which can be attenuated by Ondansetron. PMID:27459372

  18. Involvement of serotonin 2A receptor activation in modulating medial prefrontal cortex and amygdala neuronal activation during novelty-exposure.

    Science.gov (United States)

    Hervig, Mona El-Sayed; Jensen, Nadja Cecilie Hvid; Rasmussen, Nadja Bredo; Rydbirk, Rasmus; Olesen, Mikkel Vestergaard; Hay-Schmidt, Anders; Pakkenberg, Bente; Aznar, Susana

    2017-05-30

    The medial prefrontal cortex (PFC) plays a major role in executive function by exerting a top-down control onto subcortical areas. Novelty-induced frontal cortex activation is 5-HT 2A receptor (5-HT 2A R) dependent. Here, we further investigated how blockade of 5-HT 2A Rs in mice exposed to a novel open-field arena affects medial PFC activation and basolateral amygdala (BLA) reactivity. We used c-Fos immunoreactivity (IR) as a marker of neuronal activation and stereological quantification for obtaining the total number of c-Fos-IR neurons as a measure of regional activation. We further examined the impact of 5-HT 2A R blockade on the striatal-projecting BLA neurons. Systemic administration of ketanserin (0.5mg/kg) prior to novel open-field exposure resulted in reduced total numbers of c-Fos-IR cells in dorsomedial PFC areas and the BLA. Moreover, there was a positive correlation between the relative time spent in the centre of the open-field and BLA c-Fos-IR in the ketanserin-treated animals. Unilateral medial PFC lesions blocked this effect, ascertaining an involvement of this frontal cortex area. On the other hand, medial PFC lesioning exacerbated the more anxiogenic-like behaviour of the ketanserin-treated animals, upholding its involvement in modulating averseness. Ketanserin did not affect the number of activated striatal-projecting BLA neurons (measured by number of Cholera Toxin b (CTb) retrograde labelled neurons also being c-Fos-IR) following CTb injection in the ventral striatum. These results support a role of 5-HT 2A R activation in modulating mPFC and BLA activation during exposure to a novel environment, which may be interrelated. Conversely, 5-HT 2A R blockade does not seem to affect the amygdala-striatal projection. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Modulating and Measuring Intracellular H2O2 Using Genetically Encoded Tools to Study Its Toxicity to Human Cells.

    Science.gov (United States)

    Huang, Beijing K; Stein, Kassi T; Sikes, Hadley D

    2016-12-16

    Reactive oxygen species (ROS) such as H 2 O 2 play paradoxical roles in mammalian physiology. It is hypothesized that low, baseline levels of H 2 O 2 are necessary for growth and differentiation, while increased intracellular H 2 O 2 concentrations are associated with pathological phenotypes and genetic instability, eventually reaching a toxic threshold that causes cell death. However, the quantities of intracellular H 2 O 2 that lead to these different responses remain an unanswered question in the field. To address this question, we used genetically encoded constructs that both generate and quantify H 2 O 2 in a dose-response study of H 2 O 2 -mediated toxicity. We found that, rather than a simple concentration-response relationship, a combination of intracellular concentration and the cumulative metric of H 2 O 2 concentration multiplied by time (i.e., the area under the curve) determined the occurrence and level of cell death. Establishing the quantitative relationship between H 2 O 2 and cell toxicity promotes a deeper understanding of the intracellular effects of H 2 O 2 specifically as an individual reactive oxygen species, and it contributes to an understanding of its role in various redox-related diseases.

  20. Intracellular Na(+) and metabolic modulation of Na/K pump and excitability in the rat suprachiasmatic nucleus neurons.

    Science.gov (United States)

    Wang, Yi-Chi; Yang, Jyh-Jeen; Huang, Rong-Chi

    2012-10-01

    Na/K pump activity and metabolic rate are both higher during the day in the suprachiasmatic nucleus (SCN) that houses the circadian clock. Here we investigated the role of intracellular Na(+) and energy metabolism in regulating Na/K pump activity and neuronal excitability. Removal of extracellular K(+) to block the Na/K pump excited SCN neurons to fire at higher rates and return to normal K(+) to reactivate the pump produced rebound hyperpolarization to inhibit firing. In the presence of tetrodotoxin to block the action potentials, both zero K(+)-induced depolarization and rebound hyperpolarization were blocked by the cardiac glycoside strophanthidin. Ratiometric Na(+) imaging with a Na(+)-sensitive fluorescent dye indicated saturating accumulation of intracellular Na(+) in response to pump blockade with zero K(+). The Na(+) ionophore monensin also induced Na(+) loading and hyperpolarized the membrane potential, with the hyperpolarizing effect of monensin abolished in zero Na(+) or by pump blockade. Conversely, Na(+) depletion with Na(+)-free pipette solution depolarized membrane potential but retained residual Na/K pump activity. Cyanide inhibition of oxidative phosphorylation blocked the Na/K pump to depolarize resting potential and increase spontaneous firing in most cells, and to raise intracellular Na(+) levels in all cells. Nonetheless, the Na/K pump was incompletely blocked by cyanide but completely blocked by iodoacetate to inhibit glycolysis, indicating the involvement of both oxidative phosphorylation and glycolysis in fueling the Na/K pump. Together, the results indicate the importance of intracellular Na(+) and energy metabolism in regulating Na/K pump activity as well as neuronal excitability in the SCN neurons.

  1. Small non-coding RNAs: new insights in modulation of host immune response by intracellular bacterial pathogens

    Directory of Open Access Journals (Sweden)

    Waqas Ahmed

    2016-10-01

    Full Text Available Pathogenic bacteria possess intricate regulatory networks that temporally control the production of virulence factors, and enable the bacteria to survive and proliferate within host cell. Small non-coding RNAs (sRNAs have been identified as important regulators of gene expression in diverse biological contexts. Recent research has shown bacterial sRNAs involved in growth and development, cell proliferation, differentiation, metabolism, cell signaling and immune response through regulating protein–protein interactions or via their ability to base pair with RNA and DNA. In this review, we provide a brief overview of mechanism of action employed by immune-related sRNAs, their known functions in immunity, and how they can be integrated into regulatory circuits that govern virulence, which will facilitates to understand pathogenesis and the development of novel, more effective therapeutic approaches to treat infections caused by intracellular bacterial pathogens.

  2. A dualistic conformational response to substrate binding in the human serotonin transporter reveals a high affinity state for serotonin

    DEFF Research Database (Denmark)

    Bjerregaard, Henriette; Severinsen, Kasper; Said, Saida

    2015-01-01

    Serotonergic neurotransmission is modulated by the membrane-embedded serotonin transporter (SERT). SERT mediates the reuptake of serotonin into the presynaptic neurons. Conformational changes in SERT occur upon binding of ions and substrate and are crucial for translocation of serotonin across...... the membrane. Our understanding of these conformational changes is mainly based on crystal structures of a bacterial homolog in various conformations, derived homology models of eukaryotic neurotransmitter transporters, and substituted cysteine accessibility method of SERT. However, the dynamic changes...

  3. Modulation of contraction by intracellular Na+ via Na(+)-Ca2+ exchange in single shark (Squalus acanthias) ventricular myocytes.

    Science.gov (United States)

    Näbauer, M; Morad, M

    1992-01-01

    1. The effect of direct alteration of intracellular Na+ concentration on contractile properties of whole-cell clamped shark ventricular myocytes was studied using an array of 256 photodiodes to monitor the length of the isolated myocytes. 2. In myocytes dialysed with Na(+)-free solution, the voltage dependence of Ca2+ current (ICa) and contraction were similar and bell shaped. Contractions activated at all voltages were completely suppressed by nifedipine (5 microM), and failed to show significant tonic components, suggesting dependence of the contraction on Ca2+ influx through the L-type Ca2+ channel. 3. In myocytes dialysed with 60 mM Na+, a ICa-dependent and a ICa-independent component of contraction could be identified. The Ca2+ current-dependent component was prominent in voltages between -30 to +10 mV. The ICa-independent contractions were maintained for the duration of depolarization, increased with increasing depolarization between +10 to +100 mV, and were insensitive to nifedipine. 4. In such myocytes, repolarization produced slowly decaying inward tail currents closely related to the time course of relaxation and the degree of shortening prior to repolarization. 5. With 60 mM Na+ in the pipette solution, positive clamp potentials activated decaying outward currents which correlated to the size of contraction. These outward currents appeared to be generated by the Na(+)-Ca(2+)-exchanger since they depended on the presence of intracellular Na+, and were neither suppressed by nifedipine nor by K+ channel blockers. 6. The results suggest that in shark (Squalus acanthias) ventricular myocytes, which lack functionally relevant Ca2+ release pools, both Ca2+ channel and the Na(+)-Ca2+ exchanger deliver sufficient Ca2+ to activate contraction, though the effectiveness of the latter mechanism was highly dependent on the [Na+]i. PMID:1338467

  4. A shell-formation related carbonic anhydrase in Crassostrea gigas modulates intracellular calcium against CO2 exposure: Implication for impacts of ocean acidification on mollusk calcification.

    Science.gov (United States)

    Wang, Xiudan; Wang, Mengqiang; Jia, Zhihao; Song, Xiaorui; Wang, Lingling; Song, Linsheng

    2017-08-01

    Ocean acidification (OA) could decrease the shells and skeletons formation of mollusk by reducing the availability of carbonate ions at calcification sites. Carbonic anhydrases (CAs) convert CO 2 to HCO 3 - and play important roles in biomineralization process from invertebrate to vertebrate. In the present study, a CA (designated as CgCA) was identified and characterized in Pacific oyster C. gigas. The cDNA of CgCA was of 927bp encoding a predicted polypeptide of 308 amino acids with a signal peptide and a CA catalytic function domain. The mRNA transcripts of CgCA were constitutively expressed in all tested tissues with the highest levels in mantle and hemocytes. During the early development period, the mRNA transcripts of CgCA could be detected in all the stages with the highest level in D-veliger larvae. Elevated CO 2 increased the mRNA transcripts of CgCA in muscle, mantle, hepatopancreas, gill and hemocytes significantly (p<0.05) and induced the translocation of CgCA in hemocytes and mantle. Moreover, elevated CO 2 also caused the decrease of intracellular Ca 2+ in hemocytes (p<0.05). The inhibition of CA by acetazolamide and suppression of CgCA gene via RNA interference could increase the intracellular Ca 2+ in hemocytes (p<0.05). Besides, the decrease of intracellular Ca 2+ content caused by Ca 2+ reagent ionomycin could affect localization of CgCA in mantle tissue. The results indicated CgCA played essential roles in calcification and elevated CO 2 accelerated the mutual modulation between calcium and CgCA, implying reduced calcification rate and dissolved shells under OA. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. The influence of serotonin on fear learning.

    Directory of Open Access Journals (Sweden)

    Catherine Hindi Attar

    Full Text Available Learning of associations between aversive stimuli and predictive cues is the basis of Pavlovian fear conditioning and is driven by a mismatch between expectation and outcome. To investigate whether serotonin modulates the formation of such aversive cue-outcome associations, we used functional magnetic resonance imaging (fMRI and dietary tryptophan depletion to reduce brain serotonin (5-HT levels in healthy human subjects. In a Pavlovian fear conditioning paradigm, 5-HT depleted subjects compared to a non-depleted control group exhibited attenuated autonomic responses to cues indicating the upcoming of an aversive event. These results were closely paralleled by reduced aversive learning signals in the amygdala and the orbitofrontal cortex, two prominent structures of the neural fear circuit. In agreement with current theories of serotonin as a motivational opponent system to dopamine in fear learning, our data provide first empirical evidence for a role of serotonin in representing formally derived learning signals for aversive events.

  6. Auranofin, an Anti-Rheumatic Gold Compound, Modulates Apoptosis by Elevating the Intracellular Calcium Concentration ([Ca{sup 2+}]{sub i}) in MCF-7 Breast Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Varghese, Elizabeth; Büsselberg, Dietrich, E-mail: dib2015@qatar-med.cornell.edu [Weil Cornell Medical College in Qatar, Qatar Foundation-Education City, P.O. Box 24144 Doha (Qatar)

    2014-11-06

    Auranofin, a transition metal complex is used for the treatment of rheumatoid arthritis but is also an effective anti-cancer drug. We investigate the effects of Auranofin in inducing cell death by apoptosis and whether these changes are correlated to changes of intracellular calcium concentration ([Ca{sup 2+}]{sub i}) in breast cancer cells (MCF-7). Cytotoxicity of Auranofin was evaluated using MTS assay and the Trypan blue dye exclusion method. With fluorescent dyes SR-FLICA and 7-AAD apoptotic death and necrotic death were differentiated by Flow cytometry. A concentration dependent decrease in the viability occurred and cells were shifted to the apoptotic phase. Intracellular calcium ([Ca{sup 2+}]{sub i}) was recorded using florescence microscopy and a calcium sensitive dye (Fluo-4 AM) with a strong negative correlation (r = −0.713) to viability. Pharmacological modulators 2-APB (50 μM), Nimodipine (10 μM), Caffeine (10 mM), SKF 96365(20 μM) were used to modify calcium entry and release. Auranofin induced a sustained increase of [Ca{sup 2+}]{sub i} in a concentration and time dependent manner. The use of different blockers of calcium channels did not reveal the source for the rise of [Ca{sup 2+}]{sub i}. Overall, elevation of [Ca{sup 2+}]{sub i} by Auranofin might be crucial for triggering Ca{sup 2+}-dependent apoptotic pathways. Therefore, in anti-cancer therapy, modulating [Ca{sup 2+}]{sub i} should be considered as a crucial factor for the induction of cell death in cancer cells.

  7. Melatonin and N-acetyl-serotonin cross the red blood cell membrane and evoke calcium mobilization in malarial parasites

    Directory of Open Access Journals (Sweden)

    Hotta C.T.

    2003-01-01

    Full Text Available The duration of the intraerythrocytic cycle of Plasmodium is a key factor in the pathogenicity of this parasite. The simultaneous attack of the host red blood cells by the parasites depends on the synchronicity of their development. Unraveling the signals at the basis of this synchronicity represents a challenging biological question and may be very important to develop alternative strategies for therapeutic approaches. Recently, we reported that the synchrony of Plasmodium is modulated by melatonin, a host hormone that is synthesized only during the dark phases. Here we report that N-acetyl-serotonin, a melatonin precursor, also releases Ca2+ from isolated P. chabaudi parasites at micro- and nanomolar concentrations and that the release is blocked by 250 mM luzindole, an antagonist of melatonin receptors, and 20 mM U73122, a phospholipase C inhibitor. On the basis of confocal microscopy, we also report the ability of 0.1 µM melatonin and 0.1 µM N-acetyl-serotonin to cross the red blood cell membrane and to mobilize intracellular calcium in parasites previously loaded with the fluorescent calcium indicator Fluo-3 AM. The present data represent a step forward into the understanding of the signal transduction process in the host-parasite relationship by supporting the idea that the host hormone melatonin and N-acetyl-serotonin generate IP3 and therefore mobilize intracellular Ca2+ in Plasmodium inside red blood cells.

  8. Radio-prophylactic treatment with imidazole and/or Serotonin for Modulation of Tissue Catecholamines in whole body gamma irradiated Rats

    International Nuclear Information System (INIS)

    Hassan, S.H.M.; Roushdy, H.M.; Maklaad, Y.A.; El-Sayed, M.E.

    1995-01-01

    The present study has been conducted to evaluate the radioprotective effects of imidazole, serotonin and their combination on radiation induced reduction in catecholamine contents of the heart and adrenal glands in albino rat. The contribution of catecholamines in the radioprotective role of these agents has been evaluated. Whole-body gamma-irradiation (6 Gy) induced a significant reduction in heart and adrenal glands contents of catecholamine (epinephrine, norepinephrine and dopamine) one day post irradiation. Such reduction in catecholamine contents was more pronounced on the seventh day post exposure. Administration of imidazole (350 mg kg-1) or serotonin. (15 mg. kg-1) controlled the radiation induced reduction in catecholamine contents of heart as well as adrenal glands. Whereas, combination of imidazole (17 mg kg-1) serotonin (15 mg. kg-1) afforded a better protection than either agent given alone, in view that all the measured parameters could be fully restored to the values pre-irradiation. This study appreciate the usage of such combination as a prophylactic treatment for controlling the stress-state induced by irradiation which is associated with disturbed level of endogenous catecholamine contents in those sensitive patients undergoing radiotherapy. 2 tabs

  9. Peptide YY (3-36) modulates intracellular calcium through activation of the phosphatidylinositol pathway in hippocampal neurons.

    Science.gov (United States)

    Domingues, Michelle Flores; de Assis, Dênis Reis; Piovesan, Angela Regina; Belo, Cháriston André Dal; da Costa, Jaderson Costa

    2018-02-01

    Peptide YY (PYY) belongs to the neuropeptide Y (NPY) family, which also includes the pancreatic polypeptide (PP) and NPY. PYY is secreted by the intestinal L cells, being present in the blood stream in two active forms capable of crossing the blood brain barrier, PYY (1-36) and its cleavage product, PYY (3-36). PYY is a selective agonist for the Y2 receptor (Y2R) and these receptors are abundant in the hippocampus. Here we investigated the mechanisms by which PYY (3-36) regulates intracellular Ca 2+ concentrations ([Ca 2+ ] i ) in hippocampal neurons by employing a calcium imaging technique in hippocampal cultures. Alterations in [Ca 2+ ] i were detected by changes in the Fluo-4 AM reagent emission. PYY (3-36) significantly increased [Ca 2+ ] from the concentration of 10 -11 M as compared to the controls (infusion of HEPES-buffered solution (HBS) solution alone). The PYY (3-36)-increase in [Ca 2+ ] i remained unchanged even in Ca 2+ -free extracellular solutions. Sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase pump (SERCA pump) inhibition partially prevent the PYY (3-36)-increase of [Ca 2+ ] i and inositol 1,4,5-triphosphate receptor (IP3R) inhibition also decreased the PYY (3-36)-increase of [Ca 2+ ] i . Taken together, our data strongly suggest that PYY (3-36) mobilizes calcium from the neuronal endoplasmic reticulum (ER) stores towards the cytoplasm. Next, we showed that PYY (3-36) inhibited high K + -induced increases of [Ca 2+ ] i , suggesting that PYY (3-36) could also act by activating G-protein coupled inwardly rectifying potassium K + channels. Finally, the co-infusion of the Y2 receptor (Y2R) antagonist BIIE0246 with PYY (3-36) abolished the [Ca 2+ ] i increase induced by the peptide, suggesting that PYY (3-36)-induced [Ca 2+ ] i increase in hippocampal neurons occurs via Y2Rs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Brain serotonin content regulates the manifestation of tramadol-induced seizures in rats: disparity between tramadol-induced seizure and serotonin syndrome.

    Science.gov (United States)

    Fujimoto, Yohei; Funao, Tomoharu; Suehiro, Koichi; Takahashi, Ryota; Mori, Takashi; Nishikawa, Kiyonobu

    2015-01-01

    Tramadol-induced seizures might be pathologically associated with serotonin syndrome. Here, the authors investigated the relationship between serotonin and the seizure-inducing potential of tramadol. Two groups of rats received pretreatment to modulate brain levels of serotonin and one group was treated as a sham control (n = 6 per group). Serotonin modulation groups received either para-chlorophenylalanine or benserazide + 5-hydroxytryptophan. Serotonin, dopamine, and histamine levels in the posterior hypothalamus were then measured by microdialysis, while simultaneously infusing tramadol until seizure onset. In another experiment, seizure threshold with tramadol was investigated in rats intracerebroventricularly administered with either a serotonin receptor antagonist (methysergide) or saline (n = 6). Pretreatment significantly affected seizure threshold and serotonin fluctuations. The threshold was lowered in para-chlorophenylalanine group and raised in benserazide + 5-hydroxytryptophan group (The mean ± SEM amount of tramadol needed to induce seizures; sham: 43.1 ± 4.2 mg/kg, para-chlorophenylalanine: 23.2 ± 2.8 mg/kg, benserazide + 5-hydroxytryptophan: 59.4 ± 16.5 mg/kg). Levels of serotonin at baseline, and their augmentation with tramadol infusion, were less in the para-chlorophenylalanine group and greater in the benserazide + 5-hydroxytryptophan group. Furthermore, seizure thresholds were negatively correlated with serotonin levels (correlation coefficient; 0.71, P seizure threshold (P seizures, and that serotonin concentrations were negatively associated with seizure thresholds. Moreover, serotonin receptor antagonism precipitated seizure manifestation, indicating that tramadol-induced seizures are distinct from serotonin syndrome.

  11. Roselle Polyphenols Exert Potent Negative Inotropic Effects via Modulation of Intracellular Calcium Regulatory Channels in Isolated Rat Heart.

    Science.gov (United States)

    Lim, Yi-Cheng; Budin, Siti Balkis; Othman, Faizah; Latip, Jalifah; Zainalabidin, Satirah

    2017-07-01

    Roselle (Hibiscus sabdariffa Linn.) calyces have demonstrated propitious cardioprotective effects in animal and clinical studies; however, little is known about its action on cardiac mechanical function. This study was undertaken to investigate direct action of roselle polyphenols (RP) on cardiac function in Langendorff-perfused rat hearts. We utilized RP extract which consists of 12 flavonoids and seven phenolic acids (as shown by HPLC profiling) and has a safe concentration range between 125 and 500 μg/ml in this study. Direct perfusion of RP in concentration-dependent manner lowered systolic function of the heart as shown by lowered LVDP and dP/dt max , suggesting a negative inotropic effect. RP also reduced heart rate (negative chronotropic action) while simultaneously increasing maximal velocity of relaxation (positive lusitropic action). Conversely, RP perfusion increased coronary pressure, an indicator for improvement in coronary blood flow. Inotropic responses elicited by pharmacological agonists for L-type Ca 2+ channel [(±)-Bay K 8644], ryanodine receptor (4-chloro-m-cresol), β-adrenergic receptor (isoproterenol) and SERCA blocker (thapsigargin) were all abolished by RP. In conclusion, RP elicits negative inotropic, negative chronotropic and positive lusitropic responses by possibly modulating calcium entry, release and reuptake in the heart. Our findings have shown the potential use of RP as a therapeutic agent to treat conditions like arrhythmia.

  12. Interactions between Metal-binding Domains Modulate Intracellular Targeting of Cu(I)-ATPase ATP7B, as Revealed by Nanobody Binding*

    Science.gov (United States)

    Huang, Yiping; Nokhrin, Sergiy; Hassanzadeh-Ghassabeh, Gholamreza; Yu, Corey H.; Yang, Haojun; Barry, Amanda N.; Tonelli, Marco; Markley, John L.; Muyldermans, Serge; Dmitriev, Oleg Y.; Lutsenko, Svetlana

    2014-01-01

    The biologically and clinically important membrane transporters are challenging proteins to study because of their low level of expression, multidomain structure, and complex molecular dynamics that underlies their activity. ATP7B is a copper transporter that traffics between the intracellular compartments in response to copper elevation. The N-terminal domain of ATP7B (N-ATP7B) is involved in binding copper, but the role of this domain in trafficking is controversial. To clarify the role of N-ATP7B, we generated nanobodies that interact with ATP7B in vitro and in cells. In solution NMR studies, nanobodies revealed the spatial organization of N-ATP7B by detecting transient functionally relevant interactions between metal-binding domains 1–3. Modulation of these interactions by nanobodies in cells enhanced relocalization of the endogenous ATP7B toward the plasma membrane linking molecular and cellular dynamics of the transporter. Stimulation of ATP7B trafficking by nanobodies in the absence of elevated copper provides direct evidence for the important role of N-ATP7B structural dynamics in regulation of ATP7B localization in a cell. PMID:25253690

  13. [Role of hippocampal neuronal intracellular calcium overload in modulating cognitive dysfunction and the neuronprotective effect of mematine in a mouse model of chronic intermittent hypoxia].

    Science.gov (United States)

    Ming, Hong; Chen, Rui; Wang, Jing; Ju, Jingmei; Sun, Li; Zhang, Guoxing

    2014-12-01

    To investigate the role of hippocampal intracellular calcium overload in modulating cognitive dysfunction and the neuronprotective effect of mematine in a mouse model of chronic intermittent hypoxia. 45 ICR male mice were randomly divided into 3 groups: the unhandled control group (UC group, n = 15), the chronic intermittent hypoxia (CIH group, n = 15) and the pretreatment memantine group (MEM group, n = 15). CIH and MEM mice were subjected to intermittent hypoxia while UC mice to room air for 8 h per day during 4 weeks. Mice in the MEM group were pretreated with memantine (5 mg/kg) by intraperitoneal injection before the cycle started, and those in the UC group and the CIH group were treated with same volume of physiological saline. Neurobehavioral assessments were performed by Open filed and Morris water maze, [Ca²⁺]i in hippocampal neurons was evaluate by flow cytometry, and the expression of cleaved caspase-3, phospho-ERK1/2 in hippocampus were detected by Western blotting. Compared with the UC group, CIH mice displayed markedly more locomotor activity (P overload, neuron apoptosis, dephosphorylation of ERK1/2, which can be attenuated by memantine. Memantine may have a therapeutic effect in the neurocognitive impairment associated with OSAHS.

  14. Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review.

    Science.gov (United States)

    Gillman, P Ken

    2010-02-01

    The US Food and Drug Administration (FDA) have suggested that fatal serotonin syndrome (SS) is possible with selective serotonin reuptake inhibitors (SSRIs) and triptans: this warning affects millions of patients as these drugs are frequently given simultaneously. SS is a complex topic about which there is much misinformation. The misconception that 5-HT1A receptors can cause serious SS is still widely perpetuated, despite quality evidence that it is activation of the 5-HT2A receptor that is required for serious SS. This review considers SS involving serotonin agonists: ergotamine, lysergic acid diethylamide, bromocriptine, and buspirone, as well as triptans, and reviews the experimental foundation underpinning the latest understanding of SS. It is concluded that there is neither significant clinical evidence, nor theoretical reason, to entertain speculation about serious SS from triptans and SSRIs. The misunderstandings about SS exhibited by the FDA, and shared by the UK Medicines and Healthcare products Regulatory Agency (in relation to methylene blue), are an important issue with wide ramifications.

  15. Radioprotective action of serotonin

    Energy Technology Data Exchange (ETDEWEB)

    Vodop' yanova, L G; Vinogradova, M F [Leningradskij Gosudarstvennyj Univ. (USSR). Biologicheskij Nauchno-Issledovatel' skij Inst.

    1975-09-01

    Tests in vitro were performed to study the effect of serotonin on oxidative phosphorylation in the mitochondria of rat liver. Serotonin (2.10/sup -4/ M) was shown to suppress oxidation of ..cap alpha..-ketoglutaric acid without significantly changing succinic acid consumption. A comparison of the results obtained with those from the literature allowed to assume that the radioprotective effect of serotonin was based not only on its previously known ability to cause tissue hypoxia, but also on its ability to affect oxidation processes in mitochondria.

  16. [Relation between frequency modulation direction selectivity and forward masking of inferior collicular neurons: a study on in vivo intracellular recording in mice].

    Science.gov (United States)

    Fu, Zi-Ying; Zeng, Hong; Tang, Jia; Li, Jie; Li, Juan; Chen, Qi-Cai

    2013-06-25

    It has been reported that the frequency modulation (FM) or FM direction sensitivity and forward masking of central auditory neurons are related with the neural inhibition, but there are some arguments, because no direct evidence of inhibitory synaptic input was obtained in previous studies using extracellular recording. In the present study, we studied the relation between FM direction sensitivity and forward masking of the inferior collicular (IC) neurons using in vivo intracellular recordings in 20 Mus musculus Km mice. Thirty seven with complete data among 93 neurons were analyzed and discussed. There was an inhibitory area which consisted of inhibitory postsynaptic potentials (IPSP) at high frequency side of frequency tuning of up-sweep FM (FMU) sensitive neurons (n = 12) and at low frequency side of frequency tuning of down-sweep FM (FMD) selective neurons (n = 8), while there was no any inhibitory area at both sides of frequency tuning of non-FM sweep direction (FMN) sensitive neurons (n = 17). Therefore, these results show that the inhibitory area at low or high frequency side of frequency tuning is one of the mechanisms for forming FM sweep direction sensitivity of IC neurons. By comparison of forward masking produced by FMU and FMD sound stimuli in FMU, FMD and FMN neurons, the selective FM sounds could produce stronger forward masking than the non-selective in FMU and FMD neurons, while there was no forward masking difference between FMU and FMD stimuli in the FMN neurons. We suggest that the post-action potential IPSP is a potential mechanism for producing stronger forward masking in FMU and FMD neurons.

  17. Serotonin blockade delays learning performance in a cooperative fish.

    Science.gov (United States)

    Soares, Marta C; Paula, José R; Bshary, Redouan

    2016-09-01

    Animals use learning and memorizing to gather information that will help them to make ecologically relevant decisions. Neuro-modulatory adjustments enable them to make associations between stimuli and appropriate behavior. A key candidate for the modulation of cooperative behavior is serotonin. Previous research has shown that modulation of the serotonergic system spontaneously affects the behavior of the cleaner wrasse Labroides dimidiatus during interactions with so-called 'client' reef fish. Here, we asked whether shifts in serotonin function affect the cleaners' associative learning abilities when faced with the task to distinguish two artificial clients that differ in their value as a food source. We found that the administration of serotonin 1A receptor antagonist significantly slowed learning speed in comparison with saline treated fish. As reduced serotonergic signaling typically enhances fear, we discuss the possibility that serotonin may affect how cleaners appraise, acquire information and respond to client-derived stimuli via manipulation of the perception of danger.

  18. A Dualistic Conformational Response to Substrate Binding in the Human Serotonin Transporter Reveals a High Affinity State for Serotonin*

    Science.gov (United States)

    Bjerregaard, Henriette; Severinsen, Kasper; Said, Saida; Wiborg, Ove; Sinning, Steffen

    2015-01-01

    Serotonergic neurotransmission is modulated by the membrane-embedded serotonin transporter (SERT). SERT mediates the reuptake of serotonin into the presynaptic neurons. Conformational changes in SERT occur upon binding of ions and substrate and are crucial for translocation of serotonin across the membrane. Our understanding of these conformational changes is mainly based on crystal structures of a bacterial homolog in various conformations, derived homology models of eukaryotic neurotransmitter transporters, and substituted cysteine accessibility method of SERT. However, the dynamic changes that occur in the human SERT upon binding of ions, the translocation of substrate, and the role of cholesterol in this interplay are not fully elucidated. Here we show that serotonin induces a dualistic conformational response in SERT. We exploited the substituted cysteine scanning method under conditions that were sensitized to detect a more outward-facing conformation of SERT. We found a novel high affinity outward-facing conformational state of the human SERT induced by serotonin. The ionic requirements for this new conformational response to serotonin mirror the ionic requirements for translocation. Furthermore, we found that membrane cholesterol plays a role in the dualistic conformational response in SERT induced by serotonin. Our results indicate the existence of a subpopulation of SERT responding differently to serotonin binding than hitherto believed and that membrane cholesterol plays a role in this subpopulation of SERT. PMID:25614630

  19. Acute effects of nitroglycerin depend on both plasma and intracellular sulfhydryl compound levels in vivo. Effect of agents with different sulfhydryl-modulating properties

    DEFF Research Database (Denmark)

    Boesgaard, S; Poulsen, H E; Aldershvile, J

    1993-01-01

    in SH group concentrations (cysteine and glutathione [GSH]) affect the responsiveness to NTG in vivo. METHODS AND RESULTS: GSH and cysteine levels in plasma, vena cava, and aorta were measured after administration of N-acetylserine (placebo, n = 6), N-acetylcysteine (NAC, extracellular and intracellular......BACKGROUND: Changes in sulfhydryl (SH) compound availability may alter the hemodynamic effect of nitroglycerin (NTG). Data on the relation between NTG effect and thiol levels are, however, limited to in vitro experiments. The present study investigates how intracellular and extracellular changes...... SH donor, n = 6), oxothiazolidine (OXO, intracellular SH donor, n = 6), buthionine sulfoximine (BSO, intracellular GSH-depleting agent, n = 6), BSO+NAC (n = 6), and BSO+OXO (n = 6) in chronically catheterized conscious rats. In addition, the effect of 2.5 mg NTG/kg i.v. on mean arterial pressure (MAP...

  20. Kinetics of the membrane current mediated by serotonin 5-HT3 receptors in cultured mouse neuroblastoma cells.

    NARCIS (Netherlands)

    Neijt, H.C.; Plomp, J.J.; Vijverberg, H.P.M.

    1989-01-01

    1. Ionic currents mediated by serotonin 5-HT3 receptors were studied in the mouse neuroblastoma cell line N1E-115, using suction pipettes for intracellular perfusion and voltage clamp recording. The dependence of the kinetics of the membrane current on serotonin concentration was investigated. 2. At

  1. Modulation of intracellular calcium homeostasis by trimethyltin chloride in human tumour cells: Neuroblastoma SY5Y and cervix adenocarcinoma HeLa S3

    International Nuclear Information System (INIS)

    Florea, Ana-Maria; Splettstoesser, Frank; Dopp, Elke; Rettenmeier, Albert W.; Buesselberg, Dietrich

    2005-01-01

    Physiological modifications of intracellular Ca 2+ ([Ca 2+ ] i ) levels trigger and/or regulate a diversity of cellular activities (e.g. neurotransmitter release, synaptic plasticity, muscular contraction, cell proliferation), while calcium overloads could result in cytotoxicity. Previously, we have shown that trimethyltin chloride (Me 3 SnCl; TMT) modulates calcium homeostasis in cervix adenocarcinoma (HeLa S3) cells [Florea, A.-M., Dopp, E., Buesselberg, D., 2005. TMT induces elevated calcium transients in HeLa cells: types and levels of response. Cell Calcium 37, 252-258]. Here we compare [Ca 2+ ] i -changes induced by trimethyltin chloride in neuroblastoma SY5Y and HeLa S3 cells using calcium-sensitive dyes (fluo-4/AM (fluo-4) and rhod-2/AM (rhod-2)) and laser scanning microscopy (LSM). TMT-induced calcium elevations in neuroblastoma SY5Y as well as in HeLa S3 cells. [Ca 2+ ] i rose to a sustained plateau or to transient spikes. Overall, the detected averaged increase of the maximum calcium elevation were: 0.5 μM ∼125.6%; 5 μM ∼130.1%; 500 μM ∼145% in HeLa S3 cells and 0.5 μM ∼133.3%; 5 μM ∼136.1%; 500 μM ∼147.1% in neuroblastoma SY5Y cells. The calcium rise derived from internal stores did not significantly depend on the presence of calcium in the external solution: ∼109% (no calcium added) versus ∼117% (2 mM calcium; 5 μM TMT) in HeLa cells. This difference was similar in neuroblastoma SY5Y cells, were ∼127% versus ∼136% increase (5 μM TMT) were measured. Staining of calcium stores with rhod-2 showed a TMT-induced [Ca 2+ ] i -decrease in the stores followed by an increase of the calcium concentration in the nuclei of the two cell lines tested. Our results suggest that toxic effects in human tumour cells after exposure to trimethyltin compounds might be due to an elevation of [Ca 2+ ] i

  2. Positive regulation of raphe serotonin neurons by serotonin 2B receptors.

    Science.gov (United States)

    Belmer, Arnauld; Quentin, Emily; Diaz, Silvina L; Guiard, Bruno P; Fernandez, Sebastian P; Doly, Stéphane; Banas, Sophie M; Pitychoutis, Pothitos M; Moutkine, Imane; Muzerelle, Aude; Tchenio, Anna; Roumier, Anne; Mameli, Manuel; Maroteaux, Luc

    2018-06-01

    Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT 2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT 2B receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT 2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT 2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT 2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT 2B -receptor stimulation by BW723C86 counteracted 5-HT 1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT 2B receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b 5-HTKO mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT 2B receptor expression in serotonergic neurons. In Htr2b 5-HTKO mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2b lox/lox mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT 1A -autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT 2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT 2B receptor acts as a direct positive modulator of serotonin Pet1

  3. Brain-derived neurotrophic factor (Val66Met and serotonin transporter (5-HTTLPR polymorphisms modulate plasticity in inhibitory control performance over time but independent of inhibitory control training

    Directory of Open Access Journals (Sweden)

    Sören Enge

    2016-07-01

    Full Text Available Several studies reported training-induced improvements in executive function tasks and also observed transfer to untrained tasks. However, the results are mixed and there is large interindividual variability within and across studies. Given that training-related performance changes would require modification, growth or differentiation at the cellular and synaptic level in the brain, research on critical moderators of brain plasticity potentially explaining such changes is needed. In the present study, a pre-post-follow-up design (N=122 and a three-weeks training of two response inhibition tasks (Go/NoGo and Stop-Signal was employed and genetic variation (Val66Met in the brain-derived neurotrophic factor (BDNF promoting differentiation and activity-dependent synaptic plasticity was examined. Because Serotonin (5-HT signaling and the interplay of BDNF and 5-HT are known to critically mediate brain plasticity, genetic variation in the 5-HT transporter (5-HTTLPR was also addressed. The overall results show that the kind of training (i.e., adaptive vs. non-adaptive did not evoke genotype-dependent differences. However, in the Go/NoGo task, better inhibition performance (lower commission errors were observed for BDNF Val/Val genotype carriers compared to Met-allele ones supporting similar findings from other cognitive tasks. Additionally, a gene-gene interaction suggests a more impulsive response pattern (faster responses accompanied by higher commission error rates in homozygous l-allele carriers relative to those with the s-allele of 5-HTTLPR. This, however, is true only in the presence of the Met-allele of BDNF, while the Val/Val genotype seems to compensate for such non-adaptive responding. Intriguingly, similar results were obtained for the Stop-Signal task. Here, differences emerged at post-testing, while no differences were observed at T1. In sum, although no genotype-dependent differences between the relevant training groups emerged suggesting

  4. Association between salivary serotonin and the social sharing of happiness.

    Directory of Open Access Journals (Sweden)

    Masahiro Matsunaga

    Full Text Available Although human saliva contains the monoamine serotonin, which plays a key role in the modulation of emotional states, the association between salivary serotonin and empathic ability remains unclear. In order to elucidate the associations between salivary serotonin levels, trait empathy, and the sharing effect of emotions (i.e., sharing emotional experiences with others, we performed a vignette-based study. Participants were asked to evaluate their happiness when they experience several hypothetical life events, whereby we manipulated the valence of the imagined event (positive, neutral, or negative, as well as the presence of a friend (absent, positive, or negative. Results indicated that the presence of a happy friend significantly enhanced participants' happiness. Correlation analysis demonstrated that salivary serotonin levels were negatively correlated with happiness when both the self and friend conditions were positive. Correlation analysis also indicated a negative relationship between salivary serotonin levels and trait empathy (particularly in perspective taking, which was measured by the Interpersonal Reactivity Index. Furthermore, an exploratory multiple regression analysis suggested that mothers' attention during childhood predicted salivary serotonin levels. Our findings indicate that empathic abilities and the social sharing of happiness decreases as a function of salivary serotonin levels.

  5. Association between salivary serotonin and the social sharing of happiness.

    Science.gov (United States)

    Matsunaga, Masahiro; Ishii, Keiko; Ohtsubo, Yohsuke; Noguchi, Yasuki; Ochi, Misaki; Yamasue, Hidenori

    2017-01-01

    Although human saliva contains the monoamine serotonin, which plays a key role in the modulation of emotional states, the association between salivary serotonin and empathic ability remains unclear. In order to elucidate the associations between salivary serotonin levels, trait empathy, and the sharing effect of emotions (i.e., sharing emotional experiences with others), we performed a vignette-based study. Participants were asked to evaluate their happiness when they experience several hypothetical life events, whereby we manipulated the valence of the imagined event (positive, neutral, or negative), as well as the presence of a friend (absent, positive, or negative). Results indicated that the presence of a happy friend significantly enhanced participants' happiness. Correlation analysis demonstrated that salivary serotonin levels were negatively correlated with happiness when both the self and friend conditions were positive. Correlation analysis also indicated a negative relationship between salivary serotonin levels and trait empathy (particularly in perspective taking), which was measured by the Interpersonal Reactivity Index. Furthermore, an exploratory multiple regression analysis suggested that mothers' attention during childhood predicted salivary serotonin levels. Our findings indicate that empathic abilities and the social sharing of happiness decreases as a function of salivary serotonin levels.

  6. Coiled-coil domain-dependent homodimerization of intracellular barley immune receptors defines a minimal functional module for triggering cell death

    NARCIS (Netherlands)

    Maekawa, T.; Cheng, W.; Spiridon, L.N.; Töller, A.; Lukasik, E.; Saijo, Y.; Liu, P.; Shen, Q.H.; Micluta, M.A.; Somssich, I.E.; Takken, F.L.W.; Petrescu, A.J.; Chai, J.; Schulze-Lefert, P.

    2011-01-01

    Plants and animals have evolved structurally related innate immune sensors, designated NLRs, to detect intracellular nonself molecules. NLRs are modular, consisting of N-terminal coiled-coil (CC) or TOLL/interleukin-1 receptor (TIR) domains, a central nucleotide-binding (NB) domain, and C-terminal

  7. Modulation of firing and synaptic transmission of serotonergic neurons by intrinsic G protein-coupled receptors and ion channels

    Directory of Open Access Journals (Sweden)

    Takashi eMaejima

    2013-05-01

    Full Text Available Serotonergic neurons project to virtually all regions of the CNS and are consequently involved in many critical physiological functions such as mood, sexual behavior, feeding, sleep/wake cycle, memory, cognition, blood pressure regulation, breathing and reproductive success. Therefore serotonin release and serotonergic neuronal activity have to be precisely controlled and modulated by interacting brain circuits to adapt to specific emotional and environmental states. We will review the current knowledge about G protein-coupled receptors and ion channels involved in the regulation of serotonergic system, how their regulation is modulating the intrinsic activity of serotonergic neurons and its transmitter release and will discuss the latest methods for controlling the modulation of serotonin release and intracellular signaling in serotonergic neurons in vitro and in vivo.

  8. N-Acetylcysteine-induced vasodilatation is modulated by KATP channels, Na+/K+-ATPase activity and intracellular calcium concentration: An in vitro study.

    Science.gov (United States)

    Vezir, Özden; Çömelekoğlu, Ülkü; Sucu, Nehir; Yalın, Ali Erdinç; Yılmaz, Şakir Necat; Yalın, Serap; Söğüt, Fatma; Yaman, Selma; Kibar, Kezban; Akkapulu, Merih; Koç, Meryem İlkay; Seçer, Didem

    2017-08-01

    In this study, we aimed to investigate the role of ATP-sensitive potassium (K ATP ) channel, Na + /K + -ATPase activity, and intracellular calcium levels on the vasodilatory effect of N-acetylcysteine (NAC) in thoracic aorta by using electrophysiological and molecular techniques. Rat thoracic aorta ring preparations and cultured thoracic aorta cells were divided into four groups as control, 2mM NAC, 5mM NAC, and 10mM NAC. Thoracic aorta rings were isolated from rats for measurements of relaxation responses and Na + /K + -ATPase activity. In the cultured thoracic aorta cells, we measured the currents of K ATP channel, the concentration of intracellular calcium and mRNA expression level of K ATP channel subunits (KCNJ8, KCNJ11, ABCC8 and ABCC9). The relaxation rate significantly increased in all NAC groups compared to control. Similarly, Na + /K + - ATPase activity also significantly decreased in NAC groups. Outward K ATP channel current significantly increased in all NAC groups compared to the control group. Intracellular calcium concentration decreased significantly in all groups with compared control. mRNA expression level of ABCC8 subunit significantly increased in all NAC groups compared to the control group. Pearson correlation analysis showed that relaxation rate was significantly associated with K ATP current, intracellular calcium concentration, Na + /K + -ATPase activity and mRNA expression level of ABCC8 subunit. Our findings suggest that NAC relaxes vascular smooth muscle cells through a direct effect on K ATP channels, by increasing outward K+ flux, partly by increasing mRNA expression of K ATP subunit ABCC8, by decreasing in intracellular calcium and by decreasing in Na + /K + -ATPase activity. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  9. Immunomodulatory Effects Mediated by Serotonin

    Directory of Open Access Journals (Sweden)

    Rodrigo Arreola

    2015-01-01

    Full Text Available Serotonin (5-HT induces concentration-dependent metabolic effects in diverse cell types, including neurons, entherochromaffin cells, adipocytes, pancreatic beta-cells, fibroblasts, smooth muscle cells, epithelial cells, and leukocytes. Three classes of genes regulating 5-HT function are constitutively expressed or induced in these cells: (a membrane proteins that regulate the response to 5-HT, such as SERT, 5HTR-GPCR, and the 5HT3-ion channels; (b downstream signaling transduction proteins; and (c enzymes controlling 5-HT metabolism, such as IDO and MAO, which can generate biologically active catabolites, including melatonin, kynurenines, and kynurenamines. This review covers the clinical and experimental mechanisms involved in 5-HT-induced immunomodulation. These mechanisms are cell-specific and depend on the expression of serotonergic components in immune cells. Consequently, 5-HT can modulate several immunological events, such as chemotaxis, leukocyte activation, proliferation, cytokine secretion, anergy, and apoptosis. The effects of 5-HT on immune cells may be relevant in the clinical outcome of pathologies with an inflammatory component. Major depression, fibromyalgia, Alzheimer disease, psoriasis, arthritis, allergies, and asthma are all associated with changes in the serotonergic system associated with leukocytes. Thus, pharmacological regulation of the serotonergic system may modulate immune function and provide therapeutic alternatives for these diseases.

  10. Serotonin 5-HT2C receptor-independent expression of hypothalamic NOR1, a novel modulator of food intake and energy balance, in mice

    Energy Technology Data Exchange (ETDEWEB)

    Nonogaki, Katsunori, E-mail: knonogaki-tky@umin.ac.jp [Center of Excellence, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine (Japan); Department of Lifestyle Medicine, Biomedical Engineering Center, Tohoku University (Japan); Kaji, Takao [Department of Lifestyle Medicine, Biomedical Engineering Center, Tohoku University (Japan); Ohba, Yukie; Sumii, Makiko [Center of Excellence, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine (Japan); Wakameda, Mamoru; Tamari, Tomohiro [Charles River Laboratories Japan, Inc. (Japan)

    2009-08-21

    NOR1, Nur77 and Nurr1 are orphan nuclear receptors and members of the NR4A subfamily. Here, we report that the expression of hypothalamic NOR1 was remarkably decreased in mildly obese {beta}-endorphin-deficient mice and obese db/db mice with the leptin receptor mutation, compared with age-matched wild-type mice, whereas there were no genotypic differences in the expression of hypothalamic Nur77 or Nurr1 in these animals. The injection of NOR1 siRNA oligonucleotide into the third cerebral ventricle significantly suppressed food intake and body weight in mice. On the other hand, the decreases in hypothalamic NOR1 expression were not found in non-obese 5-HT2C receptor-deficient mice. Moreover, systemic administration of m-chlorophenylpiperazine (mCPP), a 5-HT2C/1B receptor agonist, had no effect on hypothalamic NOR1 expression, while suppressing food intake in {beta}-endorphin-deficient mice. These findings suggest that 5-HT2C receptor-independent proopiomelanocortin-derived peptides regulate the expression of hypothalamic NOR1, which is a novel modulator of feeding behavior and energy balance.

  11. Serotonin 5-HT2C receptor-independent expression of hypothalamic NOR1, a novel modulator of food intake and energy balance, in mice

    International Nuclear Information System (INIS)

    Nonogaki, Katsunori; Kaji, Takao; Ohba, Yukie; Sumii, Makiko; Wakameda, Mamoru; Tamari, Tomohiro

    2009-01-01

    NOR1, Nur77 and Nurr1 are orphan nuclear receptors and members of the NR4A subfamily. Here, we report that the expression of hypothalamic NOR1 was remarkably decreased in mildly obese β-endorphin-deficient mice and obese db/db mice with the leptin receptor mutation, compared with age-matched wild-type mice, whereas there were no genotypic differences in the expression of hypothalamic Nur77 or Nurr1 in these animals. The injection of NOR1 siRNA oligonucleotide into the third cerebral ventricle significantly suppressed food intake and body weight in mice. On the other hand, the decreases in hypothalamic NOR1 expression were not found in non-obese 5-HT2C receptor-deficient mice. Moreover, systemic administration of m-chlorophenylpiperazine (mCPP), a 5-HT2C/1B receptor agonist, had no effect on hypothalamic NOR1 expression, while suppressing food intake in β-endorphin-deficient mice. These findings suggest that 5-HT2C receptor-independent proopiomelanocortin-derived peptides regulate the expression of hypothalamic NOR1, which is a novel modulator of feeding behavior and energy balance.

  12. Diphenyl diselenide ameliorates monosodium glutamate induced anxiety-like behavior in rats by modulating hippocampal BDNF-Akt pathway and uptake of GABA and serotonin neurotransmitters.

    Science.gov (United States)

    Rosa, Suzan Gonçalves; Quines, Caroline Brandão; Stangherlin, Eluza Curte; Nogueira, Cristina Wayne

    2016-03-01

    Monosodium glutamate (MSG), a flavor enhancer used in food, administered to neonatal rats causes neuronal lesions and leads to anxiety when adulthood. We investigated the anxiolytic-like effect of diphenyl diselenide (PhSe)2 and its mechanisms on anxiety induced by MSG. Neonatal male and female Wistar rats received a subcutaneous injection of saline (0.9%) or MSG (4 g/kg/day) from the 1st to 10th postnatal day. At 60 days of life, the rats received (PhSe)2 (1mg/kg/day) or vehicle by the intragastric route for 7 days. The spontaneous locomotor activity (LAM), elevated plus maze test (EPM) and contextual fear conditioning test (CFC) as well as neurochemical ([(3)H]GABA and [(3)H]5-HT uptake) and molecular analyses (Akt and p-Akt and BDNF levels) were carried out after treatment with (PhSe)2. Neonatal exposure to MSG increased all anxiogenic parameters in LAM, EPM and CFC tests. MSG increased GABA and 5-HT uptake in hippocampus of rats, without changing uptake in cerebral cortex. The levels of BDNF and p-Akt were reduced in hippocampus of rats treated with MSG. The administration of (PhSe)2 to rats reversed all behavioral anxiogenic parameters altered by MSG. The increase in hippocampal GABA and 5-HT uptake induced by MSG was reversed by (PhSe)2. (PhSe)2 reversed the reduction in hippocampal BDNF and p-Akt levels induced by MSG. In conclusion, the anxiolytic-like action of (PhSe)2 in rats exposed to MSG during their neonatal period is related to its modulation of hippocampal GABA and 5-HT uptake as well as the BDNF-Akt pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Serotonin metabolism in rat brain

    International Nuclear Information System (INIS)

    Schutte, H.H.

    1976-01-01

    The metabolism of serotonin in rat brain was studied by measuring specific activities of tryptophan in plasma and of serotonin, 5-hydroxyindole acetic acid and tryptophan in the brain after intravenous injection of tritiated tryptophan. For a detailed analysis of the specific activities, a computer simulation technique was used. It was found that only a minor part of serotonin in rat brain is synthesized from tryptophan rapidly transported from the blood. It is suggested that the brain tryptophan originates from brain proteins. It was also found that the serotonin in rat brain is divided into more than one metabolic compartment

  14. Serotonin Regulates the Feeding and Reproductive Behaviors of Pratylenchus penetrans.

    Science.gov (United States)

    Han, Ziduan; Boas, Stephanie; Schroeder, Nathan E

    2017-07-01

    The success of all plant-parasitic nematodes is dependent on the completion of several complex behaviors. The lesion nematode Pratylenchus penetrans is an economically important parasite of a diverse range of plant hosts. Unlike the cyst and root-knot nematodes, P. penetrans moves both within and outside of the host roots and can feed from both locations. Adult females of P. penetrans require insemination by actively moving males for reproduction and can lay eggs both within and outside of the host roots. We do not have a complete understanding of the molecular basis for these behaviors. One candidate modulator of these behaviors is the neurotransmitter serotonin. Previous research demonstrated an effect of exogenously applied serotonin on the feeding and male mating behaviors of cyst and root-knot nematodes. However, there are no data on the role of exogenous serotonin on lesion nematodes. Similarly, there are no data on the presence and function of endogenous serotonin in any plant-parasitic nematode. Here, we establish that exogenous serotonin applied to P. penetrans regulates both feeding and sex-specific behaviors. Furthermore, using immunohistochemistry and pharmacological assays, our data suggest that P. penetrans utilizes endogenous serotonin to regulate both feeding and sex-specific behaviors.

  15. Nanoparticles for intracellular-targeted drug delivery

    International Nuclear Information System (INIS)

    Paulo, Cristiana S O; Pires das Neves, Ricardo; Ferreira, Lino S

    2011-01-01

    Nanoparticles (NPs) are very promising for the intracellular delivery of anticancer and immunomodulatory drugs, stem cell differentiation biomolecules and cell activity modulators. Although initial studies in the area of intracellular drug delivery have been performed in the delivery of DNA, there is an increasing interest in the use of other molecules to modulate cell activity. Herein, we review the latest advances in the intracellular-targeted delivery of short interference RNA, proteins and small molecules using NPs. In most cases, the drugs act at different cellular organelles and therefore the drug-containing NPs should be directed to precise locations within the cell. This will lead to the desired magnitude and duration of the drug effects. The spatial control in the intracellular delivery might open new avenues to modulate cell activity while avoiding side-effects.

  16. The Effects of Serotonin in Immune Cells

    OpenAIRE

    Herr, Nadine; Bode, Christoph; Duerschmied, Daniel

    2017-01-01

    Serotonin [5-hydroxytryptamine (5-HT)] plays an important role in many organs as a peripheral hormone. Most of the body’s serotonin is circulating in the bloodstream, transported by blood platelets and is released upon activation. The functions of serotonin are mediated by members of the 7 known mammalian serotonin receptor subtype classes (15 known subtypes), the serotonin transporter (SERT), and by covalent binding of serotonin to different effector proteins. Almost all immune cells express...

  17. Dependence of cerebral arterial contractions on intracellularly stored Ca++.

    Science.gov (United States)

    Sasaki, T; Kassell, N F; Zuccarello, M

    1986-01-01

    The purpose of the present study was to evaluate the dependence of the arterial contractions induced by different vasoactive agents upon intracellularly stored calcium in canine versus monkey cerebral arteries. The potency for inducing contractions in Ca++-free media was in the order of 9,11-epithio-11,12-metano-thromboxane A2 (STXA2) greater than prostaglandin F2 alpha (PGF2 alpha) much greater than serotonin greater than K+ in canine basilar arteries, and STXA2 greater than PGF2 alpha much greater than serotonin = K+ in monkey basilar arteries.

  18. Glucose and phosphate modulation of intracellular 45Ca incorporated into pancreatic islets during culture in the absence and presence of serum

    International Nuclear Information System (INIS)

    Bergsten, P.

    1985-01-01

    The effects of glucose and phosphate on the intracellular 45 Ca content were measured in β cell-rich pancreatic islets cultured in media containing or lacking serum. Irrespective of the glucose and serum concentrations there were no or very small increments of 45 Ca contents when phosphate was raised from 0.8 to 5.8 mM during culture for 1 day. However, after 7 days of culture in serum-free medium there was a massive accumulation of 45 Ca in the islets in response to the higher phosphate concentration. Glucose markedly reduced, and serum eliminated, the extensive accumulation probably due to increased cell viability. In the cells cultured in the presence of serum, raising the glucose concentration from 1.0 to 5.5 mM resulted in an increased incorporation of 45 Ca. This effect was particularly pronounced after culture for 7 days in 5.8 mM phosphate. A further increase of glucose to 20 mM reduced the 45 Ca content. The results are consistent with the concept that glucose both stimulates 45 Ca uptake into different β-cell pools and degranulates the cell with associated loss of intracellular calcium from the granular calcium pool. (author)

  19. Osmotic Control of opuA Expression in Bacillus subtilis and Its Modulation in Response to Intracellular Glycine Betaine and Proline Pools

    Science.gov (United States)

    Hoffmann, Tamara; Wensing, Annette; Brosius, Margot; Steil, Leif; Völker, Uwe

    2013-01-01

    Glycine betaine is an effective osmoprotectant for Bacillus subtilis. Its import into osmotically stressed cells led to the buildup of large pools, whose size was sensitively determined by the degree of the osmotic stress imposed. The amassing of glycine betaine caused repression of the formation of an osmostress-adaptive pool of proline, the only osmoprotectant that B. subtilis can synthesize de novo. The ABC transporter OpuA is the main glycine betaine uptake system of B. subtilis. Expression of opuA was upregulated in response to both sudden and sustained increases in the external osmolarity. Nonionic osmolytes exerted a stronger inducing effect on transcription than ionic osmolytes, and this was reflected in the development of corresponding OpuA-mediated glycine betaine pools. Primer extension analysis and site-directed mutagenesis pinpointed the osmotically controlled opuA promoter. Deviations from the consensus sequence of SigA-type promoters serve to keep the transcriptional activity of the opuA promoter low in the absence of osmotic stress. opuA expression was downregulated in a finely tuned manner in response to increases in the intracellular glycine betaine pool, regardless of whether this osmoprotectant was imported or was newly synthesized from choline. Such an effect was also exerted by carnitine, an effective osmoprotectant for B. subtilis that is not a substrate for the OpuA transporter. opuA expression was upregulated in a B. subtilis mutant that was unable to synthesize proline in response to osmotic stress. Collectively, our data suggest that the intracellular solute pool is a key determinant for the osmotic control of opuA expression. PMID:23175650

  20. Intracellular calcium is a target of modulation of apoptosis in MCF-7 cells in the presence of IgA adsorbed to polyethylene glycol

    Science.gov (United States)

    Honorio-França, Adenilda Cristina; Nunes, Gabriel Triches; Fagundes, Danny Laura Gomes; de Marchi, Patrícia Gelli Feres; Fernandes, Rubian Trindade da Silva; França, Juliana Luzia; França-Botelho, Aline do Carmo; Moraes, Lucélia Campelo Albuquerque; Varotti, Fernando de Pilla; França, Eduardo Luzía

    2016-01-01

    Purpose Clinical and epidemiological studies have indicated that breastfeeding has a protective effect on breast cancer risk. Protein-based drugs, including antibodies, are being developed to attain better forms of cancer therapy. Secretory IgA (SIgA) is the antibody class in human breast milk, and its activity can be linked to the protective effect of breastfeeding. The aim of this study was to investigate the effect of polyethylene glycol (PEG) microspheres with adsorbed SIgA on MCF-7 human breast cancer cells. Methods The PEG microspheres were characterized by flow cytometry and fluorescence microscopy. The MCF-7 cells were obtained from American Type Culture Collection. MCF-7 cells were pre-incubated for 24 hours with or without SIgA (100 ng/mL), PEG microspheres or SIgA adsorbed in PEG microspheres (100 ng/mL). Viability, intracellular calcium release, and apoptosis in MCF-7 cells were determined by flow cytometry. Results Fluorescence microscopy and flow cytometry analyses revealed that SIgA was able to adsorb to the PEG microspheres. The MCF-7 cells that were incubated with PEG microspheres with adsorbed SIgA showed decreased viability. MCF-7 cells that were incubated with SIgA or PEG microspheres with adsorbed SIgA had increased intracellular Ca2+ levels. In the presence of SIgA, an increase in the percentage of apoptotic cells was observed. The highest apoptosis index was observed when the cells were treated with PEG microspheres with adsorbed SIgA. Conclusion These data suggest that colostral SIgA adsorbed to PEG microspheres has antitumor effects on human MCF-7 breast cancer cells and that the presence of large amounts of this protein in secreted breast milk may provide protection against breast tumors in women who breastfed. PMID:26893571

  1. Localization of 3H-serotonin in the adrenal medullary cells of newborn rats

    International Nuclear Information System (INIS)

    Sudar, F.; Csaba, G.

    1979-01-01

    Newborn rats received 25 μCi 3 H-5-hydroxytryptophan (5-HTP); 30, 60 min or 5 hours later the adrenal glands were removed. Electronmicroscopic autoradiography was carried out after fixation and embedding. As in the cells 5-HTP is formed into serotonin, the distribution of radioactivity actually represents the distribution of serotonin. Activity was found on the cellular, nuclear and catecholamine granule-membranes, and in the nucleus. The activity increased as a function of time at all the above mentioned sites, and in line with this more and more empty catecholamine-granules appeared. Data indicate the existence of intracellular serotonin-receptors and the role of serotonin in the release of catecholamines. (L.E.)

  2. Apoptosis of leukemia K562 and Molt-4 cells induced by emamectin benzoate involving mitochondrial membrane potential loss and intracellular Ca2+ modulation.

    Science.gov (United States)

    Yun, Xinming; Rao, Wenbing; Xiao, Ciying; Huang, Qingchun

    2017-06-01

    Leukemia threatens millions of people's health and lives, and the pesticide-induced leukemia has been increasingly concerned because of the etiologic exposure. In this paper, cytotoxic effect of emamectin benzoate (EMB), an excellent natural-product insecticide, was evaluated through monitoring cell viability, cell apoptosis, mitochondrial membrane potential and intracellular Ca 2+ concentration ([Ca 2+ ] i ) in leukemia K562 and Molt-4 cells. Following the exposure to EMB, cell viability was decreased and positive apoptosis of K562 and Molt-4 cells was increased in a concentration- and time- dependent fashion. In the treatment of 10μM EMB, apoptotic cells accounted for 93.0% to K562 cells and 98.9% to Molt-4 cells based on the control, meanwhile, 63.47% of K562 cells and 81.15% of Molt-4 cells exhibited late apoptotic and necrotic features with damaged cytoplasmic membrane. 48h exposure to 10μM EMB increased significantly the great number of cells with mitochondrial membrane potential (MMP) loss, and the elevation of [Ca 2+ ] i level was peaked and persisted within 70s in K562 cells whilst 50s in Molt-4 cells. Moreover, a stronger cytotoxicity of EMB was further observed than that of imatinib. The results authenticate the efficacious effect of EMB as a potential anti-leukemia agent and an inconsistency with regard to insecticide-induced leukemia. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Sex Differences in Serotonin 1 Receptor Binding in Rat Brain

    Science.gov (United States)

    Fischette, Christine T.; Biegon, Anat; McEwen, Bruce S.

    1983-10-01

    Male and female rats exhibit sex differences in binding by serotonin 1 receptors in discrete areas of the brain, some of which have been implicated in the control of ovulation and of gonadotropin release. The sex-specific changes in binding, which occur in response to the same hormonal (estrogenic) stimulus, are due to changes in the number of binding sites. Castration alone also affects the number of binding sites in certain areas. The results lead to the conclusion that peripheral hormones modulate binding by serotonin 1 receptors. The status of the serotonin receptor system may affect the reproductive capacity of an organism and may be related to sex-linked emotional disturbances in humans.

  4. Serotonin enhances the impact of health information on food choice.

    Science.gov (United States)

    Vlaev, Ivo; Crockett, Molly J; Clark, Luke; Müller, Ulrich; Robbins, Trevor W

    2017-06-01

    Serotonin has been implicated in promoting self-control, regulation of hunger and physiological homeostasis, and regulation of caloric intake. However, it remains unclear whether the effects of serotonin on caloric intake reflect purely homeostatic mechanisms, or whether serotonin also modulates cognitive processes involved in dietary decision making. We investigated the effects of an acute dose of the serotonin reuptake inhibitor citalopram on choices between food items that differed along taste and health attributes, compared with placebo and the noradrenaline reuptake inhibitor atomoxetine. Twenty-seven participants attended three sessions and received single doses of atomoxetine, citalopram, and placebo in a double-blind randomised cross-over design. Relative to placebo, citalopram increased choices of more healthy foods over less healthy foods. Citalopram also increased the emphasis on health considerations in decisions. Atomoxetine did not affect decision making relative to placebo. The results support the hypothesis that serotonin may influence food choice by enhancing a focus on long-term goals. The findings are relevant for understanding decisions about food consumption and also for treating health conditions such as eating disorders and obesity.

  5. Modulation of intracellular Ca2+ via L-type calcium channels in heart cells by the autoantibody directed against the second extracellular loop of the alpha1-adrenoceptors.

    Science.gov (United States)

    Bkaily, Ghassan; El-Bizri, Nesrine; Bui, Michel; Sukarieh, Rami; Jacques, Danielle; Fu, Michael L X

    2003-03-01

    The effects of methoxamine, a selective alpha1-adrenergic receptor agonist, and the autoantibody directed against the second extracellular loop of alpha1-adrenoceptors were studied on intracellular free Ca2+ levels using confocal microscopy and ionic currents using the whole-cell patch clamp technique in single cells of 10-day-old embryonic chick and 20-week-old fetal human hearts. We observed that like methoxamine, the autoantibody directed against the second extracellular loop of alpha1-adrenoreceptors significantly increased the L-type calcium current (I(Ca(L))) but had no effect on the T-type calcium current (I(Ca(T))), the delayed outward potassium current, or the fast sodium current. This effect of the autoantibody was prevented by a prestimulation of the receptors with methoxamine and vice versa. Moreover, treating the cells with prazosin, a selective alpha1-adrenergic receptor antagonist blocked the methoxamine and the autoantibody-induced increase in I(Ca(L)), respectively. In absence of prazosin, both methoxamine and the autoantibody showed a substantial enhancement in the frequency of cell contraction and that of the concomitant cytosolic and nuclear free Ca2+ variations. The subsequent addition of nifedipine, a specific L-type Ca2+ channel blocker, reversed not only the methoxamine or the autoantibody-induced effect but also completely abolished cell contraction. These results demonstrated that functional alpha1-adrenoceptors exist in both 10-day-old embryonic chick and 20-week-old human fetal hearts and that the autoantibody directed against the second extracellular loop of this type of receptors plays an important role in stimulating their activity via activation of L-type calcium channels. This loop seems to have a functional significance by being the target of alpha1-receptor agonists like methoxamine.

  6. Serotonin and decision making processes.

    NARCIS (Netherlands)

    Homberg, J.R.

    2012-01-01

    Serotonin (5-HT) is an important player in decision making. Serotonergic antidepressant, anxiolytic and antipsychotic drugs are extensively used in the treatment of neuropsychiatric disorders characterized by impaired decision making, and exert both beneficial and harmful effects in patients.

  7. Intracellular Secretory Leukoprotease Inhibitor Modulates Inositol 1,4,5-Triphosphate Generation and Exerts an Anti-Inflammatory Effect on Neutrophils of Individuals with Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

    Directory of Open Access Journals (Sweden)

    Emer P. Reeves

    2013-01-01

    Full Text Available Secretory leukoprotease inhibitor (SLPI is an anti-inflammatory protein present in respiratory secretions. Whilst epithelial cell SLPI is extensively studied, neutrophil associated SLPI is poorly characterised. Neutrophil function including chemotaxis and degranulation of proteolytic enzymes involves changes in cytosolic calcium (Ca2+ levels which is mediated by production of inositol 1,4,5-triphosphate (IP3 in response to G-protein-coupled receptor (GPCR stimuli. The aim of this study was to investigate the intracellular function of SLPI and the mechanism-based modulation of neutrophil function by this antiprotease. Neutrophils were isolated from healthy controls (n=10, individuals with cystic fibrosis (CF (n=5 or chronic obstructive pulmonary disease (COPD (n=5. Recombinant human SLPI significantly inhibited fMet-Leu-Phe (fMLP and interleukin(IL-8 induced neutrophil chemotaxis (P<0.05 and decreased degranulation of matrix metalloprotease-9 (MMP-9, hCAP-18, and myeloperoxidase (MPO (P<0.05. The mechanism of inhibition involved modulation of cytosolic IP3 production and downstream Ca2+ flux. The described attenuation of Ca2+ flux was overcome by inclusion of exogenous IP3 in electropermeabilized cells. Inhibition of IP3 generation and Ca2+ flux by SLPI may represent a novel anti-inflammatory mechanism, thus strengthening the attractiveness of SLPI as a potential therapeutic molecule in inflammatory airway disease associated with excessive neutrophil influx including CF, non-CF bronchiectasis, and COPD.

  8. Serotonin Decreases the Gain of Visual Responses in Awake Macaque V1.

    Science.gov (United States)

    Seillier, Lenka; Lorenz, Corinna; Kawaguchi, Katsuhisa; Ott, Torben; Nieder, Andreas; Pourriahi, Paria; Nienborg, Hendrikje

    2017-11-22

    Serotonin, an important neuromodulator in the brain, is implicated in affective and cognitive functions. However, its role even for basic cortical processes is controversial. For example, in the mammalian primary visual cortex (V1), heterogenous serotonergic modulation has been observed in anesthetized animals. Here, we combined extracellular single-unit recordings with iontophoresis in awake animals. We examined the role of serotonin on well-defined tuning properties (orientation, spatial frequency, contrast, and size) in V1 of two male macaque monkeys. We find that in the awake macaque the modulatory effect of serotonin is surprisingly uniform: it causes a mainly multiplicative decrease of the visual responses and a slight increase in the stimulus-selective response latency. Moreover, serotonin neither systematically changes the selectivity or variability of the response, nor the interneuronal correlation unexplained by the stimulus ("noise-correlation"). The modulation by serotonin has qualitative similarities with that for a decrease in stimulus contrast, but differs quantitatively from decreasing contrast. It can be captured by a simple additive change to a threshold-linear spiking nonlinearity. Together, our results show that serotonin is well suited to control the response gain of neurons in V1 depending on the animal's behavioral or motivational context, complementing other known state-dependent gain-control mechanisms. SIGNIFICANCE STATEMENT Serotonin is an important neuromodulator in the brain and a major target for drugs used to treat psychiatric disorders. Nonetheless, surprisingly little is known about how it shapes information processing in sensory areas. Here we examined the serotonergic modulation of visual processing in the primary visual cortex of awake behaving macaque monkeys. We found that serotonin mainly decreased the gain of the visual responses, without systematically changing their selectivity, variability, or covariability. This

  9. Understanding the Role of Serotonin in Female Hypoactive Sexual Desire Disorder and Treatment Options.

    Science.gov (United States)

    Croft, Harry A

    2017-12-01

    The neurobiology of sexual response is driven in part by dopamine and serotonin-the former modulating excitatory pathways and the latter regulating inhibitory pathways. Neurobiological underpinnings of hypoactive sexual desire disorder (HSDD) are seemingly related to overactive serotonin activity that results in underactive dopamine activity. As such, pharmacologic agents that decrease serotonin, increase dopamine, or some combination thereof, have therapeutic potential for HSDD. To review the role of serotonin in female sexual function and the effects of pharmacologic interventions that target the serotonin system in the treatment of HSDD. Searches of the Medline database for articles on serotonin and female sexual function. Relevant articles from the peer-reviewed literature were included. Female sexual response is regulated not only by the sex hormones but also by several neurotransmitters. It is postulated that dopamine, norepinephrine, oxytocin, and melanocortins serve as key neuromodulators for the excitatory pathways, whereas serotonin, opioids, and endocannabinoids serve as key neuromodulators for the inhibitory pathways. Serotonin appears to be a key inhibitory modulator of sexual desire, because it decreases the ability of excitatory systems to be activated by sexual cues. Centrally acting drugs that modulate the excitatory and inhibitory pathways involved in sexual desire (eg, bremelanotide, bupropion, buspirone, flibanserin) have been investigated as treatment options for HSDD. However, only flibanserin, a multifunctional serotonin agonist and antagonist (5-hydroxytryptamine [5-HT] 1A receptor agonist and 5-HT 2A receptor antagonist), is currently approved for the treatment of HSDD. The central serotonin system is 1 biochemical target for medications intended to treat HSDD. This narrative review integrates findings from preclinical studies and clinical trials to elucidate neurobiological underpinnings of HSDD but is limited to 1 neurotransmitter system

  10. Peripheral serotonin regulates maternal calcium trafficking in mammary epithelial cells during lactation in mice.

    Directory of Open Access Journals (Sweden)

    Jimena Laporta

    Full Text Available Lactation is characterized by massive transcellular flux of calcium, from the basolateral side of the mammary alveolar epithelium (blood into the ductal lumen (milk. Regulation of calcium transport during lactation is critical for maternal and neonatal health. The monoamine serotonin (5-HT is synthesized by the mammary gland and functions as a homeostatic regulation of lactation. Genetic ablation of tryptophan hydroxylase 1 (Tph1, which encodes the rate-limiting enzyme in non-neuronal serotonin synthesis, causes a deficiency in circulating serotonin. As a consequence maternal calcium concentrations decrease, mammary epithelial cell morphology is altered, and cell proliferation is decreased during lactation. Here we demonstrate that serotonin deficiency decreases the expression and disrupts the normal localization of calcium transporters located in the apical (PMCA2 and basolateral (CaSR, ORAI-1 membranes of the lactating mammary gland. In addition, serotonin deficiency decreases the mRNA expression of calcium transporters located in intracellular compartments (SERCA2, SPCA1 and 2. Mammary expression of serotonin receptor isoform 2b and its downstream pathways (PLCβ3, PKC and MAP-ERK1/2 are also decreased by serotonin deficiency, which might explain the numerous phenotypic alterations described above. In most cases, addition of exogenous 5-hydroxy-L-tryptophan to the Tph1 deficient mice rescued the phenotype. Our data supports the hypothesis that serotonin is necessary for proper mammary gland structure and function, to regulate blood and mammary epithelial cell transport of calcium during lactation. These findings can be applicable to the treatment of lactation-induced hypocalcemia in dairy cows and can have profound implications in humans, given the wide-spread use of selective serotonin reuptake inhibitors as antidepressants during pregnancy and lactation.

  11. Theophylline and adenosine modulate the inflammatory functions of the human neutrophil by exerting an opposing influence on the stimulus-induced increase in intracellular calcium

    International Nuclear Information System (INIS)

    Schmeichel Morley, C.J.

    1988-01-01

    Based on evidence that endogenously-produced adenosine inhibited neutrophil responses, the influence of methylxanthine bronchodilators on neutrophil responses stimulated in vitro by n-formyl-methionyl-leucyl-phenylalanine (fMLP) was examined. At concentrations between 10/sup /minus/5/ M and 10/sup /minus/4/ M, theophylline potentiated lysosomal enzyme release by 30 to 50%, superoxide anion formation by 30 to 60%, and neutrophil aggregation. Theophylline at concentrations >10/sup /minus/4/ M inhibited the same responses by >90%. Adenosine deaminase mimicked, whereas adenosine reversed the theophylline potentiation. A potential role for calcium in the modulation of the neutrophil responses by theophylline and adenosine was explored. Theophylline enhanced by >150% the fMLP-stimulated increase in cytoplasmic calcium concentration ([Ca 2+ ]/sub i/) at time points between 5 and 90 sec as measured by Fura-2. Adenosine deaminase induced a comparable enhancement, whereas 3 /times/ 10/sup /minus/7/ M adenosine and 10/sup /minus/7/ M N-ethylcarboxamideadenosine decreased the [Ca 2+ ]/sub i/ in fMLP-stimulated neutrophils. Extracellular calcium was not required for the opposing influences of theophylline and adenosine and neither compound altered fMLP-stimulated 45 Ca uptake at the early time points

  12. 6-OHDA-induced apoptosis and mitochondrial dysfunction are mediated by early modulation of intracellular signals and interaction of Nrf2 and NF-κB factors

    International Nuclear Information System (INIS)

    Tobón-Velasco, Julio C.; Limón-Pacheco, Jorge H.; Orozco-Ibarra, Marisol; Macías-Silva, Marina; Vázquez-Victorio, Genaro; Cuevas, Elvis; Ali, Syed F.

    2013-01-01

    6-Hydroxydopamine (6-OHDA) is a neurotoxin that generates an experimental model of Parkinson's disease in rodents and is commonly employed to induce a lesion in dopaminergic pathways. The characterization of those molecular mechanisms linked to 6-OHDA-induced early toxicity is needed to better understand the cellular events further leading to neurodegeneration. The present work explored how 6-OHDA triggers early downstream signaling pathways that activate neurotoxicity in the rat striatum. Mitochondrial function, caspases-dependent apoptosis, kinases signaling (Akt, ERK 1/2, SAP/JNK and p38) and crosstalk between nuclear factor kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) were evaluated at early times post-lesion. We found that 6-OHDA initiates cell damage via mitochondrial complex I inhibition, cytochrome c and apoptosis-inducing factor (AIF) release, as well as activation of caspases 9 and 3 to induce apoptosis, kinase signaling modulation and NF-κB-mediated inflammatory responses, accompanied by inhibition of antioxidant systems regulated by the Nrf2 pathway. Our results suggest that kinases SAP/JNK and p38 up-regulation may play a role in the early stages of 6-OHDA toxicity to trigger intrinsic pathways for apoptosis and enhanced NF-κB activation. In turn, these cellular events inhibit the activation of cytoprotective mechanisms, thereby leading to a condition of general damage

  13. Protective effects of Cassia tora leaves in experimental cataract by modulating intracellular communication, membrane co-transporters, energy metabolism and the ubiquitin-proteasome pathway.

    Science.gov (United States)

    Sreelakshmi, V; Abraham, Annie

    2017-12-01

    Cataract is the clouding of eye lens which causes impairment in vision and accounts for the leading factor of global blindness. Functional food-based prevention of cataract finds application in vision research because of its availability and easy access to all classes of the society. Cassia tora Linn. (Caesalpinaceae) is an edible plant mentioned in the traditional systems of medicine for whole body health, especially to the eyes. The present study evaluates the potential of ethyl acetate fraction of Cassia tora leaves (ECT) on experimental cataract. Cataract was induced by a single subcutaneous injection of sodium selenite (4 μg/g body weight) on 10th day. ECT was supplemented orally from 8th day up to 12th day at a concentration of 5 μg/g body weight and marker parameters were evaluated after 30 days. The production of MPO and the activation of calpain were reduced 52.17% and 36.67% by ECT in lens tissue, respectively. It modulated the energy status by significantly increasing the activity of CCO 1 (55.56%) and ATP production (41.88%). ECT maintained the ionic balance in the lens by reducing the level of sodium (50%) and increasing the level of potassium (42.5%). It also reduced cell junction modifications and preserved a functional ubiquitin-proteasome pathway. The results reinforce the growing attention on wild plant food resources for preventive protection against cataract. The data suggest the value of Cassia tora leaves as a functional food for ameliorating cataract pathology.

  14. Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration.

    NARCIS (Netherlands)

    Matondo, R.B.; Punt, C.J.A.; Homberg, J.R.; Toussaint, M.J.; Kisjes, R.; Korporaal, S.J.; Akkerman, J.W.; Cuppen, E.; Bruin, A. de

    2009-01-01

    The serotonin transporter is implicated in the uptake of the vasoconstrictor serotonin from the circulation into the platelets, where 95% of all blood serotonin is stored and released in response to vascular injury. In vivo studies indicated that platelet-derived serotonin mediates liver

  15. Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration

    NARCIS (Netherlands)

    Matondo, R.B.; Punt, C.; Homberg, J.R.; Toussaint, M.J.; Kisjes, R.; Korporaal, S.J.; Akkerman, J.W.; Cuppen, E.; de Bruin, A.

    2009-01-01

    The serotonin transporter is implicated in the uptake of the vasoconstrictor serotonin from the circulation into the platelets, where 95% of all blood serotonin is stored and released in response to vascular injury. In vivo studies indicated that platelet-derived serotonin mediates liver

  16. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

    Science.gov (United States)

    Serotonin and norepinephrine reuptake inhibitors (SNRIs) Antidepressant SNRIs help relieve depression symptoms, such as irritability and sadness, ... effects they may cause. By Mayo Clinic Staff Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a class ...

  17. Marine Inspired 2-(5-Halo-1H-indol-3-yl)-N,N-dimethylethanamines as Modulators of Serotonin Receptors: An Example Illustrating the Power of Bromine as Part of the Uniquely Marine Chemical Space.

    Science.gov (United States)

    Ibrahim, Mohamed A; El-Alfy, Abir T; Ezel, Kelly; Radwan, Mohamed O; Shilabin, Abbas G; Kochanowska-Karamyan, Anna J; Abd-Alla, Howaida I; Otsuka, Masami; Hamann, Mark T

    2017-08-09

    In previous studies, we have isolated several marine indole alkaloids and evaluated them in the forced swim test (FST) and locomotor activity test, revealing their potential as antidepressant and sedative drug leads. Amongst the reported metabolites to display such activities was 5-bromo- N , N -dimethyltryptamine. Owing to the importance of the judicious introduction of halogens into drug candidates, we synthesized two series built on a 2-(1 H -indol-3-yl)- N , N -dimethylethanamine scaffold with different halogen substitutions. The synthesized compounds were evaluated for their in vitro and in vivo antidepressant and sedative activities using the mouse forced swim and locomotor activity tests. Receptor binding studies of these compounds to serotonin (5-HT) receptors were conducted. Amongst the prepared compounds, 2-(1 H -indol-3-yl)- N , N -dimethyl-2-oxoacetamide ( 1a ), 2-(5-bromo-1 H -indol-3-yl)- N , N -dimethyl-2-oxoacetamide ( 1d ), 2-(1 H -indol-3-yl)- N , N -dimethylethanamine ( 2a ), 2-(5-chloro-1 H -indol-3-yl)- N , N -dimethylethanamine ( 2c ), 2-(5-bromo-1 H -indol-3-yl)- N , N -dimethylethanamine ( 2d ), and 2-(5-iodo-1 H -indol-3-yl)- N , N -dimethylethanamine ( 2e ) have been shown to possess significant antidepressant-like action, while compounds 2c , 2d , and 2e exhibited potent sedative activity. Compounds 2a , 2c , 2d , and 2e showed nanomolar affinities to serotonin receptors 5-HT 1A and 5-HT₇. The in vitro data indicates that the antidepressant action exerted by these compounds in vivo is mediated, at least in part, via interaction with serotonin receptors. The data presented here shows the valuable role that bromine plays in providing novel chemical space and electrostatic interactions. Bromine is ubiquitous in the marine environment and a common element of marine natural products.

  18. The expression and role of serotonin receptor 5HTR2A in canine osteoblasts and an osteosarcoma cell line.

    Science.gov (United States)

    Bracha, Shay; Viall, Austin; Goodall, Cheri; Stang, Bernadette; Ruaux, Craig; Seguin, Bernard; Chappell, Patrick E

    2013-12-12

    The significance of the serotonergic system in bone physiology and, more specifically, the importance of the five hydroxytryptamine receptor 2A (5HTR2A) in normal osteoblast proliferation have been previously described; however the role of serotonin in osteosarcoma remains unclear. Particularly, the expression and function of 5HTR2A in canine osteosarcoma has not yet been studied, thus we sought to determine if this indoleamine modulates cellular proliferation in vitro. Using real time quantitative reverse transcription PCR and immunoblot analyses, we explored receptor expression and signaling differences between non-neoplastic canine osteoblasts (CnOb) and an osteosarcoma cell line (COS). To elucidate specific serotonergic signaling pathways triggered by 5HTR2A, we performed immunoblots for ERK and CREB. Finally, we compared cell viability and the induction of apoptosis in the presence 5HTR2A agonists and antagonists. 5HTR2A was overexpressed in the malignant cell line in comparison to normal cells. In CnOb cells, ERK phosphorylation (ERK-P) decreased in response to both serotonin and a specific 5HTR2A antagonist, ritanserin. In contrast, ERK-P abundance increased in COS cells following either treatment. While endogenous CREB was undetectable in CnOb, CREB was observed constitutively in COS, with expression and exhibited increased CREB phosphorylation following escalating concentrations of ritanserin. To determine the influence of 5HTR2A signaling on cell viability we challenged cells with ritanserin and serotonin. Our findings confirmed that serotonin treatment promoted cell viability in malignant cells but not in normal osteoblasts. Conversely, ritanserin reduced cell viability in both the normal and osteosarcoma cells. Further, ritanserin induced apoptosis in COS at the same concentrations associated with decreased cell viability. These findings confirm the existence of a functional 5HTR2A in a canine osteosarcoma cell line. Results indicate that intracellular

  19. Expression and function of serotonin 2A and 2B receptors in the mammalian respiratory network.

    Directory of Open Access Journals (Sweden)

    Marcus Niebert

    Full Text Available Neurons of the respiratory network in the lower brainstem express a variety of serotonin receptors (5-HTRs that act primarily through adenylyl cyclase. However, there is one receptor family including 5-HT(2A, 5-HT(2B, and 5-HT(2C receptors that are directed towards protein kinase C (PKC. In contrast to 5-HT(2ARs, expression and function of 5-HT(2BRs within the respiratory network are still unclear. 5-HT(2BR utilizes a Gq-mediated signaling cascade involving calcium and leading to activation of phospholipase C and IP3/DAG pathways. Based on previous studies, this signal pathway appears to mediate excitatory actions on respiration. In the present study, we analyzed receptor expression in pontine and medullary regions of the respiratory network both at the transcriptional and translational level using quantitative RT-PCR and self-made as well as commercially available antibodies, respectively. In addition we measured effects of selective agonists and antagonists for 5-HT(2ARs and 5-HT(2BRs given intra-arterially on phrenic nerve discharges in juvenile rats using the perfused brainstem preparation. The drugs caused significant changes in discharge activity. Co-administration of both agonists revealed a dominance of the 5-HT(2BR. Given the nature of the signaling pathways, we investigated whether intracellular calcium may explain effects observed in the respiratory network. Taken together, the results of this study suggest a significant role of both receptors in respiratory network modulation.

  20. Serotonin and Blood Pressure Regulation

    Science.gov (United States)

    Morrison, Shaun F.; Davis, Robert Patrick; Barman, Susan M.

    2012-01-01

    5-Hydroxytryptamine (5-HT; serotonin) was discovered more than 60 years ago as a substance isolated from blood. The neural effects of 5-HT have been well investigated and understood, thanks in part to the pharmacological tools available to dissect the serotonergic system and the development of the frequently prescribed selective serotonin-reuptake inhibitors. By contrast, our understanding of the role of 5-HT in the control and modification of blood pressure pales in comparison. Here we focus on the role of 5-HT in systemic blood pressure control. This review provides an in-depth study of the function and pharmacology of 5-HT in those tissues that can modify blood pressure (blood, vasculature, heart, adrenal gland, kidney, brain), with a focus on the autonomic nervous system that includes mechanisms of action and pharmacology of 5-HT within each system. We compare the change in blood pressure produced in different species by short- and long-term administration of 5-HT or selective serotonin receptor agonists. To further our understanding of the mechanisms through which 5-HT modifies blood pressure, we also describe the blood pressure effects of commonly used drugs that modify the actions of 5-HT. The pharmacology and physiological actions of 5-HT in modifying blood pressure are important, given its involvement in circulatory shock, orthostatic hypotension, serotonin syndrome and hypertension. PMID:22407614

  1. ROLE OF SEROTONIN IN FISH REPRODUCTION

    Directory of Open Access Journals (Sweden)

    Parvathy ePrasad

    2015-06-01

    Full Text Available The neuroendocrine mechanism regulates reproduction through the hypothalamo-pituitary-gonadal (HPG axis which is evolutionarily conserved in vertebrates. The HPG axis is regulated by a variety of internal as well as external factors. Serotonin, a monoamine neurotransmitter, is involved in a wide range of reproductive functions. In mammals, serotonin regulates sexual behaviours, gonadotropin release and gonadotropin-release hormone (GnRH secretion. However, the serotonin system in teleost may play unique role in the control of reproduction as the mechanism of reproductive control in teleosts is not always the same as in the mammalian models. In fish, the serotonin system is also regulated by natural environmental factors as well as chemical substances. In particular, selective serotonin reuptake inhibitors (SSRIs are commonly detected as pharmaceutical contaminants in the natural environment. Those factors may influence fish reproductive functions via the serotonin system. This review summarizes the functional significance of serotonin in the teleosts reproduction.

  2. Immunodetection of the serotonin transporter protein is a more valid marker for serotonergic fibers than serotonin

    DEFF Research Database (Denmark)

    Nielsen, Kirsten; Brask, Dorthe; Knudsen, Gitte M.

    2006-01-01

    Tracking serotonergic pathways in the brain through immunodetection of serotonin has widely been used for the anatomical characterization of the serotonergic system. Immunostaining for serotonin is also frequently applied for the visualization of individual serotonin containing fibers...... and quantification of serotonin positive fibers has been widely used to detect changes in the serotonergic innervation. However, particularly in conditions with enhanced serotonin metabolism the detection level of serotonin may lead to an underestimation of the true number of serotonergic fibers. The serotonin...... immunostained for serotonin and SERT protein and colocalization was quantified in several brain areas by confocal microscopy. In comparison with untreated rats, MAO inhibitor treated rats had a significantly higher number (almost 200% increase) of serotonin immunopositive fibers whereas no difference...

  3. Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac

    Science.gov (United States)

    Zhou, L; Ma, S L; Yeung, P K K; Wong, Y H; Tsim, K W K; So, K F; Lam, L C W; Chung, S K

    2016-01-01

    Intracellular cAMP and serotonin are important modulators of anxiety and depression. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) also known as Prozac, is widely used against depression, potentially by activating cAMP response element-binding protein (CREB) and increasing brain-derived neurotrophic factor (BDNF) through protein kinase A (PKA). However, the role of Epac1 and Epac2 (Rap guanine nucleotide exchange factors, RAPGEF3 and RAPGEF4, respectively) as potential downstream targets of SSRI/cAMP in mood regulations is not yet clear. Here, we investigated the phenotypes of Epac1 (Epac1−/−) or Epac2 (Epac2−/−) knockout mice by comparing them with their wild-type counterparts. Surprisingly, Epac2−/− mice exhibited a wide range of mood disorders, including anxiety and depression with learning and memory deficits in contextual and cued fear-conditioning tests without affecting Epac1 expression or PKA activity. Interestingly, rs17746510, one of the three single-nucleotide polymorphisms (SNPs) in RAPGEF4 associated with cognitive decline in Chinese Alzheimer's disease (AD) patients, was significantly correlated with apathy and mood disturbance, whereas no significant association was observed between RAPGEF3 SNPs and the risk of AD or neuropsychiatric inventory scores. To further determine the detailed role of Epac2 in SSRI/serotonin/cAMP-involved mood disorders, we treated Epac2−/− mice with a SSRI, Prozac. The alteration in open field behavior and impaired hippocampal cell proliferation in Epac2−/− mice were alleviated by Prozac. Taken together, Epac2 gene polymorphism is a putative risk factor for mood disorders in AD patients in part by affecting the hippocampal neurogenesis. PMID:27598965

  4. Type I Interferon-Mediated Skewing of the Serotonin Synthesis Is Associated with Severe Disease in Systemic Lupus Erythematosus

    Science.gov (United States)

    Lood, Christian; Tydén, Helena; Gullstrand, Birgitta; Klint, Cecilia; Wenglén, Christina; Nielsen, Christoffer T.; Heegaard, Niels H. H.; Jönsen, Andreas; Kahn, Robin; Bengtsson, Anders A.

    2015-01-01

    Serotonin, a highly pro-inflammatory molecule released by activated platelets, is formed by tryptophan. Tryptophan is also needed in the production of kynurenine, a process mediated by the type I interferon (IFN)-regulated rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO). The aim of this study was to investigate levels of serotonin in patients with the autoimmune disease systemic lupus erythematosus (SLE), association to clinical phenotype and possible involvement of IDO in regulation of serotonin synthesis. Serotonin levels were measured in serum and plasma from patients with SLE (n=148) and healthy volunteers (n=79) by liquid chromatography and ELISA, as well as intracellularly in platelets by flow cytometry. We found that SLE patients had decreased serotonin levels in serum (p=0.01) and platelets (pserotonin (p=0.0008) as well as increased IDO activity (pserotonin levels in platelets and serum (pserotonin levels were associated with severe SLE with presence of anti-dsDNA antibodies and nephritis. In all, reduced serum serotonin levels in SLE patients were related to severe disease phenotype, including nephritis, suggesting involvement of important immunopathological processes. Further, our data suggest that type I IFNs, present in SLE sera, are able to up-regulate IDO expression, which may lead to decreased serum serotonin levels. PMID:25897671

  5. Oxytocin and Serotonin Brain Mechanisms in the Nonhuman Primate.

    Science.gov (United States)

    Lefevre, Arthur; Richard, Nathalie; Jazayeri, Mina; Beuriat, Pierre-Aurélien; Fieux, Sylvain; Zimmer, Luc; Duhamel, Jean-René; Sirigu, Angela

    2017-07-12

    strategy is to study the interaction between these systems. Here we depict the interplay between oxytocin and serotonin in the nonhuman primate brain. We found that oxytocin provokes the release of serotonin, which in turn impacts on the serotonin 1A receptor system, by modulating its availability. This happens in several key brain regions for social behavior, such as the amygdala and insula. This novel finding can open ways to advance treatments where drugs are combined to influence several neurotransmission networks. Copyright © 2017 the authors 0270-6474/17/376741-10$15.00/0.

  6. Intracellular cholesterol level regulates sensitivity of glioblastoma cells against temozolomide-induced cell death by modulation of caspase-8 activation via death receptor 5-accumulation and activation in the plasma membrane lipid raft.

    Science.gov (United States)

    Yamamoto, Yutaro; Tomiyama, Arata; Sasaki, Nobuyoshi; Yamaguchi, Hideki; Shirakihara, Takuya; Nakashima, Katsuhiko; Kumagai, Kosuke; Takeuchi, Satoru; Toyooka, Terushige; Otani, Naoki; Wada, Kojiro; Narita, Yoshitaka; Ichimura, Koichi; Sakai, Ryuichi; Namba, Hiroki; Mori, Kentaro

    2018-01-01

    Development of resistance against temozolomide (TMZ) in glioblastoma (GBM) after continuous treatment with TMZ is one of the critical problems in clinical GBM therapy. Intracellular cholesterol regulates cancer cell biology, but whether intracellular cholesterol is involved in TMZ resistance of GBM cells remains unclear. The involvement of intracellular cholesterol in acquired resistance against TMZ in GBM cells was investigated. Intracellular cholesterol levels were measured in human U251 MG cells with acquired TMZ resistance (U251-R cells) and TMZ-sensitive control U251 MG cells (U251-Con cells), and found that the intracellular cholesterol level was significantly lower in U251-R cells than in U251-Con cells. In addition, treatment by intracellular cholesterol remover, methyl-beta cyclodextrin (MβCD), or intracellular cholesterol inducer, soluble cholesterol (Chol), regulated TMZ-induced U251-Con cell death in line with changes in intracellular cholesterol level. Involvement of death receptor 5 (DR5), a death receptor localized in the plasma membrane, was evaluated. TMZ without or with MβCD and/or Chol caused accumulation of DR5 into the plasma membrane lipid raft and formed a complex with caspase-8, an extrinsic caspase cascade inducer, reflected in the induction of cell death. In addition, treatment with caspase-8 inhibitor or knockdown of DR5 dramatically suppressed U251-Con cell death induced by combination treatment with TMZ, MβCD, and Chol. Combined treatment of Chol with TMZ reversed the TMZ resistance of U251-R cells and another GBM cell model with acquired TMZ resistance, whereas clinical antihypercholesterolemia agents at physiological concentrations suppressed TMZ-induced cell death of U251-Con cells. These findings suggest that intracellular cholesterol level affects TMZ treatment of GBM mediated via a DR5-caspase-8 mechanism. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Intrinsic neuromodulation in the Tritonia swim CPG: serotonin mediates both neuromodulation and neurotransmission by the dorsal swim interneurons.

    Science.gov (United States)

    Katz, P S; Frost, W N

    1995-12-01

    1. Neuromodulation has previously been shown to be intrinsic to the central pattern generator (CPG) circuit that generates the escape swim of the nudibranch mollusk Tritonia diomedea; the dorsal swim interneurons (DSIs) make conventional monosynaptic connections and evoke neuromodulatory effects within the swim motor circuit. The conventional synaptic potentials evoked by a DSI onto cerebral neuron 2 (C2) and onto the dorsal flexion neurons (DFNs) consist of a fast excitatory postsynaptic potential (EPSP) followed by a prolonged slow EPSP. In their neuromodulatory role, the DSIs produce an enhancement of the monosynaptic connections made by C2 onto other CPG circuit interneurons and onto efferent flexion neurons. Previous work showed that the DSIs are immunoreactive for serotonin. Here we provide evidence that both the neurotransmission and the neuromodulation evoked by the DSIs are produced by serotonin, and that these effects may be pharmacologically separable. 2. Previously it was shown that bath-applied serotonin both mimics and occludes the modulation of the C2 synapses by the DSIs. Here we find that pressure-applied puffs of serotonin mimic both the fast and slow EPSPs evoked by a DSI onto a DFN, whereas high concentrations of bath-applied serotonin occlude both of these synaptic components. 3. Consistent with the hypothesis that serotonin mediates the actions of the DSIs, the serotonin reuptake inhibitor imipramine prolongs the duration of the fast DSI-DFN EPSP, increases the amplitude of the slow DSI-DFN EPSP, and increases both the amplitude and duration of the modulation of the C2-DFN synapse by the DSIs. 4. Two serotonergic antagonists were found that block the actions of the DSIs. Gramine blocks the fast DSI-DFN EPSP, and has far less of an effect on the slow EPSP and the modulation. Gramine also diminishes the depolarization evoked by pressure-applied serotonin, showing that it is a serotonin antagonist in this system. In contrast, methysergide greatly

  8. Context-dependent fluctuation of serotonin in the auditory midbrain: the influence of sex, reproductive state and experience

    Science.gov (United States)

    Hanson, Jessica L.; Hurley, Laura M.

    2014-01-01

    In the face of changing behavioral situations, plasticity of sensory systems can be a valuable mechanism to facilitate appropriate behavioral responses. In the auditory system, the neurotransmitter serotonin is an important messenger for context-dependent regulation because it is sensitive to both external events and internal state, and it modulates neural activity. In male mice, serotonin increases in the auditory midbrain region, the inferior colliculus (IC), in response to changes in behavioral context such as restriction stress and social contact. Female mice have not been measured in similar contexts, although the serotonergic system is sexually dimorphic in many ways. In the present study, we investigated the effects of sex, experience and estrous state on the fluctuation of serotonin in the IC across contexts, as well as potential relationships between behavior and serotonin. Contrary to our expectation, there were no sex differences in increases of serotonin in response to a restriction stimulus. Both sexes had larger increases in second exposures, suggesting experience plays a role in serotonergic release in the IC. In females, serotonin increased during both restriction and interactions with males; however, the increase was more rapid during restriction. There was no effect of female estrous phase on the serotonergic change for either context, but serotonin was related to behavioral activity in females interacting with males. These results show that changes in behavioral context induce increases in serotonin in the IC by a mechanism that appears to be uninfluenced by sex or estrous state, but may depend on experience and behavioral activity. PMID:24198252

  9. Serotonin-induced down-regulation of cell surface serotonin transporter

    DEFF Research Database (Denmark)

    Jørgensen, Trine Nygaard; Christensen, Peter Møller; Gether, Ulrik

    2014-01-01

    The serotonin transporter (SERT) terminates serotonergic signaling and enables refilling of synaptic vesicles by mediating reuptake of serotonin (5-HT) released into the synaptic cleft. The molecular and cellular mechanisms controlling SERT activity and surface expression are not fully understood...

  10. SEROTONIN METABOLISM FOLLOWING PLATINUM-BASED CHEMOTHERAPY COMBINED WITH THE SEROTONIN TYPE-3 ANTAGONIST TROPISETRON

    NARCIS (Netherlands)

    SCHRODER, CP; VANDERGRAAF, WTA; KEMA, IP; GROENEWEGEN, A; SLEIJFER, DT; DEVRIES, EGE

    1995-01-01

    The administration of platinum-based chemotherapy induces serotonin release from the enterochromaffin cells, causing nausea and vomiting. This study was conducted to evaluate parameters of serotonin metabolism following platinum-based chemotherapy given in combination with the serotonin type-3

  11. The Role of Serotonin (5-HT) in Behavioral Control: Findings from Animal Research and Clinical Implications

    Science.gov (United States)

    Sanchez, CL; Biskup, CS; Herpertz, S; Gaber, TJ; Kuhn, CM; Hood, SH

    2015-01-01

    The neurotransmitters serotonin and dopamine both have a critical role in the underlying neurobiology of different behaviors. With focus on the interplay between dopamine and serotonin, it has been proposed that dopamine biases behavior towards habitual responding, and with serotonin offsetting this phenomenon and directing the balance toward more flexible, goal-directed responding. The present focus paper stands in close relationship to the publication by Worbe et al. (2015), which deals with the effects of acute tryptophan depletion, a neurodietary physiological method to decrease central nervous serotonin synthesis in humans for a short period of time, on the balance between hypothetical goal-directed and habitual systems. In that research, acute tryptophan depletion challenge administration and a following short-term reduction in central nervous serotonin synthesis were associated with a shift of behavioral performance towards habitual responding, providing further evidence that central nervous serotonin function modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. In the present focus paper, we discuss the findings by Worbe and colleagues in light of animal experiments as well as clinical implications and discuss potential future avenues for related research. PMID:25991656

  12. Effect of plasma membrane fluidity on serotonin transport by endothelial cells

    International Nuclear Information System (INIS)

    Block, E.R.; Edwards, D.

    1987-01-01

    To evaluate the effect of plasma membrane fluidity of lung endothelial cells on serotonin transport, porcine pulmonary artery endothelial cells were incubated for 3 h with either 0.1 mM cholesterol hemisuccinate, 0.1 mM cis-vaccenic acid, or vehicle (control), after which plasma membrane fluidity and serotinin transport were measured. Fluorescence spectroscopy was used to measure fluidity in the plasma membrane. Serotonin uptake was calculated from the disappearance of [ 14 C]-serotonin from the culture medium. Cholesterol decreased fluidity in the subpolar head group and central and midacyl side-chain regions of the plasma membrane and decreased serotonin transport, whereas cis-vaccenic acid increased fluidity in the central and midacyl side-chain regions of the plasma membrane and also increased serotonin transport. Cis-vaccenic acid had no effect of fluidity in the subpolar head group region of the plasma membrane. These results provide evidence that the physical state of the central and midacyl chains within the pulmonary artery endothelial cell plasma membrane lipid bilayer modulates transmembrane transport of serotonin by these cells

  13. Automated mass spectrometric analysis of urinary and plasma serotonin

    NARCIS (Netherlands)

    de Jong, Wilhelmina H. A.; Wilkens, Marianne H. L. I.; de Vries, Elisabeth G. E.; Kema, Ido P.

    Serotonin emerges as crucial neurotransmitter and hormone in a growing number of different physiologic processes. Besides extensive serotonin production previously noted in patients with metastatic carcinoid tumors, serotonin now is implicated in liver cell regeneration and bone formation. The aim

  14. Serotonin 6 receptor controls Alzheimer's disease and depression.

    Science.gov (United States)

    Yun, Hyung-Mun; Park, Kyung-Ran; Kim, Eun-Cheol; Kim, Sanghyeon; Hong, Jin Tae

    2015-09-29

    Alzheimer's disease (AD) and depression in late life are one of the most severe health problems in the world disorders. Serotonin 6 receptor (5-HT6R) has caused much interest for potential roles in AD and depression. However, a causative role of perturbed 5-HT6R function between two diseases was poorly defined. In the present study, we found that a 5-HT6R antagonist, SB271036 rescued memory impairment by attenuating the generation of Aβ via the inhibition of γ-secretase activity and the inactivation of astrocytes and microglia in the AD mouse model. It was found that the reduction of serotonin level was significantly recovered by SB271036, which was mediated by an indirect regulation of serotonergic neurons via GABA. Selective serotonin reuptake inhibitor (SSRI), fluoxetine significantly improved cognitive impairment and behavioral changes. In human brain of depression patients, we then identified the potential genes, amyloid beta (A4) precursor protein-binding, family A, member 2 (APBA2), well known AD modulators by integrating datasets from neuropathology, microarray, and RNA seq. studies with correlation analysis tools. And also, it was demonstrated in mouse models and patients of AD. These data indicate functional network of 5-HT6R between AD and depression.

  15. Larvae of small white butterfly, Pieris rapae, express a novel serotonin receptor

    Science.gov (United States)

    The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter in vertebrates and invertebrates. It acts in regulation and modulation of many physiological and behavioral processes through G protein-coupled receptors. Insects express five 5-HT receptor subtypes that share high simila...

  16. Serotonin shapes risky decision making in monkeys

    OpenAIRE

    Long, Arwen B.; Kuhn, Cynthia M.; Platt, Michael L.

    2009-01-01

    Some people love taking risks, while others avoid gambles at all costs. The neural mechanisms underlying individual variation in preference for risky or certain outcomes, however, remain poorly understood. Although behavioral pathologies associated with compulsive gambling, addiction and other psychiatric disorders implicate deficient serotonin signaling in pathological decision making, there is little experimental evidence demonstrating a link between serotonin and risky decision making, in ...

  17. The serotonin transporter knockout rat : A review

    NARCIS (Netherlands)

    Olivier, Jocelien; Cools, Alexander; Ellenbroek, Bart A.; Cuppen, E.; Homberg, Judith; Kalueff, Allan V.; LaPorte, Justin L.

    2010-01-01

    This chapter dicusses the most recent data on the serotonin transporter knock-out rat, a unique rat model that has been generated by target-selected N-ethyl-N-nitrosourea (ENU) driven mutagenesis. The knock-out rat is the result of a premature stopcodon in the serotonin transporter gene, and the

  18. Serotonin, neural markers and memory

    Directory of Open Access Journals (Sweden)

    Alfredo eMeneses

    2015-07-01

    Full Text Available Diverse neuropsychiatric disorders present dysfunctional memory and no effective treatment exits for them; likely as result of the absence of neural markers associated to memory. Neurotransmitter systems and signaling pathways have been implicated in memory and dysfunctional memory; however, their role is poorly understood. Hence, neural markers and cerebral functions and dysfunctions are revised. To our knowledge no previous systematic works have been published addressing these issues. The interactions among behavioral tasks, control groups and molecular changes and/or pharmacological effects are mentioned. Neurotransmitter receptors and signaling pathways, during normal and abnormally functioning memory with an emphasis on the behavioral aspects of memory are revised. With focus on serotonin, since as it is a well characterized neurotransmitter, with multiple pharmacological tools, and well characterized downstream signaling in mammals’ species. 5-HT1A, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 receptors as well as SERT (serotonin transporter seem to be useful neural markers and/or therapeutic targets. Certainly, if the mentioned evidence is replicated, then the translatability from preclinical and clinical studies to neural changes might be confirmed. Hypothesis and theories might provide appropriate limits and perspectives of evidence

  19. Characterization of the effects of serotonin on the release of [3H]dopamine from rat nucleus accumbens and striatal slices

    International Nuclear Information System (INIS)

    Nurse, B.; Russell, V.A.; Taljaard, J.J.

    1988-01-01

    The effect of serotonin agonists on the depolarization (K+)-induced, calcium-dependent, release of [ 3 H]dopamine (DA) from rat nucleus accumbens and striatal slices was investigated. Serotonin enhanced basal 3 H overflow and reduced K+-induced release of [ 3 H]DA from nucleus accumbens slices. The effect of serotonin on basal 3 H overflow was not altered by the serotonin antagonist, methysergide, or the serotonin re-uptake blocker, chlorimipramine, but was reversed by the DA re-uptake carrier inhibitors nomifensine and benztropine. With the effect on basal overflow blocked, serotonin did not modulate K+-induced release of [ 3 H]DA in the nucleus accumbens or striatum. The serotonin agonists, quipazine (in the presence of nomifensine) and 5-methoxytryptamine, did not significantly affect K+-induced release of [ 3 H]DA in the nucleus accumbens. This study does not support suggestions that serotonin receptors inhibit the depolarization-induced release of dopamine in the nucleus accumbens or striatum of the rat brain. The present results do not preclude the possibility that serotonin may affect the mesolimbic reward system at a site which is post-synaptic to dopaminergic terminals in the nucleus accumbens

  20. Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior.

    Science.gov (United States)

    Patrick, Rhonda P; Ames, Bruce N

    2015-06-01

    Serotonin regulates a wide variety of brain functions and behaviors. Here, we synthesize previous findings that serotonin regulates executive function, sensory gating, and social behavior and that attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, and impulsive behavior all share in common defects in these functions. It has remained unclear why supplementation with omega-3 fatty acids and vitamin D improve cognitive function and behavior in these brain disorders. Here, we propose mechanisms by which serotonin synthesis, release, and function in the brain are modulated by vitamin D and the 2 marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Brain serotonin is synthesized from tryptophan by tryptophan hydroxylase 2, which is transcriptionally activated by vitamin D hormone. Inadequate levels of vitamin D (∼70% of the population) and omega-3 fatty acids are common, suggesting that brain serotonin synthesis is not optimal. We propose mechanisms by which EPA increases serotonin release from presynaptic neurons by reducing E2 series prostaglandins and DHA influences serotonin receptor action by increasing cell membrane fluidity in postsynaptic neurons. We propose a model whereby insufficient levels of vitamin D, EPA, or DHA, in combination with genetic factors and at key periods during development, would lead to dysfunctional serotonin activation and function and may be one underlying mechanism that contributes to neuropsychiatric disorders and depression. This model suggests that optimizing vitamin D and marine omega-3 fatty acid intake may help prevent and modulate the severity of brain dysfunction. © FASEB.

  1. Characterization of a novel serotonin receptor coupled to adenylate cyclase in the hybrid neuroblastoma cell line NCB. 20

    Energy Technology Data Exchange (ETDEWEB)

    Conner, D.A.

    1988-01-01

    Pharmacological characterization of the serotonin activation of adenylate cyclase in membrane preparation using over 40 serotonergic and non-serotonergic compounds demonstrated that the receptor mediating the response was distinct from previously described mammalian serotonin receptors. Agonist activity was only observed with tryptamine and ergoline derivatives. Potent antagonism was observed with several ergoline derivatives and with compounds such as mianserin and methiothepine. A comparison of the rank order of potency of a variety of compounds for the NCB.20 cell receptor with well characterized mammalian and non-mammalian serotonin receptors showed a pharmacological similarity, but not identity, with the mammalian 5-HT{sub 1C} receptor, which modulates phosphatidylinositol metabolism, and with serotonin receptors in the parasitic trematodes Fasciola hepatica and Schistosoma mansoni, which are coupled to adenylate cyclase. Equilibrium binding analysis utilizing ({sup 3}H)serotonin, ({sup 3}H)lysergic acid diethylamide or ({sup 3}H)dihydroergotamine demonstrated that there are no abundant high affinity serotonergic sites, which implies that the serotonin activation of adenylate cyclase is mediated by receptors present in low abundance. Incubation of intact NCB.20 cells with serotinin resulted in a time and concentration dependent desensitization of the serotonin receptor.

  2. Different components of 3H-imipramine binding in rat brain membranes: relation to serotonin uptake sites

    International Nuclear Information System (INIS)

    Gobbi, M.; Taddei, C.; Mennini, T.

    1988-01-01

    In the present paper, the authors confirm and extend previous studies showing heterogeneous 3 H-imipramine ( 3 H-IMI) binding sites. Inhibition curves of various drugs (serotonin, imipramine, desmethyl-imipramine, d-fenfluramine, d-norfenfluramine and indalpine, a potent serotonin uptake inhibitor) obtained using 2 nM 3 H-IMI and in presence of 120 mM NaCl, confirmed the presence of at least three 3 H-IMI binding sites: two of these were serotonin-insensitive while the third one was selectively inhibited by serotonin and indalpine with nanomolar affinities. Moreover this last component was found to be selectively modulated by chronic imipramine treatment thus suggesting a close relation to serontonin uptake mechanism. These data indicate that the use of a more selective inhibitors of the serotonin-sensitive component (like indalpine or serotonin itself) to define non specific 3 H-IMI, may be of help in understanding its relation with serotonin uptake system. 22 references, 2 figures, 2 tables

  3. Characterization of a novel serotonin receptor coupled to adenylate cyclase in the hybrid neuroblastoma cell line NCB.20

    International Nuclear Information System (INIS)

    Conner, D.A.

    1988-01-01

    Pharmacological characterization of the serotonin activation of adenylate cyclase in membrane preparation using over 40 serotonergic and non-serotonergic compounds demonstrated that the receptor mediating the response was distinct from previously described mammalian serotonin receptors. Agonist activity was only observed with tryptamine and ergoline derivatives. Potent antagonism was observed with several ergoline derivatives and with compounds such as mianserin and methiothepine. A comparison of the rank order of potency of a variety of compounds for the NCB.20 cell receptor with well characterized mammalian and non-mammalian serotonin receptors showed a pharmacological similarity, but not identity, with the mammalian 5-HT 1C receptor, which modulates phosphatidylinositol metabolism, and with serotonin receptors in the parasitic trematodes Fasciola hepatica and Schistosoma mansoni, which are coupled to adenylate cyclase. Equilibrium binding analysis utilizing [ 3 H]serotonin, [ 3 H]lysergic acid diethylamide or [ 3 H]dihydroergotamine demonstrated that there are no abundant high affinity serotonergic sites, which implies that the serotonin activation of adenylate cyclase is mediated by receptors present in low abundance. Incubation of intact NCB.20 cells with serotinin resulted in a time and concentration dependent desensitization of the serotonin receptor

  4. Serotonin shapes risky decision making in monkeys.

    Science.gov (United States)

    Long, Arwen B; Kuhn, Cynthia M; Platt, Michael L

    2009-12-01

    Some people love taking risks, while others avoid gambles at all costs. The neural mechanisms underlying individual variation in preference for risky or certain outcomes, however, remain poorly understood. Although behavioral pathologies associated with compulsive gambling, addiction and other psychiatric disorders implicate deficient serotonin signaling in pathological decision making, there is little experimental evidence demonstrating a link between serotonin and risky decision making, in part due to the lack of a good animal model. We used dietary rapid tryptophan depletion (RTD) to acutely lower brain serotonin in three macaques performing a simple gambling task for fluid rewards. To confirm the efficacy of RTD experiments, we measured total plasma tryptophan using high-performance liquid chromatography (HPLC) with electrochemical detection. Reducing brain serotonin synthesis decreased preference for the safe option in a gambling task. Moreover, lowering brain serotonin function significantly decreased the premium required for monkeys to switch their preference to the risky option, suggesting that diminished serotonin signaling enhances the relative subjective value of the risky option. These results implicate serotonin in risk-sensitive decision making and, further, suggest pharmacological therapies for treating pathological risk preferences in disorders such as problem gambling and addiction.

  5. Preparation and evaluation of serotonin labelled with 125I

    International Nuclear Information System (INIS)

    Sivaprasad, N.; Geetha, R.; Ghodke, A.S.; Karmalkar, C.P.; Pilkhwal, N.S.; Sarnaik, J.S.; Borkute, S.D.; Nadkarni, G.D.

    1999-01-01

    Radiolabelled serotonin is an important tool for studying serotonin receptors and estimating serotonin levels in plants and animals. In this paper we report the synthesis of serotonin - 125 I. Tyrosine Methyl Ester (TME) was first labelled with 125 I using chloramine-T method. 125 I-TME was then conjugated with serotonin using carbodimide. The labelled conjugate was purified using gel filtration. Yield and radiochemical purity were estimated using electrophoresis and ITLC in different solvent systems. The binding of the purified tracer to serotonin receptors and serotonin antibodies was studied. (author)

  6. Serotonin 1B Receptors Regulate Prefrontal Function by Gating Callosal and Hippocampal Inputs

    DEFF Research Database (Denmark)

    Kjaerby, Celia; Athilingam, Jegath; Robinson, Sarah E

    2016-01-01

    Both medial prefrontal cortex (mPFC) and serotonin play key roles in anxiety; however, specific mechanisms through which serotonin might act on the mPFC to modulate anxiety-related behavior remain unknown. Here, we use a combination of optogenetics and synaptic physiology to show that serotonin...... acts presynaptically via 5-HT1B receptors to selectively suppress inputs from the contralateral mPFC and ventral hippocampus (vHPC), while sparing those from mediodorsal thalamus. To elucidate how these actions could potentially regulate prefrontal circuit function, we infused a 5-HT1B agonist...... into the mPFC of freely behaving mice. Consistent with previous studies that have optogenetically inhibited vHPC-mPFC projections, activating prefrontal 5-HT1B receptors suppressed theta-frequency mPFC activity (4-12 Hz), and reduced avoidance of anxiogenic regions in the elevated plus maze. These findings...

  7. Common selective serotonin reuptake inhibitor side effects in older adults associated with genetic polymorphisms in the serotonin transporter and receptors: data from a randomized controlled trial.

    Science.gov (United States)

    Garfield, Lauren D; Dixon, David; Nowotny, Petra; Lotrich, Francis E; Pollock, Bruce G; Kristjansson, Sean D; Doré, Peter M; Lenze, Eric J

    2014-10-01

    Antidepressant side effects are a significant public health issue, associated with poor adherence, premature treatment discontinuation, and, rarely, significant harm. Older adults assume the largest and most serious burden of medication side effects. We investigated the association between antidepressant side effects and genetic variation in the serotonin system in anxious, older adults participating in a randomized, placebo-controlled trial of the selective serotonin reuptake inhibitor (SSRI) escitalopram. Adults (N = 177) aged ≥ 60 years were randomized to active treatment or placebo for 12 weeks. Side effects were assessed using the Udvalg fur Kliniske Undersøgelser side-effect rating scale. Genetic polymorphisms were putative functional variants in the promoters of the serotonin transporter and 1A and 2A receptors (5-HTTLPR [L/S + rs25531], HTR1A rs6295, HTR2A rs6311, respectively). Four significant drug-placebo side-effect differences were found: increased duration of sleep, dry mouth, diarrhea, and diminished sexual desire. Analyses using putative high- versus low-transcription genotype groupings revealed six pharmacogenetic effects: greater dry mouth and decreased sexual desire for the low- and high-expressing serotonin transporter genotypes, respectively, and greater diarrhea with the 1A receptor low-transcription genotype. Diminished sexual desire was experienced significantly more by high-expressing genotypes in the serotonin transporter, 1A, or 2A receptors. There was not a significant relationship between drug concentration and side effects nor a mean difference in drug concentration between low- and high-expressing genotypes. Genetic variation in the serotonin system may predict who develops common SSRI side effects and why. More work is needed to further characterize this genetic modulation and to translate research findings into strategies useful for more personalized patient care. Published by Elsevier Inc.

  8. Disruption of Transient Serotonin Accumulation by Non-Serotonin-Producing Neurons Impairs Cortical Map Development

    Directory of Open Access Journals (Sweden)

    Xiaoning Chen

    2015-01-01

    Full Text Available Polymorphisms that alter serotonin transporter SERT expression and functionality increase the risks for autism and psychiatric traits. Here, we investigate how SERT controls serotonin signaling in developing CNS in mice. SERT is transiently expressed in specific sets of glutamatergic neurons and uptakes extrasynaptic serotonin during perinatal CNS development. We show that SERT expression in glutamatergic thalamocortical axons (TCAs dictates sensory map architecture. Knockout of SERT in TCAs causes lasting alterations in TCA patterning, spatial organizations of cortical neurons, and dendritic arborization in sensory cortex. Pharmacological reduction of serotonin synthesis during the first postnatal week rescues sensory maps in SERTGluΔ mice. Furthermore, knockdown of SERT expression in serotonin-producing neurons does not impair barrel maps. We propose that spatiotemporal SERT expression in non-serotonin-producing neurons represents a determinant in early life genetic programming of cortical circuits. Perturbing this SERT function could be involved in the origin of sensory and cognitive deficits associated with neurodevelopmental disorders.

  9. The evolution of violence in men: the function of central cholesterol and serotonin.

    Science.gov (United States)

    Wallner, Bernard; Machatschke, Ivo H

    2009-04-30

    Numerous studies point to central serotonin as an important modulator of maladaptive behaviors. In men, for instance, low concentrations of this neurotransmitter are related to hostile aggression. A key player in serotonin metabolism seems to be central cholesterol. It plays a fundamental role in maintaining the soundness of neuron membranes, especially in the exocytosis transport of serotonin vesicles into the synaptic cleft. In this review, we attempt an evolutionary approach to the neurobiological basis of human male violence. Hominid evolution was shaped by periods of starvation but also by energy demands of an increasingly complex brain. A lack of food resources reduces uptake of glucose and results in a decreased energy-supply for autonomous brain cholesterol synthesis. Consequently, concentrations of neuromembrane cholesterol decrease, which lead to a failure of the presynaptic re-uptake mechanism of serotonin and ultimately to low central serotonin. We propose that starvation might have affected the larger male brains earlier than those of females. Furthermore, this neurophysiological process diminished the threshold for hostile aggression, which in effect represented a prerequisite for being a successful hunter or scavenger. In a Darwinian sense, the odds to acquire reliable energetic resources made those males to attractive spouses in terms of paternal care and mate support. To underpin these mechanisms, a hypothetical four-stage model of synaptic membrane destabilization effected by a prolonged shortage of high-energy, cholesterol-containing food is illustrated.

  10. [Metabolism of serotonin in autism in children].

    Science.gov (United States)

    Bursztejn, C; Ferrari, P; Dreux, C; Braconnier, A; Lancrenon, S

    1988-01-01

    In this controlled study of 22 autistic children and 22 normal controls matched for age and sex, the frequency of hyperserotonemia in infantile autism was confirmed. Platelet serotonin was elevated in patients. Comparative to controls, serotonin was also high in urine of autistic patients, while, on the contrary there was no difference for the urinary excretion of 5-HIAA. No difference was observed either for serotonin uptake and efflux or for MAO activity, in isolated platelets. The elevation of plasma free tryptophan - significant only with the Kolmogorov Smirnov test - suggests that 5-HT biosynthesis might be enhanced. In the group of patient reported in this study, disorders of serotonin metabolism are associated with disturbances of platelet catecholamines, and also with elevated immunoglobulins and enhanced cellular immunity reactions.

  11. Effects of LSD on grooming behavior in serotonin transporter heterozygous (Sert⁺/⁻) mice.

    Science.gov (United States)

    Kyzar, Evan J; Stewart, Adam Michael; Kalueff, Allan V

    2016-01-01

    Serotonin (5-HT) plays a crucial role in the brain, modulating mood, cognition and reward. The serotonin transporter (SERT) is responsible for the reuptake of 5-HT from the synaptic cleft and regulates serotonin signaling in the brain. In humans, SERT genetic variance is linked to the pathogenesis of various psychiatric disorders, including anxiety, autism spectrum disorders (ASD) and obsessive-compulsive disorder (OCD). Rodent self-grooming is a complex, evolutionarily conserved patterned behavior relevant to stress, ASD and OCD. Genetic ablation of mouse Sert causes various behavioral deficits, including increased anxiety and grooming behavior. The hallucinogenic drug lysergic acid diethylamide (LSD) is a potent serotonergic agonist known to modulate human and animal behavior. Here, we examined heterozygous Sert(+/-) mouse behavior following acute administration of LSD (0.32 mg/kg). Overall, Sert(+/-) mice displayed a longer duration of self-grooming behavior regardless of LSD treatment. In contrast, LSD increased serotonin-sensitive behaviors, such as head twitching, tremors and backwards gait behaviors in both Sert(+/+) and Sert(+/-) mice. There were no significant interactions between LSD treatment and Sert gene dosage in any of the behavioral domains measured. These results suggest that Sert(+/-) mice may respond to the behavioral effects of LSD in a similar manner to wild-type mice. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Induced thermal stress on serotonin levels in the blue swimmer crab, Portunus pelagicus

    Directory of Open Access Journals (Sweden)

    Saravanan Rajendiran

    2016-03-01

    Full Text Available The temperature of habitat water has a drastic influence on the behavioral, physiological and biochemical mechanisms of crustaceans. Hyperglycemia is a typical response of many aquatic animals to harmful physical and chemical environmental changes. In crustaceans increased circulating crustacean hyperglycemic hormone (CHH and hyperglycemia are reported to occur following exposure to several environmental stress. The biogenic amine, serotonin has been found to modulate the CHH levels and oxidation of serotonin into its metabolites is catalysed by monoamine oxidase. The blue swimmer crab, Portunus pelagicus is a dominant intertidal species utilized throughout the indo-pacific region and is a particularly important species of Palk bay. It has high nutritional value and delicious taste and hence their requirements of capture and cultivation of this species are constantly increasing. This species experiences varying and increasing temperature levels as it resides in an higher intertidal zone of Thondi coast. The present study examines the effect of thermal stress on the levels of serotonin and crustacean hyperglycemic hormone in the hemolymph of P. pelagicus and analyzes the effect of the monoamine oxidase inhibitor, pargyline on serotonin and CHH level after thermal stress. The results showed increased levels of glucose, CHH and serotonin on exposure to 26 °C in control animals. Pargyline injected crabs showed highly significant increase in the levels of CHH and serotonin on every 2 °C increase or decrease in temperature. A greater CHH level of 268.86±2.87 fmol/ml and a greater serotonin level of 177.69±10.10 ng/ml was observed at 24 °C. This could be due to the effect of in maintaining the level of serotonin in the hemolymph and preventing its oxidation, which in turn induces hyperglycemia by releasing CHH into hemolymph. Thus, the study demonstrates the effect of thermal stress on the hemolymph metabolites studied and the role of

  13. Induced thermal stress on serotonin levels in the blue swimmer crab, Portunus pelagicus.

    Science.gov (United States)

    Rajendiran, Saravanan; Muhammad Iqbal, Beema Mahin; Vasudevan, Sugumar

    2016-03-01

    The temperature of habitat water has a drastic influence on the behavioral, physiological and biochemical mechanisms of crustaceans. Hyperglycemia is a typical response of many aquatic animals to harmful physical and chemical environmental changes. In crustaceans increased circulating crustacean hyperglycemic hormone (CHH) and hyperglycemia are reported to occur following exposure to several environmental stress. The biogenic amine, serotonin has been found to modulate the CHH levels and oxidation of serotonin into its metabolites is catalysed by monoamine oxidase. The blue swimmer crab, Portunus pelagicus is a dominant intertidal species utilized throughout the indo-pacific region and is a particularly important species of Palk bay. It has high nutritional value and delicious taste and hence their requirements of capture and cultivation of this species are constantly increasing. This species experiences varying and increasing temperature levels as it resides in an higher intertidal zone of Thondi coast. The present study examines the effect of thermal stress on the levels of serotonin and crustacean hyperglycemic hormone in the hemolymph of P. pelagicus and analyzes the effect of the monoamine oxidase inhibitor, pargyline on serotonin and CHH level after thermal stress. The results showed increased levels of glucose, CHH and serotonin on exposure to 26 °C in control animals. Pargyline injected crabs showed highly significant increase in the levels of CHH and serotonin on every 2 °C increase or decrease in temperature. A greater CHH level of 268.86±2.87 fmol/ml and a greater serotonin level of 177.69±10.10 ng/ml was observed at 24 °C. This could be due to the effect of in maintaining the level of serotonin in the hemolymph and preventing its oxidation, which in turn induces hyperglycemia by releasing CHH into hemolymph. Thus, the study demonstrates the effect of thermal stress on the hemolymph metabolites studied and the role of pargyline in elevating the

  14. Serotonin increases synaptic activity in olfactory bulb glomeruli.

    Science.gov (United States)

    Brill, Julia; Shao, Zuoyi; Puche, Adam C; Wachowiak, Matt; Shipley, Michael T

    2016-03-01

    Serotoninergic fibers densely innervate olfactory bulb glomeruli, the first sites of synaptic integration in the olfactory system. Acting through 5HT2A receptors, serotonin (5HT) directly excites external tufted cells (ETCs), key excitatory glomerular neurons, and depolarizes some mitral cells (MCs), the olfactory bulb's main output neurons. We further investigated 5HT action on MCs and determined its effects on the two major classes of glomerular interneurons: GABAergic/dopaminergic short axon cells (SACs) and GABAergic periglomerular cells (PGCs). In SACs, 5HT evoked a depolarizing current mediated by 5HT2C receptors but did not significantly impact spike rate. 5HT had no measurable direct effect in PGCs. Serotonin increased spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) in PGCs and SACs. Increased sEPSCs were mediated by 5HT2A receptors, suggesting that they are primarily due to enhanced excitatory drive from ETCs. Increased sIPSCs resulted from elevated excitatory drive onto GABAergic interneurons and augmented GABA release from SACs. Serotonin-mediated GABA release from SACs was action potential independent and significantly increased miniature IPSC frequency in glomerular neurons. When focally applied to a glomerulus, 5HT increased MC spontaneous firing greater than twofold but did not increase olfactory nerve-evoked responses. Taken together, 5HT modulates glomerular network activity in several ways: 1) it increases ETC-mediated feed-forward excitation onto MCs, SACs, and PGCs; 2) it increases inhibition of glomerular interneurons; 3) it directly triggers action potential-independent GABA release from SACs; and 4) these network actions increase spontaneous MC firing without enhancing responses to suprathreshold sensory input. This may enhance MC sensitivity while maintaining dynamic range. Copyright © 2016 the American Physiological Society.

  15. Serotonin and brain function: a tale of two receptors.

    Science.gov (United States)

    Carhart-Harris, R L; Nutt, D J

    2017-09-01

    Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain's default response to adversity but that an improved ability to change one's situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important - and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.

  16. Serotonin Syndrome: A Case Report

    Directory of Open Access Journals (Sweden)

    Pedro Oliveira

    2018-01-01

    Full Text Available Serotonin Syndrome (SS is a potentially fatal iatrogenic condition that occurs as a result of an over-stimulation of the serotonergic receptors. Its typical presentation consists of the triad altered mental status, autonomic hyperactivity and neuromuscular alterations, although the clinical condition is highly variable. Despite being potentially treatable, many cases per year are underdiagnosed, a fact that has been mainly attributed to the lack of knowledge of this condition by the physicians. SS treatment relies on four pillars: removal of the precipitating agent and supportive therapy, antagonism of 5-HT2A receptors, and control of agitation, autonomic instability and hyperthermia. It is expected that its incidence will accompany the growth of the prescription of antidepressants, andincreasing physician’s awareness about its occurrence, could contribute to a timely diagnosis and to the success of the treatment. We present a clinical case of a patient diagnosed with Bipolar Affective Disorder, hospitalized for a depressive episode with a psychotic component, which developed a SS compatible condition. Based on this case report the authors undertake a theoretical review of this condition.

  17. Serotonin and decision making processes.

    Science.gov (United States)

    Homberg, Judith R

    2012-01-01

    Serotonin (5-HT) is an important player in decision making. Serotonergic antidepressant, anxiolytic and antipsychotic drugs are extensively used in the treatment of neuropsychiatric disorders characterized by impaired decision making, and exert both beneficial and harmful effects in patients. Detailed insight into the serotonergic mechanisms underlying decision making is needed to strengthen the first and weaken the latter. Although much remains to be done to achieve this, accumulating studies begin to deliver a coherent view. Thus, high central 5-HT levels are generally associated with improved reversal learning, improved attentional set shifting, decreased delay discounting, and increased response inhibition, but a failure to use outcome representations. Based on 5-HT's evolutionary role, I hypothesize that 5-HT integrates expected, or changes in, relevant sensory and emotional internal/external information, leading to vigilance behaviour affecting various decision making processes. 5-HT receptor subtypes play distinctive roles in decision making. 5-HT(2A) agonists and 5-HT2c antagonists decrease compulsivity, whereas 5-HT(2A) antagonists and 5-HT(2C) agonists decrease impulsivity. 5-HT(6) antagonists univocally affect decision making processes. Copyright © 2011 Elsevier Ltd. All rights reserved.

  18. Clarification of serotonin-induced effects in peripheral artery disease observed through the femoral artery response in models of diabetes and vascular occlusion: The role of calcium ions.

    Science.gov (United States)

    Stojanović, Marko; Prostran, Milica; Janković, Radmila; Radenković, Miroslav

    2017-07-01

    Recent findings have demonstrated that serotonin is an important participant in the development and progression of peripheral artery diseases. Taking this into consideration, the goals of this study were to investigate the effects of serotonin on isolated Wistar rat femoral arteries in both healthy and diabetic animals, with and without artery occlusion, with a particular focus on determining the role of calcium in this process. Contraction experiments with serotonin on intact and denuded femoral artery rings, in the presence or absence of nifedipine and ouabain (both separately, or in combination), as well as Ca 2+ -free Krebs-Ringer bicarbonate solution were performed. The serotonin-induced results were concentration dependent, but only in healthy animals. The endothelium-dependent contraction of the femoral artery was assessed. In healthy animals, the endothelium-reliant part of contraction was dependent on the extracellular calcium, while the smooth muscle-related part was instead dependent on the intracellular calcium. In diabetic animals, both nifedipine and ouabain influenced serotonin-induced vascular effects by blocking intracellular calcium pathways. However, this was diminished after the simultaneous administration of both blockers. © 2017 John Wiley & Sons Australia, Ltd.

  19. Salivary serotonin does not correlate with central serotonin turnover in adult phenylketonuria (PKU patients

    Directory of Open Access Journals (Sweden)

    Joseph Leung

    2018-06-01

    Full Text Available Introduction: Phenylketonuria (PKU is an inborn error of metabolism associated with an increased risk of behavioural and mood disorders. There are currently no reliable markers for monitoring mood in PKU. The purpose of this study was to evaluate salivary serotonin as a possible non-invasive marker of long-term mood symptoms and central serotonin activity in patients with PKU. Methods: 20 patients were recruited from our Adult Metabolic Diseases Clinic. Age, sex, plasma phenylalanine (Phe level, DASS (Depression Anxiety Stress Scales depression score, DASS anxiety score, BMI, salivary serotonin, salivary cortisol, 2-year average Phe, 2-year average tyrosine (Tyr, and 2-year average Phe:Tyr ratio were collected for each patient. Spearman's ρ correlation analysis was used to determine if there was any relationship between any of the parameters. Results: There were positive correlations between DASS anxiety and DASS depression scores (Spearman's ρ = 0.8708, p-value < 0.0001, BMI and plasma Phe level (Spearman's ρ = 0.6228, p-value = .0034, and 2-year average Phe and BMI (Spearman's ρ = 0.5448, p-value = .0130. There was also a negative correlation between salivary cortisol and plasma Phe level (Spearman's ρ = −0.5018, p-value = .0338. All other correlations were not statistically significant. Conclusion: Salivary serotonin does not correlate with peripheral phenylalanine levels, DASS depression scale scores, or DASS anxiety scale scores, implying that salivary serotonin does not reflect central serotonin turnover. Additionally, this study suggests that salivary serotonin is not a suitable marker for monitoring dietary control, mood, or anxiety in PKU. Synopsis: Salivary serotonin does not correlate with peripheral phenylalanine levels, DASS depression scale scores, or DASS anxiety scale scores, suggesting that salivary serotonin is not a suitable marker for monitoring dietary control, mood, or anxiety in PKU

  20. Mapping neurotransmitter networks with PET: an example on serotonin and opioid systems.

    Science.gov (United States)

    Tuominen, Lauri; Nummenmaa, Lauri; Keltikangas-Järvinen, Liisa; Raitakari, Olli; Hietala, Jarmo

    2014-05-01

    All functions of the human brain are consequences of altered activity of specific neural pathways and neurotransmitter systems. Although the knowledge of "system level" connectivity in the brain is increasing rapidly, we lack "molecular level" information on brain networks and connectivity patterns. We introduce novel voxel-based positron emission tomography (PET) methods for studying internal neurotransmitter network structure and intercorrelations of different neurotransmitter systems in the human brain. We chose serotonin transporter and μ-opioid receptor for this analysis because of their functional interaction at the cellular level and similar regional distribution in the brain. Twenty-one healthy subjects underwent two consecutive PET scans using [(11)C]MADAM, a serotonin transporter tracer, and [(11)C]carfentanil, a μ-opioid receptor tracer. First, voxel-by-voxel "intracorrelations" (hub and seed analyses) were used to study the internal structure of opioid and serotonin systems. Second, voxel-level opioid-serotonin intercorrelations (between neurotransmitters) were computed. Regional μ-opioid receptor binding potentials were uniformly correlated throughout the brain. However, our analyses revealed nonuniformity in the serotonin transporter intracorrelations and identified a highly connected local network (midbrain-striatum-thalamus-amygdala). Regionally specific intercorrelations between the opioid and serotonin tracers were found in anteromedial thalamus, amygdala, anterior cingulate cortex, dorsolateral prefrontal cortex, and left parietal cortex, i.e., in areas relevant for several neuropsychiatric disorders, especially affective disorders. This methodology enables in vivo mapping of connectivity patterns within and between neurotransmitter systems. Quantification of functional neurotransmitter balances may be a useful approach in etiological studies of neuropsychiatric disorders and also in drug development as a biomarker-based rationale for targeted

  1. Intracellular pH gradients in migrating cells

    DEFF Research Database (Denmark)

    Martin, Christine; Pedersen, Stine Helene Falsig; Schwab, Albrecht

    2011-01-01

    might function as such unevenly distributed regulators as they modulate the interaction of focal adhesion proteins and components of the cytoskeleton in vitro. However, an intracellular pH (pH(i)) gradient reflecting a spatial asymmetry of protons has not been shown so far. One major regulator of p...

  2. Brain serotonin, psychoactive drugs, and effects on reproduction.

    Science.gov (United States)

    Ayala, María Elena

    2009-12-01

    Serotonin, a biogenic amine, is present in significant amounts in many structures of the CNS. It is involved in regulation of a wide variety of physiological functions, such as sensory and motor functions, memory, mood, and secretion of hormones including reproductive hormones. It has also been implicated in the etiology of a range of psychiatric disorders such as anxiety, depression, and eating disorders, along with other conditions such as obesity and migraine. While some drugs that affect serotonin, such as fenfluramine and fluoxetine, have been successfully used in treatment of a range of psychiatric diseases, others, such as the amphetamine analogues MDMA and METH, are potent psychostimulant drugs of abuse. Alterations in serotonergic neurons caused by many of these drugs are well characterized; however, little is known about the reproductive consequences of such alterations. This review evaluates the effects of drugs such as MDMA, pCA, fenfluramine, and fluoxetine on serotonergic transmission in the brain, examines the relationships of these drug effects with the neuroendocrine mechanisms modulating reproductive events such as gonadotropin secretion, ovulation, spermatogenesis, and sexual behavior in animal models, and discusses possible reproductive implications of these drugs in humans.

  3. Role of serotonin in pathogenesis of analgesic induced headache

    Energy Technology Data Exchange (ETDEWEB)

    Srikiatkhachorn, A.

    1999-12-16

    Analgesic abuse has recently been recognized as a cause of deterioration in primary headache patients. Although the pathogenesis of this headache transformation is still obscure, and alteration of central pain control system is one possible mechanism. A number of recent studies indicated that simple analgesics exert their effect by modulating the endogenous pain control system rather than the effect at the peripheral tissue, as previously suggested. Serotonin (5-hydroxytryptamine ; 5-HT) has long been known to play a pivotal role in the pain modulatory system in the brainstem. In the present study, we investigated the changes in 5-HT system in platelets and brain tissue. A significant decrease in platelet 5-HT concentration (221.8{+-}30.7, 445.3{+-}37.4 and 467.2{+-}38.5 ng/10{sup 9} platelets, for patients with analgesic-induced headache and migraine patients, respectively, p<0.02) were evident in patients with analgesic induced headache. Chronic paracetamol administration induced a decrease in 5-HT{sub 2} serotonin receptor in cortical and brain stem tissue in experimental animals (B{sub max}=0.93{+-}0.04 and 1.79{+-}0.61 pmol/mg protein for paracetamol treated rat and controls, respectively, p<0.05). Our preliminary results suggested that chronic administration of analgesics interferes with central and peripheral 5-HT system and therefore possibly alters the 5-HT dependent antinociceptive system. (author)

  4. Oscillatory serotonin function in depression.

    Science.gov (United States)

    Salomon, Ronald M; Cowan, Ronald L

    2013-11-01

    Oscillations in brain activities with periods of minutes to hours may be critical for normal mood behaviors. Ultradian (faster than circadian) rhythms of mood behaviors and associated central nervous system activities are altered in depression. Recent data suggest that ultradian rhythms in serotonin (5HT) function also change in depression. In two separate studies, 5HT metabolites in cerebrospinal fluid (CSF) were measured every 10 min for 24 h before and after chronic antidepressant treatment. Antidepressant treatments were associated with enhanced ultradian amplitudes of CSF metabolite levels. Another study used resting-state functional magnetic resonance imaging (fMRI) to measure amplitudes of dorsal raphé activation cycles following sham or active dietary depletions of the 5HT precursor (tryptophan). During depletion, amplitudes of dorsal raphé activation cycles increased with rapid 6 s periods (about 0.18 Hz) while functional connectivity weakened between dorsal raphé and thalamus at slower periods of 20 s (0.05 Hz). A third approach studied MDMA (ecstasy, 3,4-methylenedioxy-N-methylamphetamine) users because of their chronically diminished 5HT function compared with non-MDMA polysubstance users (Karageorgiou et al., 2009). Compared with a non-MDMA using cohort, MDMA users showed diminished fMRI intra-regional coherence in motor regions along with altered functional connectivity, again suggesting effects of altered 5HT oscillatory function. These data support a hypothesis that qualities of ultradian oscillations in 5HT function may critically influence moods and behaviors. Dysfunctional 5HT rhythms in depression may be a common endpoint and biomarker for depression, linking dysfunction of slow brain network oscillators to 5HT mechanisms affected by commonly available treatments. 5HT oscillatory dysfunction may define illness subtypes and predict responses to serotonergic agents. Further studies of 5HT oscillations in depression are indicated. Copyright

  5. Immunohistological localization of serotonin in the CNS and feeding system of the stable fly stomoxys calcitrans L. (Diptera: muscidae)

    Science.gov (United States)

    Serotonin, or 5-hydroxytryptamine (5-HT), plays critical roles as a neurotransmitter and neuromodulator that control or modulate many behaviors in insects, such as feeding. Neurons immunoreactive (IR)to 5-HT were detected in the central nervous system (CNS) of the larval and adult stages of the stab...

  6. Temperament, character and serotonin activity in the human brain

    DEFF Research Database (Denmark)

    Tuominen, L; Salo, J; Hirvonen, J

    2013-01-01

    The psychobiological model of personality by Cloninger and colleagues originally hypothesized that interindividual variability in the temperament dimension 'harm avoidance' (HA) is explained by differences in the activity of the brain serotonin system. We assessed brain serotonin transporter (5-HTT...

  7. Induced thermal stress on serotonin levels in the blue swimmer crab, Portunus pelagicus

    OpenAIRE

    Rajendiran, Saravanan; Muhammad Iqbal, Beema Mahin; Vasudevan, Sugumar

    2016-01-01

    The temperature of habitat water has a drastic influence on the behavioral, physiological and biochemical mechanisms of crustaceans. Hyperglycemia is a typical response of many aquatic animals to harmful physical and chemical environmental changes. In crustaceans increased circulating crustacean hyperglycemic hormone (CHH) and hyperglycemia are reported to occur following exposure to several environmental stress. The biogenic amine, serotonin has been found to modulate the CHH levels and oxid...

  8. The serotonin transporter in psychiatric disorders

    DEFF Research Database (Denmark)

    Spies, Marie; Knudsen, Karen Birgitte Moos; Lanzenberger, Rupert

    2015-01-01

    Over the past 20 years, psychotropics affecting the serotonergic system have been used extensively in the treatment of psychiatric disorders. Molecular imaging, in particular PET, has allowed for elucidation of the essential contribution of the serotonin transporter to the pathophysiology...... of various psychiatric disorders and their treatment. We review studies that use PET to measure cerebral serotonin transporter activity in psychiatric disorders, focusing on major depressive disorder and antidepressant treatment. We also discuss opportunities and limitations in the application...... of this neuroimaging method in clinical practice. Although results from individual studies diverge, meta-analysis indicates a trend towards reduced serotonin transporter availability in patients with major depressive disorder. Inconsistencies in results might suggest symptom heterogeneity in major depressive disorder...

  9. Stochastic models of intracellular transport

    KAUST Repository

    Bressloff, Paul C.; Newby, Jay M.

    2013-01-01

    mechanisms for intracellular transport: passive diffusion and motor-driven active transport. Diffusive transport can be formulated in terms of the motion of an overdamped Brownian particle. On the other hand, active transport requires chemical energy, usually

  10. Intracellular calcium levels can regulate Importin-dependent nuclear import

    International Nuclear Information System (INIS)

    Kaur, Gurpreet; Ly-Huynh, Jennifer D.; Jans, David A.

    2014-01-01

    Highlights: • High intracellular calcium inhibits Impα/β1- or Impβ1-dependent nuclear protein import. • The effect of Ca 2+ on nuclear import does not relate to changes in the nuclear pore. • High intracellular calcium can result in mislocalisation of Impβ1, Ran and RCC1. - Abstract: We previously showed that increased intracellular calcium can modulate Importin (Imp)β1-dependent nuclear import of SRY-related chromatin remodeling proteins. Here we extend this work to show for the first time that high intracellular calcium inhibits Impα/β1- or Impβ1-dependent nuclear protein import generally. The basis of this relates to the mislocalisation of the transport factors Impβ1 and Ran, which show significantly higher nuclear localization in contrast to various other factors, and RCC1, which shows altered subnuclear localisation. The results here establish for the first time that intracellular calcium modulates conventional nuclear import through direct effects on the nuclear transport machinery

  11. Intracellular calcium levels can regulate Importin-dependent nuclear import

    Energy Technology Data Exchange (ETDEWEB)

    Kaur, Gurpreet; Ly-Huynh, Jennifer D.; Jans, David A., E-mail: David.Jans@monash.edu

    2014-07-18

    Highlights: • High intracellular calcium inhibits Impα/β1- or Impβ1-dependent nuclear protein import. • The effect of Ca{sup 2+} on nuclear import does not relate to changes in the nuclear pore. • High intracellular calcium can result in mislocalisation of Impβ1, Ran and RCC1. - Abstract: We previously showed that increased intracellular calcium can modulate Importin (Imp)β1-dependent nuclear import of SRY-related chromatin remodeling proteins. Here we extend this work to show for the first time that high intracellular calcium inhibits Impα/β1- or Impβ1-dependent nuclear protein import generally. The basis of this relates to the mislocalisation of the transport factors Impβ1 and Ran, which show significantly higher nuclear localization in contrast to various other factors, and RCC1, which shows altered subnuclear localisation. The results here establish for the first time that intracellular calcium modulates conventional nuclear import through direct effects on the nuclear transport machinery.

  12. Serotonin transporter gene promoter polymorphisms modify the association between paroxetine serotonin transporter occupancy and clinical response in major depressive disorder

    NARCIS (Netherlands)

    Ruhé, Henricus G.; Ooteman, Wendy; Booij, Jan; Michel, Martin C.; Moeton, Martina; Baas, Frank; Schene, Aart H.

    2009-01-01

    BACKGROUND: In major depressive disorder, selective serotonin reuptake inhibitors target the serotonin transporter (SERT). Their response rates (30-50%) are modified by SERT promotor polymorphisms (5-HTTLPR). OBJECTIVES: To quantify the relationship between SERT occupancy and response, and whether

  13. Serotonin: Is it a marker for the diagnosis of hepatocellular ...

    African Journals Online (AJOL)

    Impaired metabolic function in liver cirrhosis and slow uptake and storage of serotonin by the platelets is a sequelae of kinetic change of serotonin transport mechanisms or abnormal serotonin release from dense granules of activated platelets is a condition defined as ''platelet exhaustion'', contributes to elevated plasma ...

  14. Regulation of Pituitary Beta Endorphin Release: Role of Serotonin Neurons

    Science.gov (United States)

    1983-12-15

    endogenous) may be related to pain and its transmission in the nervous system. Areas known to have a large number of opiate receptors both in primates and...serotonin meta- bolite 5-hydroxytrvptamine; serotonin 5-hydroxtryptophan; serotonin precursor intra- cerebro -ventricular administration intermediate lobe

  15. Serotonin has early, cilia-independent roles in Xenopus left-right patterning

    Directory of Open Access Journals (Sweden)

    Laura N. Vandenberg

    2013-01-01

    Consistent left-right (LR patterning of the heart and viscera is a crucial part of normal embryogenesis. Because errors of laterality form a common class of birth defects, it is important to understand the molecular mechanisms and stage at which LR asymmetry is initiated. Frog embryos are a system uniquely suited to analysis of the mechanisms involved in orientation of the LR axis because of the many genetic and pharmacological tools available for use and the fate-map and accessibility of early blastomeres. Two major models exist for the origin of LR asymmetry and both implicate pre-nervous serotonergic signaling. In the first, the charged serotonin molecule is instructive for LR patterning; it is redistributed asymmetrically along the LR axis and signals intracellularly on the right side at cleavage stages. A second model suggests that serotonin is a permissive factor required to specify the dorsal region of the embryo containing chiral cilia that generate asymmetric fluid flow during neurulation, a much later process. We performed theory-neutral experiments designed to distinguish between these models. The results uniformly support a role for serotonin in the cleavage-stage embryo, long before the appearance of cilia, in ventral right blastomeres that do not contribute to the ciliated organ.

  16. A Novel Role of Serotonin Receptor 2B Agonist as an Anti-Melanogenesis Agent

    Directory of Open Access Journals (Sweden)

    Eun Ju Oh

    2016-04-01

    Full Text Available BW723C86, a serotonin receptor 2B agonist, has been investigated as a potential therapeutic for various conditions such as anxiety, hyperphagia and hypertension. However, the functional role of BW723C86 against melanogenesis remains unclear. In this study, we investigate the effect of serotonin receptor 2B (5-HTR2B agonist on melanogenesis and elucidate the mechanism involved. BW723C86 reduced melanin synthesis and intracellular tyrosinase activity in melan-A cells and normal human melanocytes. The expression of melanogenesis-related proteins (tyrosinase, TRP-1 and TRP-2 and microphthalmia-associated transcription factor (MITF in melan-A cells decreased after BW723C86 treatment. The promoter activity of MITF was also reduced by BW723C86 treatment. The reduced level of MITF was associated with inhibition of protein kinase A (PKA and cAMP response element-binding protein (CREB activation by BW723C86 treatment. These results suggest that the serotonin agonist BW723C86 could be a potential therapeutic agent for skin hyperpigmentation disorders.

  17. The translational repressor T-cell intracellular antigen-1 (TIA-1) is a key modulator of Th2 and Th17 responses driving pulmonary inflammation induced by exposure to house dust mite.

    Science.gov (United States)

    Simarro, Maria; Giannattasio, Giorgio; Xing, Wei; Lundequist, Emma-Maria; Stewart, Samantha; Stevens, Richard L; Orduña, Antonio; Boyce, Joshua A; Anderson, Paul J

    2012-08-30

    T-cell intracellular antigen-1 (TIA-1) is a translational repressor that dampens the production of proinflammatory cytokines and enzymes. In this study we investigated the role of TIA-1 in a mouse model of pulmonary inflammation induced by exposure to the allergenic extract (Df) of the house dust mite Dermatophagoides farinae. When intranasally challenged with a low dose of Df, mice lacking TIA-1 protein (Tia-1(-/-)) showed more severe airway and tissue eosinophilia, infiltration of lung bronchovascular bundles, and goblet cell metaplasia than wild-type littermates. Tia-1(-/-) mice also had higher levels of Df-specific IgE and IgG(1) in serum and ex vivo restimulated Tia-1(-/-) lymph node cells and splenocytes transcribed and released more Th2/Th17 cytokines. To evaluate the site of action of TIA-1, we studied the response to Df in bone marrow chimeras. These experiments revealed that TIA-1 acts on both hematopoietic and non-hematopoietic cells to dampen pulmonary inflammation. Our results identify TIA-1 as a negative regulator of allergen-mediated pulmonary inflammation in vivo. Thus, TIA-1 might be an important player in the pathogenesis of bronchial asthma. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. An approach for serotonin depletion in pigs: effects on serotonin receptor binding

    DEFF Research Database (Denmark)

    Ettrup, Anders; Kornum, Birgitte R; Weikop, Pia

    2011-01-01

    Depletion of central serotonin (5-HT) levels and dysfunction in serotonergic transmission are implicated in a variety of human CNS disorders. The mechanisms behind these serotonergic deficits have been widely studied using rodent models, but only to a limited extent in larger animal models. The pig...... is increasingly used as an experimental animal model especially in neuroscience research. Here, we present an approach for serotonin depletion in the pig brain. Central serotonin depletion in Danish Landrace pigs was achieved following 4 days treatment with para-chlorophenylalanine (pCPA). On day 5, tissue...... average decreases in 5-HT concentrations of 61% ± 14% and 66% ± 16%, respectively, and a substantial loss of 5-HT immunostaining was seen throughout the brain. The serotonin depletion significantly increased 5-HT₄ receptor binding in nucleus accumbens, but did not alter 5-HT(1A) and 5-HT(2A) receptor...

  19. An approach for serotonin depletion in pigs: effects on serotonin receptor binding

    DEFF Research Database (Denmark)

    Ettrup, Anders; Kornum, Birgitte R; Weikop, Pia

    2011-01-01

    Depletion of central serotonin (5-HT) levels and dysfunction in serotonergic transmission are implicated in a variety of human CNS disorders. The mechanisms behind these serotonergic deficits have been widely studied using rodent models, but only to a limited extent in larger animal models. The pig...... is increasingly used as an experimental animal model especially in neuroscience research. Here, we present an approach for serotonin depletion in the pig brain. Central serotonin depletion in Danish Landrace pigs was achieved following 4 days treatment with para-chlorophenylalanine (pCPA). On day 5, tissue...... average decreases in 5-HT concentrations of 61% ± 14% and 66% ± 16%, respectively, and a substantial loss of 5-HT immunostaining was seen throughout the brain. The serotonin depletion significantly increased 5-HT4 receptor binding in nucleus accumbens, but did not alter 5-HT(1A) and 5-HT(2A) receptor...

  20. Intracellular signaling by diffusion: can waves of hydrogen peroxide transmit intracellular information in plant cells?

    DEFF Research Database (Denmark)

    Vestergaard, Christian L.; Flyvbjerg, Henrik; Møller, Ian Max

    2012-01-01

    of the physical and biochemical conditions in plant cells. As model system, we use a H(2)O(2) signal originating at the plasma membrane (PM) and spreading through the cytosol. We consider two maximally simple types of signals, isolated pulses and harmonic oscillations. First we consider the basic limits......Amplitude- and frequency-modulated waves of Ca(2+) ions transmit information inside cells. Reactive Oxygen Species (ROS), specifically hydrogen peroxide, have been proposed to have a similar role in plant cells. We consider the feasibility of such an intracellular communication system in view...

  1. Uremic anorexia: a consequence of persistently high brain serotonin levels? The tryptophan/serotonin disorder hypothesis.

    Science.gov (United States)

    Aguilera, A; Selgas, R; Codoceo, R; Bajo, A

    2000-01-01

    Anorexia is a frequent part of uremic syndrome, contributing to malnutrition in dialysis patients. Many factors have been suggested as responsible for uremic anorexia. In this paper we formulate a new hypothesis to explain the appetite disorders in dialysis patients: "the tryptophan/serotonin disorder hypothesis." We review current knowledge of normal hunger-satiety cycle control and the disorders described in uremic patients. There are four phases in food intake regulation: (1) the gastric phase, during which food induces satiety through gastric distention and satiety peptide release; (2) the post absorptive phase, during which circulating compounds, including glucose and amino acids, cause satiety by hepatic receptors via the vagus nerve; (3) the hepatic phase, during which adenosine triphosphate (ATP) concentration is the main stimulus inducing hunger or satiety, with cytokines inhibiting ATP production; and (4) the central phase, during which appetite is regulated through peripheral (circulating plasma substances and neurotransmitters) and brain stimuli. Brain serotonin is the final target for peripheral mechanisms controlling appetite. High brain serotonin levels and a lower serotonin/dopamine ratio cause anorexia. Plasma and brain amino acid concentrations are recognized factors involved in neurotransmitter synthesis and appetite control. Tryptophan is the substrate of serotonin synthesis. High plasma levels of anorectics such as tryptophan (plasma and brain), cholecystokinin, tumor necrosis factor alpha, interleukin-1, and leptin, and deficiencies of nitric oxide and neuropeptide Y have been described in uremia; all increase intracerebral serotonin. We suggest that brain serotonin hyperproduction due to a uremic-dependent excess of tryptophan may be the final common pathway involved in the genesis of uremic anorexia. Various methods of ameliorating anorexia by decreasing the central effects of serotonin are proposed.

  2. Measuring the serotonin uptake site using [3H]paroxetine--a new serotonin uptake inhibitor

    International Nuclear Information System (INIS)

    Gleiter, C.H.; Nutt, D.J.

    1988-01-01

    Serotonin is an important neurotransmitter that may be involved in ethanol preference and dependence. It is possible to label the serotonin uptake site in brain using the tricyclic antidepressant imipramine, but this also binds to other sites. We have used the new high-affinity uptake blocker paroxetine to define binding to this site and report it to have advantages over imipramine as a ligand

  3. BLOOD CHEMISTRY AND PLATELET SEROTONIN UPTAKE AS ...

    African Journals Online (AJOL)

    A cross sectional study was conducted to investigate the blood chemistry and platelet serotonin uptake as alternative method of determining HIV disease stage in HIV/AIDS patients. Whole blood was taken from subjects at the Human Virology of the Nigerian Institute of Medical Research. Subjects were judged suitable for ...

  4. Extracellular Protein Kinase A Modulates Intracellular Calcium/Calmodulin-Dependent Protein Kinase II, Nitric Oxide Synthase, and the Glutamate-Nitric Oxide-cGMP Pathway in Cerebellum. Differential Effects in Hyperammonemia.

    Science.gov (United States)

    Cabrera-Pastor, Andrea; Llansola, Marta; Felipo, Vicente

    2016-12-21

    Extracellular protein kinases, including cAMP-dependent protein kinase (PKA), modulate neuronal functions including N-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation. NMDA receptor activation increases calcium, which binds to calmodulin and activates nitric oxide synthase (NOS), increasing nitric oxide (NO), which activates guanylate cyclase, increasing cGMP, which is released to the extracellular fluid, allowing analysis of this glutamate-NO-cGMP pathway in vivo by microdialysis. The function of this pathway is impaired in hyperammonemic rats. The aims of this work were to assess (1) whether the glutamate-NO-cGMP pathway is modulated in cerebellum in vivo by an extracellular PKA, (2) the role of phosphorylation and activity of calcium/calmodulin-dependent protein kinase II (CaMKII) and NOS in the pathway modulation by extracellular PKA, and (3) whether the effects are different in hyperammonemic and control rats. The pathway was analyzed by in vivo microdialysis. The role of extracellular PKA was analyzed by inhibiting it with a membrane-impermeable inhibitor. The mechanisms involved were analyzed in freshly isolated cerebellar slices from control and hyperammonemic rats. In control rats, inhibiting extracellular PKA reduces the glutamate-NO-cGMP pathway function in vivo. This is due to reduction of CaMKII phosphorylation and activity, which reduces NOS phosphorylation at Ser1417 and NOS activity, resulting in reduced guanylate cyclase activation and cGMP formation. In hyperammonemic rats, under basal conditions, CaMKII phosphorylation and activity are increased, increasing NOS phosphorylation at Ser847, which reduces NOS activity, guanylate cyclase activation, and cGMP. Inhibiting extracellular PKA in hyperammonemic rats normalizes CaMKII phosphorylation and activity, NOS phosphorylation, NOS activity, and cGMP, restoring normal function of the pathway.

  5. Subversion of the cytoskeleton by intracellular bacteria: lessons from Listeria, Salmonella, and Vibrio

    Science.gov (United States)

    de Souza Santos, Marcela; Orth, Kim

    2018-01-01

    Summary Entry into host cells and intracellular persistence by invasive bacteria are tightly coupled to the ability of the bacterium to disrupt the eukaryotic cytoskeletal machinery. Herein we review the main strategies used by three intracellular pathogens to harness key modulators of the cytoskeleton. Two of these bacteria, namely Listeria monocytogenes and Salmonella enterica serovar Typhimurium, exhibit quite distinct intracellular lifestyles, and therefore, provide a comprehensive panel for the understanding of the intricate bacteria-cytoskeleton interplay during infections. The emerging intracellular pathogen Vibrio parahaemolyticus is depicted as a developing model for the uncovering of novel mechanisms used to hijack the cytoskeleton. PMID:25440316

  6. Insecticide resistance and intracellular proteases.

    Science.gov (United States)

    Wilkins, Richard M

    2017-12-01

    Pesticide resistance is an example of evolution in action with mechanisms of resistance arising from mutations or increased expression of intrinsic genes. Intracellular proteases have a key role in maintaining healthy cells and in responding to stressors such as pesticides. Insecticide-resistant insects have constitutively elevated intracellular protease activity compared to corresponding susceptible strains. This increase was shown for some cases originally through biochemical enzyme studies and subsequently putatively by transcriptomics and proteomics methods. Upregulation and expression of proteases have been characterised in resistant strains of some insect species, including mosquitoes. This increase in proteolysis results in more degradation products (amino acids) of intracellular proteins. These may be utilised in the resistant strain to better protect the cell from stress. There are changes in insect intracellular proteases shortly after insecticide exposure, suggesting a role in stress response. The use of protease and proteasome inhibitors or peptide mimetics as synergists with improved application techniques and through protease gene knockdown using RNA interference (possibly expressed in crop plants) may be potential pest management strategies, in situations where elevated intracellular proteases are relevant. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

  7. [Intracellular signaling mechanisms in thyroid cancer].

    Science.gov (United States)

    Mondragón-Terán, Paul; López-Hernández, Luz Berenice; Gutiérrez-Salinas, José; Suárez-Cuenca, Juan Antonio; Luna-Ceballos, Rosa Isela; Erazo Valle-Solís, Aura

    2016-01-01

    Thyroid cancer is the most common malignancy of the endocrine system, the papillary variant accounts for 80-90% of all diagnosed cases. In the development of papillary thyroid cancer, BRAF and RAS genes are mainly affected, resulting in a modification of the system of intracellular signaling proteins known as «protein kinase mitogen-activated» (MAPK) which consist of «modules» of internal signaling proteins (Receptor/Ras/Raf/MEK/ERK) from the cell membrane to the nucleus. In thyroid cancer, these signanling proteins regulate diverse cellular processes such as differentiation, growth, development and apoptosis. MAPK play an important role in the pathogenesis of thyroid cancer as they are used as molecular biomarkers for diagnostic, prognostic and as possible therapeutic molecular targets. Mutations in BRAF gene have been correlated with poor response to treatment with traditional chemotherapy and as an indicator of poor prognosis. To review the molecular mechanisms involved in intracellular signaling of BRAF and RAS genes in thyroid cancer. Molecular therapy research is in progress for this type of cancer as new molecules have been developed in order to inhibit any of the components of the signaling pathway (RET/PTC)/Ras/Raf/MEK/ERK; with special emphasis on the (RET/PTC)/Ras/Raf section, which is a major effector of ERK pathway. Copyright © 2016 Academia Mexicana de Cirugía A.C. Publicado por Masson Doyma México S.A. All rights reserved.

  8. Elevating serotonin pre-partum alters the Holstein dairy cow hepatic adaptation to lactation

    Science.gov (United States)

    Weaver, Samantha R.; Prichard, Allan S.; Maerz, Noah L.; Prichard, Austin P.; Endres, Elizabeth L.; Hernández-Castellano, Lorenzo E.; Akins, Matthew S.; Bruckmaier, Rupert M.

    2017-01-01

    Serotonin is known to regulate energy and calcium homeostasis in several mammalian species. The objective of this study was to determine if pre-partum infusions of 5-hydroxytryptophan (5-HTP), the immediate precursor to serotonin synthesis, could modulate energy homeostasis at the level of the hepatocyte in post-partum Holstein and Jersey dairy cows. Twelve multiparous Holstein cows and twelve multiparous Jersey cows were intravenously infused daily for approximately 7 d pre-partum with either saline or 1 mg/kg bodyweight of 5-HTP. Blood was collected for 14 d post-partum and on d30 post-partum. Liver biopsies were taken on d1 and d7 post-partum. There were no changes in the circulating concentrations of glucose, insulin, glucagon, non-esterified fatty acids, or urea nitrogen in response to treatment, although there were decreased beta-hydroxybutyrate concentrations with 5-HTP treatment around d6 to d10 post-partum, particularly in Jersey cows. Cows infused with 5-HTP had increased hepatic serotonin content and increased mRNA expression of the serotonin 2B receptor on d1 and d7 post-partum. Minimal changes were seen in the hepatic mRNA expression of various gluconeogenic enzymes. There were no changes in the mRNA expression profile of cell-cycle progression marker cyclin-dependent kinase 4 or apoptotic marker caspase 3, although proliferating cell nuclear antigen expression tended to be increased in Holstein cows infused with 5-HTP on d1 post-partum. Immunofluorescence assays showed an increased number of CASP3- and Ki67-positive cells in Holstein cows infused with 5-HTP on d1 post-partum. Given the elevated hepatic serotonin content and increased mRNA abundance of 5HTR2B, 5-HTP infusions may be stimulating an autocrine-paracrine adaptation to lactation in the Holstein cow liver. PMID:28922379

  9. Elevating serotonin pre-partum alters the Holstein dairy cow hepatic adaptation to lactation.

    Directory of Open Access Journals (Sweden)

    Samantha R Weaver

    Full Text Available Serotonin is known to regulate energy and calcium homeostasis in several mammalian species. The objective of this study was to determine if pre-partum infusions of 5-hydroxytryptophan (5-HTP, the immediate precursor to serotonin synthesis, could modulate energy homeostasis at the level of the hepatocyte in post-partum Holstein and Jersey dairy cows. Twelve multiparous Holstein cows and twelve multiparous Jersey cows were intravenously infused daily for approximately 7 d pre-partum with either saline or 1 mg/kg bodyweight of 5-HTP. Blood was collected for 14 d post-partum and on d30 post-partum. Liver biopsies were taken on d1 and d7 post-partum. There were no changes in the circulating concentrations of glucose, insulin, glucagon, non-esterified fatty acids, or urea nitrogen in response to treatment, although there were decreased beta-hydroxybutyrate concentrations with 5-HTP treatment around d6 to d10 post-partum, particularly in Jersey cows. Cows infused with 5-HTP had increased hepatic serotonin content and increased mRNA expression of the serotonin 2B receptor on d1 and d7 post-partum. Minimal changes were seen in the hepatic mRNA expression of various gluconeogenic enzymes. There were no changes in the mRNA expression profile of cell-cycle progression marker cyclin-dependent kinase 4 or apoptotic marker caspase 3, although proliferating cell nuclear antigen expression tended to be increased in Holstein cows infused with 5-HTP on d1 post-partum. Immunofluorescence assays showed an increased number of CASP3- and Ki67-positive cells in Holstein cows infused with 5-HTP on d1 post-partum. Given the elevated hepatic serotonin content and increased mRNA abundance of 5HTR2B, 5-HTP infusions may be stimulating an autocrine-paracrine adaptation to lactation in the Holstein cow liver.

  10. Nanobodies: Chemical Functionalization Strategies and Intracellular Applications

    Science.gov (United States)

    Schumacher, Dominik; Helma, Jonas; Schneider, Anselm F. L.; Leonhardt, Heinrich

    2018-01-01

    Abstract Nanobodies can be seen as next‐generation tools for the recognition and modulation of antigens that are inaccessible to conventional antibodies. Due to their compact structure and high stability, nanobodies see frequent usage in basic research, and their chemical functionalization opens the way towards promising diagnostic and therapeutic applications. In this Review, central aspects of nanobody functionalization are presented, together with selected applications. While early conjugation strategies relied on the random modification of natural amino acids, more recent studies have focused on the site‐specific attachment of functional moieties. Such techniques include chemoenzymatic approaches, expressed protein ligation, and amber suppression in combination with bioorthogonal modification strategies. Recent applications range from sophisticated imaging and mass spectrometry to the delivery of nanobodies into living cells for the visualization and manipulation of intracellular antigens. PMID:28913971

  11. Nanobodies: Chemical Functionalization Strategies and Intracellular Applications.

    Science.gov (United States)

    Schumacher, Dominik; Helma, Jonas; Schneider, Anselm F L; Leonhardt, Heinrich; Hackenberger, Christian P R

    2018-02-23

    Nanobodies can be seen as next-generation tools for the recognition and modulation of antigens that are inaccessible to conventional antibodies. Due to their compact structure and high stability, nanobodies see frequent usage in basic research, and their chemical functionalization opens the way towards promising diagnostic and therapeutic applications. In this Review, central aspects of nanobody functionalization are presented, together with selected applications. While early conjugation strategies relied on the random modification of natural amino acids, more recent studies have focused on the site-specific attachment of functional moieties. Such techniques include chemoenzymatic approaches, expressed protein ligation, and amber suppression in combination with bioorthogonal modification strategies. Recent applications range from sophisticated imaging and mass spectrometry to the delivery of nanobodies into living cells for the visualization and manipulation of intracellular antigens. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  12. Bacillus licheniformis Isolated from Traditional Korean Food Resources Enhances the Longevity of Caenorhabditis elegans through Serotonin Signaling.

    Science.gov (United States)

    Park, Mi Ri; Oh, Sangnam; Son, Seok Jun; Park, Dong-June; Oh, Sejong; Kim, Sae Hun; Jeong, Do-Youn; Oh, Nam Su; Lee, Youngbok; Song, Minho; Kim, Younghoon

    2015-12-02

    In this study, we investigated potentially probiotic Bacillus licheniformis strains isolated from traditional Korean food sources for ability to enhance longevity using the nematode Caenorhabditis elegans as a simple in vivo animal model. We first investigated whether B. licheniformis strains were capable of modulating the lifespan of C. elegans. Among the tested strains, preconditioning with four B. licheniformis strains significantly enhanced the longevity of C. elegans. Unexpectedly, plate counting and transmission electron microscopy (TEM) results indicated that B. licheniformis strains were not more highly attached to the C. elegans intestine compared with Escherichia coli OP50 or Lactobacillus rhamnosus GG controls. In addition, qRT-PCR and an aging assay with mutant worms showed that the conditioning of B. licheniformis strain 141 directly influenced genes associated with serotonin signaling in nematodes, including tph-1 (tryptophan hydroxylase), bas-1 (serotonin- and dopamine-synthetic aromatic amino acid decarboxylase), mod-1 (serotonin-gated chloride channel), ser-1, and ser-7 (serotonin receptors) during C. elegans aging. Our findings suggest that B. licheniformis strain 141, which is isolated from traditional Korean foods, is a probiotic generally recognized as safe (GRAS) strain that enhances the lifespan of C. elegans via host serotonin signaling.

  13. A role for the serotonin reuptake transporter in the brain and intestinal features of autism spectrum disorders and developmental antidepressant exposure.

    Science.gov (United States)

    Margolis, Kara Gross

    2017-10-01

    Many disease conditions considered CNS-predominant harbor significant intestinal comorbidities. Serotonin (5-HT) and the serotonin reuptake transporter (SERT) have increasingly been shown to play important roles in both brain and intestinal development and long-term function. 5-HT and SERT may thus modulate critical functions in the development and perpetuation of brain-gut axis disease. We discuss the potential roles of 5-HT and SERT in the brain and intestinal manifestations of autism spectrum disorders and developmental antidepressant exposure. The potential therapeutic value of 5-HT 4 modulation in the subsequent treatment of these conditions is also addressed. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System

    DEFF Research Database (Denmark)

    Beliveau, Vincent; Ganz-Benjaminsen, Melanie; Feng, Ling

    2017-01-01

    The serotonin (5-hydroxytryptamine, 5-HT) system modulates many important brain functions and is critically involved in many neuropsychiatric disorders. Here, we present a high-resolution, multidimensional, in vivo atlas of four of the human brain's 5-HT receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4...... with postmortem human brain autoradiography outcomes showed a high correlation for the five 5-HT targets and this enabled us to transform the atlas to represent protein densities (in picomoles per milliliter). We also assessed the regional association between protein concentration and mRNA expression in the human...... brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor- and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system...

  15. Serotonin Neuron Abnormalities in the BTBR Mouse Model of Autism

    Science.gov (United States)

    Guo, Yue-Ping; Commons, Kathryn G.

    2017-01-01

    The inbred mouse strain BTBR T+ Itpr3tf/J (BTBR) i studied as a model of idiopathic autism because they are less social and more resistant to change than other strains. Forebrain serotonin receptors and the response to serotonin drugs are altered in BTBR mice, yet it remains unknown if serotonin neurons themselves are abnormal. In this study, we found that serotonin tissue content and the density of serotonin axons is reduced in the hippocampus of BTBR mice in comparison to C57BL/6J (C57) mice. This was accompanied by possible compensatory changes in serotonin neurons that were most pronounced in regions known to provide innervation to the hippocampus: the caudal dorsal raphe (B6) and the median raphe. These changes included increased numbers of serotonin neurons and hyperactivation of Fos expression. Metrics of serotonin neurons in the rostral 2/3 of the dorsal raphe and serotonin content of the prefrontal cortex were less impacted. Thus, serotonin neurons exhibit region-dependent abnormalities in the BTBR mouse that may contribute to their altered behavioral profile. PMID:27478061

  16. Serotonin dependent masking of hippocampal sharp wave ripples.

    Science.gov (United States)

    ul Haq, Rizwan; Anderson, Marlene L; Hollnagel, Jan-Oliver; Worschech, Franziska; Sherkheli, Muhammad Azahr; Behrens, Christoph J; Heinemann, Uwe

    2016-02-01

    Sharp wave ripples (SPW-Rs) are thought to play an important role in memory consolidation. By rapid replay of previously stored information during slow wave sleep and consummatory behavior, they result from the formation of neural ensembles during a learning period. Serotonin (5-HT), suggested to be able to modify SPW-Rs, can affect many neurons simultaneously by volume transmission and alter network functions in an orchestrated fashion. In acute slices from dorsal hippocampus, SPW-Rs can be induced by repeated high frequency stimulation that induces long-lasting LTP. We used this model to study SPW-R appearance and modulation by 5-HT. Although stimulation in presence of 5-HT permitted LTP induction, SPW-Rs were "masked"--but appeared after 5-HT wash-out. This SPW-R masking was dose dependent with 100 nM 5-HT being sufficient--if the 5-HT re-uptake inhibitor citalopram was present. Fenfluramine, a serotonin releaser, could also mask SPW-Rs. Masking was due to 5-HT1A and 5-HT2A/C receptor activation. Neither membrane potential nor membrane conductance changes in pyramidal cells caused SPW-R blockade since both remained unaffected by combining 5-HT and citalopram. Moreover, 10 and 30 μM 5-HT mediated SPW-R masking preceded neuronal hyperpolarization and involved reduced presynaptic transmitter release. 5-HT, as well as a 5-HT1A agonist, augmented paired pulse facilitation and affected the coefficient of variance. Spontaneous SPW-Rs in mice hippocampal slices were also masked by 5-HT and fenfluramine. While neuronal ensembles can acquire long lasting LTP during higher 5-HT levels, lower 5-HT levels enable neural ensembles to replay previously stored information and thereby permit memory consolidation memory. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Exploring anti-bacterial compounds against intracellular Legionella.

    Directory of Open Access Journals (Sweden)

    Christopher F Harrison

    Full Text Available Legionella pneumophila is a ubiquitous fresh-water bacterium which reproduces within its erstwhile predators, environmental amoeba, by subverting the normal pathway of phagocytosis and degradation. The molecular mechanisms which confer resistance to amoeba are apparently conserved and also allow replication within macrophages. Thus, L. pneumophila can act as an 'accidental' human pathogen and cause a severe pneumonia known as Legionnaires' disease. The intracellular localisation of L. pneumophila protects it from some antibiotics, and this fact must be taken into account to develop new anti-bacterial compounds. In addition, the intracellular lifestyle of L. pneumophila may render the bacteria susceptible to compounds diminishing bacterial virulence and decreasing intracellular survival and replication of this pathogen. The development of a single infection cycle intracellular replication assay using GFP-producing L. pneumophila and Acanthamoebacastellanii amoeba is reported here. This fluorescence-based assay allows for continuous monitoring of intracellular replication rates, revealing the effect of bacterial gene deletions or drug treatment. To examine how perturbations of the host cell affect L. pneumophila replication, several known host-targeting compounds were tested, including modulators of cytoskeletal dynamics, vesicle scission and Ras GTPase localisation. Our results reveal a hitherto unrealized potential antibiotic property of the β-lactone-based Ras depalmitoylation inhibitor palmostatin M, but not the closely related inhibitor palmostatin B. Further characterisation indicated that this compound caused specific growth inhibition of Legionella and Mycobacterium species, suggesting that it may act on a common bacterial target.

  18. Exploring Anti-Bacterial Compounds against Intracellular Legionella

    Science.gov (United States)

    Harrison, Christopher F.; Kicka, Sébastien; Trofimov, Valentin; Berschl, Kathrin; Ouertatani-Sakouhi, Hajer; Ackermann, Nikolaus; Hedberg, Christian; Cosson, Pierre; Soldati, Thierry; Hilbi, Hubert

    2013-01-01

    Legionella pneumophila is a ubiquitous fresh-water bacterium which reproduces within its erstwhile predators, environmental amoeba, by subverting the normal pathway of phagocytosis and degradation. The molecular mechanisms which confer resistance to amoeba are apparently conserved and also allow replication within macrophages. Thus, L. pneumophila can act as an ‘accidental’ human pathogen and cause a severe pneumonia known as Legionnaires’ disease. The intracellular localisation of L. pneumophila protects it from some antibiotics, and this fact must be taken into account to develop new anti-bacterial compounds. In addition, the intracellular lifestyle of L. pneumophila may render the bacteria susceptible to compounds diminishing bacterial virulence and decreasing intracellular survival and replication of this pathogen. The development of a single infection cycle intracellular replication assay using GFP-producing L. pneumophila and Acanthamoeba castellanii amoeba is reported here. This fluorescence-based assay allows for continuous monitoring of intracellular replication rates, revealing the effect of bacterial gene deletions or drug treatment. To examine how perturbations of the host cell affect L. pneumophila replication, several known host-targeting compounds were tested, including modulators of cytoskeletal dynamics, vesicle scission and Ras GTPase localisation. Our results reveal a hitherto unrealized potential antibiotic property of the β-lactone-based Ras depalmitoylation inhibitor palmostatin M, but not the closely related inhibitor palmostatin B. Further characterisation indicated that this compound caused specific growth inhibition of Legionella and Mycobacterium species, suggesting that it may act on a common bacterial target. PMID:24058631

  19. Tramadol: seizures, serotonin syndrome, and coadministered antidepressants.

    Science.gov (United States)

    Sansone, Randy A; Sansone, Lori A

    2009-04-01

    This ongoing column is dedicated to the challenging clinical interface between psychiatry and primary care-two fields that are inexorably linked.Tramadol (Ultram(®)) is a commonly prescribed analgesic because of its relatively lower risk of addiction and better safety profile in comparison with other opiates. However, two significant adverse reactions are known to potentially occur with tramadol-seizures and serotonin syndrome. These two adverse reactions may develop during tramadol monotherapy, but appear much more likely to emerge during misuse/overdose as well as with the coadministration of other drugs, particularly antidepressants. In this article, we review the data relating to tramadol, seizures, and serotonin syndrome. This pharmacologic intersection is of clear relevance to both psychiatrists and primary care clinicians.

  20. Binding of Serotonin to Lipid Membranes

    DEFF Research Database (Denmark)

    Peters, Günther H.J.; Wang, Chunhua; Cruys-Bagger, Nicolaj

    2013-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is a prevalent neurotransmitter throughout the animal kingdom. It exerts its effect through the specific binding to the serotonin receptor, but recent research has suggested that neural transmission may also be affected by its nonspecific interactions...... with the lipid matrix of the synaptic membrane. However, membrane–5-HT interactions remain controversial and superficially investigated. Fundamental knowledge of this interaction appears vital in discussions of putative roles of 5-HT, and we have addressed this by thermodynamic measurements and molecular...... dynamics (MD) simulations. 5-HT was found to interact strongly with lipid bilayers (partitioning coefficient ∼1200 in mole fraction units), and this is highly unusual for a hydrophilic solute like 5-HT which has a bulk, oil–water partitioning coefficient well below unity. It follows that membrane affinity...

  1. Peripheral Serotonin: a New Player in Systemic Energy Homeostasis

    Science.gov (United States)

    Namkung, Jun; Kim, Hail; Park, Sangkyu

    2015-01-01

    Whole body energy balance is achieved through the coordinated regulation of energy intake and energy expenditure in various tissues including liver, muscle and adipose tissues. A positive energy imbalance by excessive energy intake or insufficient energy expenditure results in obesity and related metabolic diseases. Although there have been many obesity treatment trials aimed at the reduction of energy intake, these strategies have achieved only limited success because of their associated adverse effects. An ancient neurotransmitter, serotonin is among those traditional pharmacological targets for anti-obesity treatment because it exhibits strong anorectic effect in the brain. However, recent studies suggest the new functions of peripheral serotonin in energy homeostasis ranging from the endocrine regulation by gut-derived serotonin to the autocrine/paracrine regulation by adipocyte-derived serotonin. Here, we discuss the role of serotonin in the regulation of energy homeostasis and introduce peripheral serotonin as a possible target for anti-obesity treatment. PMID:26628041

  2. Serotonin projection patterns to the cochlear nucleus.

    Science.gov (United States)

    Thompson, A M; Thompson, G C

    2001-07-13

    The cochlear nucleus is well known as an obligatory relay center for primary auditory nerve fibers. Perhaps not so well known is the neural input to the cochlear nucleus from cells containing serotonin that reside near the midline in the midbrain raphe region. Although the specific locations of the main, if not sole, sources of serotonin within the dorsal cochlear nucleus subdivision are known to be the dorsal and median raphe nuclei, sources of serotonin located within other cochlear nucleus subdivisions are not currently known. Anterograde tract tracing was used to label fibers originating from the dorsal and median raphe nuclei while fluorescence immunohistochemistry was used to simultaneously label specific serotonin fibers in cat. Biotinylated dextran amine was injected into the dorsal and median raphe nuclei and was visualized with Texas Red, while serotonin was visualized with fluorescein. Thus, double-labeled fibers were unequivocally identified as serotoninergic and originating from one of the labeled neurons within the dorsal and median raphe nuclei. Double-labeled fiber segments, typically of fine caliber with oval varicosities, were observed in many areas of the cochlear nucleus. They were found in the molecular layer of the dorsal cochlear nucleus, in the small cell cap region, and in the granule cell and external regions of the cochlear nuclei, bilaterally, of all cats. However, the density of these double-labeled fiber segments varied considerably depending upon the exact region in which they were found. Fiber segments were most dense in the dorsal cochlear nucleus (especially in the molecular layer) and the large spherical cell area of the anteroventral cochlear nucleus; they were moderately dense in the small cell cap region; and fiber segments were least dense in the octopus and multipolar cell regions of the posteroventral cochlear nucleus. Because of the presence of labeled fiber segments in subdivisions of the cochlear nucleus other than the

  3. Docosahexaenoyl serotonin emerges as most potent inhibitor of IL-17 and CCL-20 released by blood mononuclear cells from a series of N-acyl serotonins identified in human intestinal tissue.

    Science.gov (United States)

    Wang, Ya; Balvers, Michiel G J; Hendriks, Henk F J; Wilpshaar, Tessa; van Heek, Tjarda; Witkamp, Renger F; Meijerink, Jocelijn

    2017-09-01

    Fatty acid amides (FAAs), conjugates of fatty acids with ethanolamine, mono-amine neurotransmitters or amino acids are a class of molecules that display diverse functional roles in different cells and tissues. Recently we reported that one of the serotonin-fatty acid conjugates, docosahexaenoyl serotonin (DHA-5-HT), previously found in gut tissue of mouse and pig, attenuates the IL-23-IL-17 signaling axis in LPS-stimulated mice macrophages. However, its presence and effects in humans remained to be elucidated. Here, we report for the first time its identification in human intestinal (colon) tissue, along with a series of related N-acyl serotonins. Furthermore, we tested these fatty acid conjugates for their ability to inhibit the release of IL-17 and CCL-20 by stimulated human peripheral blood mononuclear cells (PBMCs). Serotonin conjugates with palmitic acid (PA-5-HT), stearic acid (SA-5-HT) and oleic acid (OA-5-HT) were detected in higher levels than arachidonoyl serotonin (AA-5-HT) and DHA-5-HT, while eicosapentaenoyl serotonin (EPA-5-HT) could not be quantified. Among these, DHA-5-HT was the most potent in inhibiting IL-17 and CCL-20, typical Th17 pro-inflammatory mediators, by Concanavalin A (ConA)-stimulated human PBMCs. These results underline the idea that DHA-5-HT is a gut-specific endogenously produced mediator with the capacity to modulate the IL-17/Th17 signaling response. Our findings may be of relevance in relation to intestinal inflammatory diseases like Crohn's disease and Ulcerative colitis. Copyright © 2017. Published by Elsevier B.V.

  4. Infrared Thermography in Serotonin-Induced Itch Model in Rats

    DEFF Research Database (Denmark)

    Jasemian, Yousef; Gazerani, Parisa; Dagnæs-Hansen, Frederik

    2012-01-01

    The study validated the application of infrared thermography in a serotonin-induced itch model in rats since the only available method in animal models of itch is the count of scratching bouts. Twenty four adult Sprague-Dawley male rats were used in 3 experiments: 1) local vasomotor response...... with no scratching reflex was investigated. Serotonin elicited significant scratching and lowered the local temperature at the site of injection. A negative dose-temperature relationship of serotonin was found by thermography. Vasoregulation at the site of serotonin injection took place in the absence of scratching...

  5. Serotonin synthesis, release and reuptake in terminals: a mathematical model

    Directory of Open Access Journals (Sweden)

    Best Janet

    2010-08-01

    Full Text Available Abstract Background Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels, in most cases the causal mechanisms are unknown. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders in the serotonergic signaling system. Methods We construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data. Results We compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct in silico experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to

  6. Serotonin control of thermotaxis memory behavior in nematode Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Yinxia Li

    Full Text Available Caenorhabditis elegans is as an ideal model system for the study of mechanisms underlying learning and memory. In the present study, we employed C. elegans assay system of thermotaxis memory to investigate the possible role of serotonin neurotransmitter in memory control. Our data showed that both mutations of tph-1, bas-1, and cat-4 genes, required for serotonin synthesis, and mutations of mod-5 gene, encoding a serotonin reuptake transporter, resulted in deficits in thermotaxis memory behavior. Exogenous treatment with serotonin effectively recovered the deficits in thermotaxis memory of tph-1 and bas-1 mutants to the level of wild-type N2. Neuron-specific activity assay of TPH-1 suggests that serotonin might regulate the thermotaxis memory behavior by release from the ADF sensory neurons. Ablation of ADF sensory neurons by expressing a cell-death activator gene egl-1 decreased the thermotaxis memory, whereas activation of ADF neurons by expression of a constitutively active protein kinase C homologue (pkc-1(gf increased the thermotaxis memory and rescued the deficits in thermotaxis memory in tph-1 mutants. Moreover, serotonin released from the ADF sensory neurons might act through the G-protein-coupled serotonin receptors of SER-4 and SER-7 to regulate the thermotaxis memory behavior. Genetic analysis implies that serotonin might further target the insulin signaling pathway to regulate the thermotaxis memory behavior. Thus, our results suggest the possible crucial role of serotonin and ADF sensory neurons in thermotaxis memory control in C. elegans.

  7. Serotonin control of thermotaxis memory behavior in nematode Caenorhabditis elegans.

    Science.gov (United States)

    Li, Yinxia; Zhao, Yunli; Huang, Xu; Lin, Xingfeng; Guo, Yuling; Wang, Daoyong; Li, Chaojun; Wang, Dayong

    2013-01-01

    Caenorhabditis elegans is as an ideal model system for the study of mechanisms underlying learning and memory. In the present study, we employed C. elegans assay system of thermotaxis memory to investigate the possible role of serotonin neurotransmitter in memory control. Our data showed that both mutations of tph-1, bas-1, and cat-4 genes, required for serotonin synthesis, and mutations of mod-5 gene, encoding a serotonin reuptake transporter, resulted in deficits in thermotaxis memory behavior. Exogenous treatment with serotonin effectively recovered the deficits in thermotaxis memory of tph-1 and bas-1 mutants to the level of wild-type N2. Neuron-specific activity assay of TPH-1 suggests that serotonin might regulate the thermotaxis memory behavior by release from the ADF sensory neurons. Ablation of ADF sensory neurons by expressing a cell-death activator gene egl-1 decreased the thermotaxis memory, whereas activation of ADF neurons by expression of a constitutively active protein kinase C homologue (pkc-1(gf)) increased the thermotaxis memory and rescued the deficits in thermotaxis memory in tph-1 mutants. Moreover, serotonin released from the ADF sensory neurons might act through the G-protein-coupled serotonin receptors of SER-4 and SER-7 to regulate the thermotaxis memory behavior. Genetic analysis implies that serotonin might further target the insulin signaling pathway to regulate the thermotaxis memory behavior. Thus, our results suggest the possible crucial role of serotonin and ADF sensory neurons in thermotaxis memory control in C. elegans.

  8. Metabolomics Approach Reveals Integrated Metabolic Network Associated with Serotonin Deficiency

    Science.gov (United States)

    Weng, Rui; Shen, Sensen; Tian, Yonglu; Burton, Casey; Xu, Xinyuan; Liu, Yi; Chang, Cuilan; Bai, Yu; Liu, Huwei

    2015-07-01

    Serotonin is an important neurotransmitter that broadly participates in various biological processes. While serotonin deficiency has been associated with multiple pathological conditions such as depression, schizophrenia, Alzheimer’s disease and Parkinson’s disease, the serotonin-dependent mechanisms remain poorly understood. This study therefore aimed to identify novel biomarkers and metabolic pathways perturbed by serotonin deficiency using metabolomics approach in order to gain new metabolic insights into the serotonin deficiency-related molecular mechanisms. Serotonin deficiency was achieved through pharmacological inhibition of tryptophan hydroxylase (Tph) using p-chlorophenylalanine (pCPA) or genetic knockout of the neuronal specific Tph2 isoform. This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-). Non-targeted metabolic profiling and a targeted pCPA dose-response study identified 21 biomarkers in the pCPA-treated mice while 17 metabolites in the Tph2-/- mice were found to be significantly altered compared with the control mice. These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms. Oxidative stress was also found to be significantly increased in the serotonin deficient mice. These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states.

  9. Effect of serotonin on small intestinal contractility in healthy volunteers

    DEFF Research Database (Denmark)

    Hansen, M.B.; Arif, F.; Gregersen, H.

    2008-01-01

    The physiological significance of serotonin released into the intestinal lumen for the regulation of motility is unknown in humans. The aim of this study was to evaluate the effect of serotonin infused into the lumen of the gastric antrum, duodenum or the jejunum, on antro-duodeno-jejunal contrac......The physiological significance of serotonin released into the intestinal lumen for the regulation of motility is unknown in humans. The aim of this study was to evaluate the effect of serotonin infused into the lumen of the gastric antrum, duodenum or the jejunum, on antro......-duodeno-jejunal contractility in healthy human volunteers. Manometric recordings were obtained and the effects of either a standard meal, continuous intravenous infusion of serotonin (20 nmol/kg/min) or intraluminal bolus infusions of graded doses of serotonin (2.5, 25 or 250 nmol) were compared. In addition, platelet......-depleted plasma levels of serotonin, blood pressure, heart rate and electrocardiogram were evaluated. All subjects showed similar results. Intravenous serotonin increased migrating motor complex phase In frequency 3-fold and migrating velocity 2-fold. Intraluminal infusion of serotonin did not change contractile...

  10. Plasma serotonin in horses undergoing surgery for small intestinal colic

    Science.gov (United States)

    Torfs, Sara C.; Maes, An A.; Delesalle, Catherine J.; Pardon, Bart; Croubels, Siska M.; Deprez, Piet

    2015-01-01

    This study compared serotonin concentrations in platelet poor plasma (PPP) from healthy horses and horses with surgical small intestinal (SI) colic, and evaluated their association with postoperative ileus, strangulation and non-survival. Plasma samples (with EDTA) from 33 horses with surgical SI colic were collected at several pre- and post-operative time points. Serotonin concentrations were determined using liquid-chromatography tandem mass spectrometry. Results were compared with those for 24 healthy control animals. The serotonin concentrations in PPP were significantly lower (P serotonin was not a suitable prognostic factor in horses with SI surgical colic. PMID:25694668

  11. Stimulation of aortic smooth muscle cell mitogenesis by serotonin

    International Nuclear Information System (INIS)

    Nemecek, G.M.; Coughlin, S.R.; Handley, D.A.; Moskowitz, M.A.

    1986-01-01

    Bovine aortic smooth muscle cells in vitro responded to 1 nM to 10 μM serotonin with increased incorporation of [ 3 H]thymidine into DNA. The mitogenic effect of serotonin was half-maximal at 80 nM and maximal above 1 μM. At a concentration of 1 μM, serotonin stimulated smooth muscle cell mitogenesis to the same extent as human platelet-derived growth factor (PDGF) at 12 ng/ml. Tryptamine was ≅ 1/10th as potent as serotonin as a mitogen for smooth muscle cells. Other indoles that are structurally related to serotonin (D- and L-tryptophan, 5-hydroxy-L-tryptophan, N-acetyl-5-hydroxytryptamine, melatonin, 5-hydroxyindoleacetic acid, and 5-hydroxytryptophol) and quipazine were inactive. The stimulatory effect of serotonin on smooth muscle cell DNA synthesis required prolonged (20-24 hr) exposure to the agonist and was attenuated in the presence of serotonin D receptor antagonists. When smooth muscle cells were incubated with submaximal concentrations of serotonin and PDGF, synergistic rather than additive mitogenic responses were observed. These data indicate that serotonin has a significant mitogenic effect on smooth muscle cells in vitro, which appears to be mediated by specific plasma membrane receptors

  12. Molecular imaging of serotonin degeneration in mild cognitive impairment.

    Science.gov (United States)

    Smith, Gwenn S; Barrett, Frederick S; Joo, Jin Hui; Nassery, Najlla; Savonenko, Alena; Sodums, Devin J; Marano, Christopher M; Munro, Cynthia A; Brandt, Jason; Kraut, Michael A; Zhou, Yun; Wong, Dean F; Workman, Clifford I

    2017-09-01

    Neuropathological and neuroimaging studies have consistently demonstrated degeneration of monoamine systems, especially the serotonin system, in normal aging and Alzheimer's disease. The evidence for degeneration of the serotonin system in mild cognitive impairment is limited. Thus, the goal of the present study was to measure the serotonin transporter in vivo in mild cognitive impairment and healthy controls. The serotonin transporter is a selective marker of serotonin terminals and of the integrity of serotonin projections to cortical, subcortical and limbic regions and is found in high concentrations in the serotonergic cell bodies of origin of these projections (raphe nuclei). Twenty-eight participants with mild cognitive impairment (age 66.6±6.9, 16 males) and 28 healthy, cognitively normal, demographically matched controls (age 66.2±7.1, 15 males) underwent magnetic resonance imaging for measurement of grey matter volumes and high-resolution positron emission tomography with well-established radiotracers for the serotonin transporter and regional cerebral blood flow. Beta-amyloid imaging was performed to evaluate, in combination with the neuropsychological testing, the likelihood of subsequent cognitive decline in the participants with mild cognitive impairment. The following hypotheses were tested: 1) the serotonin transporter would be lower in mild cognitive impairment compared to controls in cortical and limbic regions, 2) in mild cognitive impairment relative to controls, the serotonin transporter would be lower to a greater extent and observed in a more widespread pattern than lower grey matter volumes or lower regional cerebral blood flow and 3) lower cortical and limbic serotonin transporters would be correlated with greater deficits in auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls. Reduced serotonin transporter availability was observed in mild cognitive impairment compared to controls in cortical and limbic

  13. Ca++ dependent bistability induced by serotonin in spinal motoneurons

    DEFF Research Database (Denmark)

    Hounsgaard, J.; Kiehn, O.

    1985-01-01

    The plateau potential, responsible for the bistable state of spinal motoneurons, recently described in the decerebrate cat, was suggested to depend on serotonin (Hounsgaard et al. 1984). In an in vitro preparation of the spinal cord of the turtle we now show that serotonin, applied directly...... to the bath, transforms the intrinsic response properties of motoneurons, uncovering a plateau potential and voltage sensitive bistability. The changes induced by serotonin were blocked by Mn++, while the plateau potential and the bistability remained after application of tetrodotoxin. We conclude...... that serotonin controls the expression of a Ca++ dependent plateau potential in motoneurons....

  14. Serotonin Control of Thermotaxis Memory Behavior in Nematode Caenorhabditis elegans

    Science.gov (United States)

    Guo, Yuling; Wang, Daoyong; Li, Chaojun; Wang, Dayong

    2013-01-01

    Caenorhabditis elegans is as an ideal model system for the study of mechanisms underlying learning and memory. In the present study, we employed C. elegans assay system of thermotaxis memory to investigate the possible role of serotonin neurotransmitter in memory control. Our data showed that both mutations of tph-1, bas-1, and cat-4 genes, required for serotonin synthesis, and mutations of mod-5 gene, encoding a serotonin reuptake transporter, resulted in deficits in thermotaxis memory behavior. Exogenous treatment with serotonin effectively recovered the deficits in thermotaxis memory of tph-1 and bas-1 mutants to the level of wild-type N2. Neuron-specific activity assay of TPH-1 suggests that serotonin might regulate the thermotaxis memory behavior by release from the ADF sensory neurons. Ablation of ADF sensory neurons by expressing a cell-death activator gene egl-1 decreased the thermotaxis memory, whereas activation of ADF neurons by expression of a constitutively active protein kinase C homologue (pkc-1(gf)) increased the thermotaxis memory and rescued the deficits in thermotaxis memory in tph-1 mutants. Moreover, serotonin released from the ADF sensory neurons might act through the G-protein-coupled serotonin receptors of SER-4 and SER-7 to regulate the thermotaxis memory behavior. Genetic analysis implies that serotonin might further target the insulin signaling pathway to regulate the thermotaxis memory behavior. Thus, our results suggest the possible crucial role of serotonin and ADF sensory neurons in thermotaxis memory control in C. elegans. PMID:24223727

  15. Serotonin and conditioning: focus on Pavlovian psychostimulant drug conditioning.

    Science.gov (United States)

    Carey, Robert J; Damianopoulos, Ernest N

    2015-04-01

    Serotonin containing neurons are located in nuclei deep in the brainstem and send axons throughout the central nervous system from the spinal cord to the cerebral cortex. The vast scope of these connections and interactions enable serotonin and serotonin analogs to have profound effects upon sensory/motor processes. In that conditioning represents a neuroplastic process that leads to new sensory/motor connections, it is apparent that the serotonin system has the potential for a critical role in conditioning. In this article we review the basics of conditioning as well as the serotonergic system and point up the number of non-associative ways in which manipulations of serotonin neurotransmission have an impact upon conditioning. We focus upon psychostimulant drug conditioning and review the contribution of drug stimuli in the use of serotonin drugs to investigate drug conditioning and the important impact drug stimuli can have on conditioning by introducing new sensory stimuli that can create or mask a CS. We also review the ways in which experimental manipulations of serotonin can disrupt conditioned behavioral effects but not the associative processes in conditioning. In addition, we propose the use of the recently developed memory re-consolidation model of conditioning as an approach to assess the possible role of serotonin in associative processes without the complexities of performance effects related to serotonin treatment induced alterations in sensory/motor systems. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Stochastic models of intracellular transport

    KAUST Repository

    Bressloff, Paul C.

    2013-01-09

    The interior of a living cell is a crowded, heterogenuous, fluctuating environment. Hence, a major challenge in modeling intracellular transport is to analyze stochastic processes within complex environments. Broadly speaking, there are two basic mechanisms for intracellular transport: passive diffusion and motor-driven active transport. Diffusive transport can be formulated in terms of the motion of an overdamped Brownian particle. On the other hand, active transport requires chemical energy, usually in the form of adenosine triphosphate hydrolysis, and can be direction specific, allowing biomolecules to be transported long distances; this is particularly important in neurons due to their complex geometry. In this review a wide range of analytical methods and models of intracellular transport is presented. In the case of diffusive transport, narrow escape problems, diffusion to a small target, confined and single-file diffusion, homogenization theory, and fractional diffusion are considered. In the case of active transport, Brownian ratchets, random walk models, exclusion processes, random intermittent search processes, quasi-steady-state reduction methods, and mean-field approximations are considered. Applications include receptor trafficking, axonal transport, membrane diffusion, nuclear transport, protein-DNA interactions, virus trafficking, and the self-organization of subcellular structures. © 2013 American Physical Society.

  17. Characterization of Leptin Intracellular Trafficking

    Directory of Open Access Journals (Sweden)

    E Walum

    2009-12-01

    Full Text Available Leptin is produced by adipose tissue, and its concentration in plasma is related to the amount of fat in the body. The leptin receptor (OBR is a member of the class I cytokine receptor family and several different isoforms, produced by alternative mRNA splicing are found in many tissues, including the hypothalamus. The two predominant isoforms includes a long form (OBRl with an intracellular domain of 303 amino acids and a shorter form (OBRs with an intracellular domain of 34 amino acids. Since OBRl is mainly expressed in the hypotalamus, it has been suggested to be the main signalling form. The peripheral production of leptin by adipocyte tissue and its effects as a signal of satiety in the central nervous system imply that leptin gains access to regions of the brain regulating in energy balance by crossing the blood-brain barrier. In an attempt to characterize the intracellular transport of leptin, we have followed binding internalization and degradation of leptin in HEK293 cells. We have also monitored the intracellular transport pathway of fluorescent conjugated leptin in HEK293 cells. Phenylarsine oxide, a general inhibitor of endocytosis, as well as incubation at mild hypertonic conditions, prevented the uptake of leptin, confirming a receptor-mediated internalization process. When internalized, 125I-leptin was rapidly accumulated inside the cells and reached a maximum after 10 min. After 70 minutes about 40-50% of total counts in each time point were found in the medium as TCA-soluble material. Leptin sorting, at the level of early endosomes, did not seem to involve recycling endosomes, since FITC-leptin was sorted from Cy3- transferrin containing compartments at 37°C. At 45 minutes of continuos internalization, FITC-leptin appeared mainly accumulated in late endocytic structures colocalizing with internalized rhodamine coupled epidermial growth factor (EGF and the lysosomal marker protein lamp-1. The transport of leptin was also shown

  18. Characterization of an allosteric citalopram-binding site at the serotonin transporter

    DEFF Research Database (Denmark)

    Chen, Fenghua; Breum Larsen, Mads; Neubauer, Henrik Amtoft

    2005-01-01

    The serotonin transporter (SERT), which belongs to a family of       sodium/chloride-dependent transporters, is the major pharmacological       target in the treatment of several clinical disorders, including       depression and anxiety. In the present study we show that the dissociation......       rate, of [3H]S-citalopram from human SERT, is retarded by the presence of       serotonin, as well as by several antidepressants, when present in the       dissociation buffer. Dissociation of [3H]S-citalopram from SERT is most       potently inhibited by S-citalopram followed by R......-citalopram, sertraline,       serotonin and paroxetine. EC50 values for S- and R-citalopram are 3.6 +/-       0.4 microm and 19.4 +/- 2.3 microm, respectively. Fluoxetine, venlafaxine       and duloxetine have no significant effect on the dissociation of       [3H]S-citalopram. Allosteric modulation of dissociation...

  19. Regulation of serotonin release from enterochromaffin cells of rat cecum mucosa

    International Nuclear Information System (INIS)

    Simon, C.; Ternaux, J.P.

    1990-01-01

    The release of endogenous serotonin or previously taken up tritiated serotonin from isolated strips of rat cecum mucosa containing enterochromaffin cells was studied in vitro. Release of tritiated serotonin was increased by potassium depolarization and was decreased by tetrodotoxin, veratridine and the absence of calcium. Endogenous serotonin was released at a lower rate than tritiated serotonin; endogenous serotonin release was stimulated by potassium depolarization but was unaffected by tetrodotoxin, veratridine or the absence of calcium. Carbachol, norepinephrine, clonidine and isoproterenol decreased release of tritiated serotonin but had less or reverse effect on release of endogenous serotonin. The results suggest two different serotoninergic pools within the enterochromaffin cell population

  20. Mutational scanning of the human serotonin transporter reveals fast translocating serotonin transporter mutants

    DEFF Research Database (Denmark)

    Kristensen, Anders S; Larsen, Mads B; Johnsen, Laust B

    2004-01-01

    The serotonin transporter (SERT) belongs to a family of sodium-chloride-dependent transporters responsible for uptake of amino acids and biogenic amines from the extracellular space. SERT represents a major pharmacological target in the treatment of several clinical conditions, including depressi...

  1. Serotonin-S2 and dopamine-D2 receptors are the same size in membranes

    International Nuclear Information System (INIS)

    Brann, M.R.

    1985-01-01

    Target size analysis was used to compare the sizes of serotonin-S2 and dopamine-D2 receptors in rat brain membranes. The sizes of these receptors were standardized by comparison with the muscarinic receptor, a receptor of known size. The number of serotonin-S2 receptors labeled with (3H)ketanserin or (3H)spiperone in frontal cortex decreased as an exponential function of radiation dose, and receptor affinity was not affected. The number of dopamine-D2 receptors labeled with (3H)spiperone in striatum also decreased as an exponential function of radiation dose, and D2 and S2 receptors were equally sensitive to radiation. In both striatum and frontal cortex, the number of muscarinic receptors labeled with (3H)QNB decreased as an exponential function of radiation dose, and were much less sensitive to radiation than S2 and D2 receptors. These data indicate that in rat brain membranes, S2 and D2 receptors are of similar size, and both molecules are much larger than the muscarinic receptor

  2. No link of serotonin 2C receptor editing to serotonin transporter genotype

    NARCIS (Netherlands)

    Lyddon, R.; Cuppen, E.; Haroutunian, V.; Siever, L.J.; Dracheva, S.

    2010-01-01

    RNA editing is a post-transcriptional process, which has the potential to alter the function of encoded proteins. In particular, serotonin 2C receptor (5-HT2cR) mRNA editing can produce 24 protein isoforms of varying functionality. Rodent studies have shown that 5-HT2cR editing is dynamically

  3. Serotonergic modulation of spinal motor control

    DEFF Research Database (Denmark)

    Perrier, Jean-Francois Marie; Cotel, Florence

    2015-01-01

    Serotonin (5-HT) is a monoamine that powerfully modulates spinal motor control by acting on intrasynaptic and extrasynaptic receptors. Here we review the diversity of 5-HT actions on locomotor and motoneuronal activities. Two approaches have been used on in vitro spinal cord preparations: either...

  4. CONTRIBUTIONS OF INTRACELLULAR IONS TO Kv CHANNEL VOLTAGE SENSOR DYNAMICS.

    Directory of Open Access Journals (Sweden)

    Samuel eGoodchild

    2012-06-01

    Full Text Available Voltage sensing domains of Kv channels control ionic conductance through coupling of the movement of charged residues in the S4 segment to conformational changes at the cytoplasmic region of the pore domain, that allow K+ ions to flow. Conformational transitions within the voltage sensing domain caused by changes in the applied voltage across the membrane field are coupled to the conducting pore region and the gating of ionic conductance. However, several other factors not directly linked to the voltage dependent movement of charged residues within the voltage sensor impact the dynamics of the voltage sensor, such as inactivation, ionic conductance, intracellular ion identity and block of the channel by intracellular ligands. The effect of intracellular ions on voltage sensor dynamics is of importance in the interpretation of gating current measurements and the physiology of pore/voltage sensor coupling. There is a significant amount of variability in the reported kinetics of voltage sensor deactivation kinetics of Kv channels attributed to different mechanisms such as open state stabilization, immobilization and relaxation processes of the voltage sensor. Here we separate these factors and focus on the causal role that intracellular ions can play in allosterically modulating the dynamics of Kv voltage sensor deactivation kinetics. These considerations are of critical importance in understanding the molecular determinants of the complete channel gating cycle from activation to deactivation.

  5. Electron Microscopy of Intracellular Protozoa

    Science.gov (United States)

    1988-12-20

    Classification) " ELECTRON MICROSCOPY OF INTRACELLULAR PROTOZOA 12. PERSONAL AUTHOR(S) Aikawa, Masamichi 13a. TYPE OF REPORT I13b. TIME COVERED 114...authors suggest that anti-CS protein antibody is important in reducing the prevalence of malaria with increasing age among persons in such areas and... Hygine 33, 220-226. 0Giudice, G.D., Engers, H.D., Tougne, C., Biro, S.S., Weiss, N., Verdini, A.S., Pessi, A., Degremont, A.A., Freyvogel, T.A., Lambert

  6. Looking on the bright side of serotonin transporter gene variation.

    NARCIS (Netherlands)

    Homberg, J.R.; Lesch, K.P.

    2011-01-01

    Converging evidence indicates an association of the short (s), low-expressing variant of the repeat length polymorphism, serotonin transporter-linked polymorphic region (5-HTTLPR), in the human serotonin transporter gene (5-HTT, SERT, SLC6A4) with anxiety-related traits and increased risk for

  7. Acute serotonin depletion releases motivated inhibition of response vigour

    NARCIS (Netherlands)

    Ouden, H.E.M. den; Swart, J.C.; Schmidt, K.; Fekkes, D.; Geurts, D.E.M.; Cools, R.

    2015-01-01

    Rationale The neurotransmitter serotonin has long been implicated in the motivational control of behaviour. Recent theories propose that the role of serotonin can be understood in terms of an interaction between a motivational and a behavioural activation axis. Experimental support for these ideas,

  8. Acute serotonin depletion releases motivated inhibition of response vigour

    NARCIS (Netherlands)

    Ouden, H.E.M. den; Swart, J.C.; Schmidt, K.; Fekkes, D.; Geurts, D.E.M.; Cools, R.

    2015-01-01

    RATIONALE: The neurotransmitter serotonin has long been implicated in the motivational control of behaviour. Recent theories propose that the role of serotonin can be understood in terms of an interaction between a motivational and a behavioural activation axis. Experimental support for these ideas,

  9. Effect of serotonin infusions on the mean plasma concentrations of ...

    African Journals Online (AJOL)

    SERVER

    hhazali@hotmail.com, tabeshyarnoor@yahoo.com. neurotransmitters. It has been shown that neurons secreting serotonin may be co-locolized with neurons secreting GHRH and TRH (Bujatti et al., 1976; Bulsa et al., 1998; Savard et al., 1986; Savard et al., 1983). This indicate that serotonin as a neurotransmitter may control.

  10. Serotonin synthesis rate and the tryptophan hydroxylase-2

    DEFF Research Database (Denmark)

    Furmark, Tomas; Marteinsdottir, Ina; Frick, Andreas

    2016-01-01

    It is disputed whether anxiety disorders, like social anxiety disorder, are characterized by serotonin over- or underactivity. Here, we evaluated whether our recent finding of elevated neural serotonin synthesis rate in patients with social anxiety disorder could be reproduced in a separate cohor...

  11. Brain serotonin content - Increase following ingestion of carbohydrate diet.

    Science.gov (United States)

    Fernstrom, J. D.; Wurtman, R. J.

    1971-01-01

    In the rat, the injection of insulin or the consumption of carbohydrate causes sequential increases in the concentrations of tryptophan in the plasma and the brain and of serotonin in the brain. Serotonin-containing neurons may thus participate in systems whereby the rat brain integrates information about the metabolic state in its relation to control of homeostasis and behavior.

  12. Interaction of antidepressants with the serotonin and norepinephrine transporters

    DEFF Research Database (Denmark)

    Sørensen, Lena; Andersen, Jacob; Thomsen, Mette

    2012-01-01

    The serotonin transporter (SERT) and the norepinephrine transporter (NET) are sodium-dependent neurotransmitter transporters responsible for reuptake of released serotonin and norepinephrine, respectively, into nerve terminals in the brain. A wide range of inhibitors of SERT and NET are used...

  13. The rat frontal cortex serotonin receptors. Influence of supraletal irradiation

    International Nuclear Information System (INIS)

    Chanez, P.O.; Timmermans, R.; Gerber, G.B.

    1984-01-01

    The density of the frontal cortex serotonin-2 receptors was determined after a supralethal irradiation (20 Gy) in Wistar rat. Using spiperone as ligand, we observed an important decrease in the density of serotonin-2 receptor and an increase in the dissociation constant receptor-ligand, 3 days after exposure [fr

  14. Understanding the role of serotonin in psychiatric diseases [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Donatella Marazziti

    2017-02-01

    Full Text Available Serotonin (5-HT continues to attract researchers’ interest after almost a century. However, despite these efforts, its role has not yet been fully elucidated. It is now evident that 5-HT does not modulate single functions but rather a multiplicity of activities and behaviors present in both normal and several pathological conditions in a less deterministic way than previously assumed. This article aims to briefly review some of the latest advancements in the general role of 5-HT in psychiatry, particularly in depression, and offer the author’s personal reflections.

  15. Distribution of catecholamines and serotonin in the rat cerebral cortex:

    International Nuclear Information System (INIS)

    Reader, T.A.

    1981-01-01

    The rat cerebral cortex was dissected in five regions and analyzed for the catecholamines noradrenaline, adrenaline and dopamine, and for the indoleamine seroton in using sensitive radioenzymatic assay methods with thin-layer-chromatography. The noradrenaline concentration was highest in the ventral cortex, lateral to the hypothalamus, had intermediate values for the prefrontal, frontal and parietal cortical areas and was lowest in the occipital cortex. Dopamine levels were also highest in the cortex lateral to the hypothalamus, and moderate in the prefrontal and frontal cortical areas, with the lowest values measured for the occipital cortex. The ratios dopamine/noradrenaline further support the hypothesis that they are independent transmitters. Traces of adrenaline were measured in all regions examined. The serotonin distribution was found to be non-homogeneous, with the highest values for the prefrontal cortex and ventral cortex lateral to the hypothalamus. The functional significance of these amines and their ratios are discussed in relation to their role as putative modulators of cortical neuronal excitability. (author)

  16. Pathogenic mechanisms of intracellular bacteria.

    Science.gov (United States)

    Niller, Hans Helmut; Masa, Roland; Venkei, Annamária; Mészáros, Sándor; Minarovits, Janos

    2017-06-01

    We wished to overview recent data on a subset of epigenetic changes elicited by intracellular bacteria in human cells. Reprogramming the gene expression pattern of various host cells may facilitate bacterial growth, survival, and spread. DNA-(cytosine C5)-methyltransferases of Mycoplasma hyorhinis targeting cytosine-phosphate-guanine (CpG) dinucleotides and a Mycobacterium tuberculosis methyltransferase targeting non-CpG sites methylated the host cell DNA and altered the pattern of gene expression. Gene silencing by CpG methylation and histone deacetylation, mediated by cellular enzymes, also occurred in M. tuberculosis-infected macrophages. M. tuberculosis elicited cell type-specific epigenetic changes: it caused increased DNA methylation in macrophages, but induced demethylation, deposition of euchromatic histone marks and activation of immune-related genes in dendritic cells. A secreted transposase of Acinetobacter baumannii silenced a cellular gene, whereas Mycobacterium leprae altered the epigenotype, phenotype, and fate of infected Schwann cells. The 'keystone pathogen' oral bacterium Porphyromonas gingivalis induced local DNA methylation and increased the level of histone acetylation in host cells. These epigenetic changes at the biofilm-gingiva interface may contribute to the development of periodontitis. Epigenetic regulators produced by intracellular bacteria alter the epigenotype and gene expression pattern of host cells and play an important role in pathogenesis.

  17. Effect of serotonin on the expression of antigens and DNA levels in Yersinia pestis cells with different plasmid content

    Science.gov (United States)

    Klueva, Svetlana N.; Korsukov, Vladimir N.; Schukovskaya, Tatyana N.; Kravtsov, Alexander L.

    2004-08-01

    Using flow cytometry (FCM) the influence of exogenous serotonin on culture growth, DNA content and fluorescence intensity of cells binding FITC-labelled plague polyclonal immunoglobulins was studied in Yersinia pestis EV (pFra+, pCad+, pPst+), Yersinia pestis KM218 (pFra-, pCad-, pPst-), Yersinia pestis KM 216 (pFra-, pCad-, pPst+). The results have been obtained by FCM showed serotonin accelerated Yersinia pestis EV (pFra+, pCad+, pPst+), Yersinia pestis KM218 (pFra-, pCad-, pPst-) culture growth during cultivation in Hottinger broth pH 7.2 at 28°C at concentration of 10-5 M. The presence of 10-5 M serotonin in nutrient broth could modulate DNA content in 37°C growing population of plague microbe independently of their plasmid content. Serotonin have been an impact on the distribution pattern of the cells according to their phenotypical characteristics, which was reflected in the levels of population heterogeneity in the intensity of specific immunofluorescence determined by FMC.

  18. Am5-HT7: molecular and pharmacological characterization of the first serotonin receptor of the honeybee (Apis mellifera).

    Science.gov (United States)

    Schlenstedt, Jana; Balfanz, Sabine; Baumann, Arnd; Blenau, Wolfgang

    2006-09-01

    The biogenic amine serotonin (5-HT) plays a key role in the regulation and modulation of many physiological and behavioural processes in both vertebrates and invertebrates. These functions are mediated through the binding of serotonin to its receptors, of which 13 subtypes have been characterized in vertebrates. We have isolated a cDNA from the honeybee Apis mellifera (Am5-ht7) sharing high similarity to members of the 5-HT(7) receptor family. Expression of the Am5-HT(7) receptor in HEK293 cells results in an increase in basal cAMP levels, suggesting that Am5-HT(7) is expressed as a constitutively active receptor. Serotonin application to Am5-ht7-transfected cells elevates cyclic adenosine 3',5'-monophosphate (cAMP) levels in a dose-dependent manner (EC(50) = 1.1-1.8 nm). The Am5-HT(7) receptor is also activated by 5-carboxamidotryptamine, whereas methiothepin acts as an inverse agonist. Receptor expression has been investigated by RT-PCR, in situ hybridization, and western blotting experiments. Receptor mRNA is expressed in the perikarya of various brain neuropils, including intrinsic mushroom body neurons, and in peripheral organs. This study marks the first comprehensive characterization of a serotonin receptor in the honeybee and should facilitate further analysis of the role(s) of the receptor in mediating the various central and peripheral effects of 5-HT.

  19. Melatonin and serotonin effects on gastrointestinal motility.

    Science.gov (United States)

    Thor, P J; Krolczyk, G; Gil, K; Zurowski, D; Nowak, L

    2007-12-01

    The gastrointestinal tract represents the most important extra pineal source of melatonin. Presence of melatonin (M) suggests that this hormone is somehow involved in digestive pathophysiology. Release of GI melatonin from serotonin-rich enterochromaffin EC cells of the GI mucosa suggest close antagonistic relationship with serotonin (S) and seem to be related to periodicity of food intake. Food deprivation resulted in an increase of tissue and plasma concentrations of M. Its also act as an autocrine and paracrine hormone affecting not only epithelium and immune system but also smooth muscle of the digestive tract. Low doses M improve gastrointestinal transit and affect MMC. M reinforce MMCs cyclic pattern but inhibits spiking bowel activity. Pharmacological doses of M delay gastric emptying via mechanisms that involve CCK2 and 5HT3 receptors. M released in response to lipid infusion exerts a modulatory influence that decreases the inhibitory effects of the ileal brake on gastric emptying. On isolated bowel S induces dose dependent increase in tone and reduction in amplitude of contraction which is affected by M. M reduced the tone but not amplitude or frequency of contraction. M is a promising therapeutic agent for IBS with activities independent of its effects on sleep, anxiety or depression. Since of its unique properties M could be considered for prevention or treatment of colorectal cancer, ulcerative colitis, gastric ulcers and irritable bowel syndrome.

  20. Emerging Paradigm of Intracellular Targeting of G Protein-Coupled Receptors.

    Science.gov (United States)

    Chaturvedi, Madhu; Schilling, Justin; Beautrait, Alexandre; Bouvier, Michel; Benovic, Jeffrey L; Shukla, Arun K

    2018-05-04

    G protein-coupled receptors (GPCRs) recognize a diverse array of extracellular stimuli, and they mediate a broad repertoire of signaling events involved in human physiology. Although the major effort on targeting GPCRs has typically been focused on their extracellular surface, a series of recent developments now unfold the possibility of targeting them from the intracellular side as well. Allosteric modulators binding to the cytoplasmic surface of GPCRs have now been described, and their structural mechanisms are elucidated by high-resolution crystal structures. Furthermore, pepducins, aptamers, and intrabodies targeting the intracellular face of GPCRs have also been successfully utilized to modulate receptor signaling. Moreover, small molecule compounds, aptamers, and synthetic intrabodies targeting β-arrestins have also been discovered to modulate GPCR endocytosis and signaling. Here, we discuss the emerging paradigm of intracellular targeting of GPCRs, and outline the current challenges, potential opportunities, and future outlook in this particular area of GPCR biology. Copyright © 2018 Elsevier Ltd. All rights reserved.

  1. Serotonin 2c receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis

    Science.gov (United States)

    Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor a...

  2. Modeling serotonin uptake in the lung shows endothelial transporters dominate over cleft permeation

    Science.gov (United States)

    Bassingthwaighte, James B.

    2013-01-01

    A four-region (capillary plasma, endothelium, interstitial fluid, cell) multipath model was configured to describe the kinetics of blood-tissue exchange for small solutes in the lung, accounting for regional flow heterogeneity, permeation of cell membranes and through interendothelial clefts, and intracellular reactions. Serotonin uptake data from the Multiple indicator dilution “bolus sweep” experiments of Rickaby and coworkers (Rickaby DA, Linehan JH, Bronikowski TA, Dawson CA. J Appl Physiol 51: 405–414, 1981; Rickaby DA, Dawson CA, and Linehan JH. J Appl Physiol 56: 1170–1177, 1984) and Malcorps et al. (Malcorps CM, Dawson CA, Linehan JH, Bronikowski TA, Rickaby DA, Herman AG, Will JA. J Appl Physiol 57: 720–730, 1984) were analyzed to distinguish facilitated transport into the endothelial cells (EC) and the inhibition of tracer transport by nontracer serotonin in the bolus of injectate from the free uninhibited permeation through the clefts into the interstitial fluid space. The permeability-surface area products (PS) for serotonin via the inter-EC clefts were ∼0.3 ml·g−1·min−1, low compared with the transporter-mediated maximum PS of 13 ml·g−1·min−1 (with Km = ∼0.3 μM and Vmax = ∼4 nmol·g−1·min−1). The estimates of serotonin PS values for EC transporters from their multiple data sets were similar and were influenced only modestly by accounting for the cleft permeability in parallel. The cleft PS estimates in these Ringer-perfused lungs are less than half of those for anesthetized dogs (Yipintsoi T. Circ Res 39: 523–531, 1976) with normal hematocrits, but are compatible with passive noncarrier-mediated transport observed later in the same laboratory (Dawson CA, Linehan JH, Rickaby DA, Bronikowski TA. Ann Biomed Eng 15: 217–227, 1987; Peeters FAM, Bronikowski TA, Dawson CA, Linehan JH, Bult H, Herman AG. J Appl Physiol 66: 2328–2337, 1989) The identification and quantitation of the cleft pathway conductance from these

  3. The effect of an inhibitor of gut serotonin (LP533401) during the induction of periodontal disease.

    Science.gov (United States)

    Lima, G M G; Corazza, B J M; Moraes, R M; de Oliveira, F E; de Oliveira, L D; Franco, G C N; Perrien, D S; Elefteriou, F; Anbinder, A L

    2016-10-01

    LP533401 is an inhibitor of tryptophan hydroxylase 1, which regulates serotonin production in the gut. Previous work indicates that LP533401 has an anabolic effect in bone. Thus, we hypothesized that inhibition of gut serotonin production may modulate the host response in periodontal disease. In this study, we aimed to analyze the effects of LP533401 in a rat periodontitis model to evaluate the role of gut serotonin in periodontitis pathophysiology. Twenty-four rats were divided into three groups: treated group (T: ligature-induced periodontal disease and LP533401, 25 mg/kg/d) by gavage; ligature group (L: ligature-induced periodontal disease only); and control group (C: without ligature-induced periodontal disease). After 28 d, radiographic alveolar bone support was measured on digital radiographs, and alveolar bone volume fraction, tissue mineral density and trabeculae characteristics were quantified by microcomputed tomography in the right hemi-mandible. Left hemi-mandibles were decalcified and alveolar bone loss, attachment loss and area of collagen in the gingiva were histologically analyzed. Significant difference between the L and C groups was found, confirming that periodontal disease was induced. We observed no difference between the T and L groups regarding alveolar bone destruction and area of collagen. LP533401 (25 mg/kg/d) for 28 d does not prevent bone loss and does not modulate host response in a rat model of induced periodontal disease. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin-Enhanced Platelet Function

    Science.gov (United States)

    Lin, Olivia A.; Karim, Zubair A.; Vemana, Hari Priya; Espinosa, Enma V. P.; Khasawneh, Fadi T.

    2014-01-01

    There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EMD 281014, and to clopidogrel, a commonly used antiplatelet drug, again, in a fashion comparable to clopidogrel and EMD 281014. Collectively, our data indicate that the antidepressant 5-HT2A antagonists, cyproheptadine and pizotifen do exert antiplatelet and thromboprotective effects, but similar to clopidogrel and EMD 281014, their

  5. Selective serotonin reuptake inhibitors and risk for gastrointestinal bleeding

    Directory of Open Access Journals (Sweden)

    Batić-Mujanović Olivera

    2014-01-01

    Full Text Available The most of the known effects of selective serotonin reuptake inhibitors, beneficial or harmful, are associated with the inhibitory action of the serotonin reuptake transporter. This mechanism is present not only in neurons, but also in other cells such as platelets. Serotoninergic mechanism seems to have an important role in hemostasis, which has long been underestimated. Abnormal activation may lead to a prothrombotic state in patients treated with selective serotonin reuptake inhibitors. On one hand there may be an increased risk of bleeding, and on the other hand reduction in thrombotic risk may be possible. Serotonin is critical to maintain a platelet haemostatic function, such as platelet aggregation. Evidences from the studies support the hypothesis that antidepressants with a relevant blockade of action of serotonin reuptake mechanism may increase the risk of bleeding, which can occur anywhere in the body. Epidemiological evidences are, however, the most robust for upper gastrointestinal bleeding. It is estimated that this bleeding can occur in 1 in 100 to 1 in 1.000 patient-years of exposure to the high-affinity selective serotonin reuptake inhibitors, with very old patients at the highest risk. The increased risk may be of particular relevance when selective serotonin reuptake inhibitors are taken simultaneously with nonsteroidal anti-inflammatory drugs, low dose of aspirin or warfarin.

  6. The Role of Serotonin in Ventricular Repolarization in Pregnant Mice.

    Science.gov (United States)

    Cui, Shanyu; Park, Hyewon; Park, Hyelim; Mun, Dasom; Lee, Seung Hyun; Kim, Hyoeun; Yun, Nuri; Kim, Hail; Kim, Michael; Pak, Hui Nam; Lee, Moon Hyoung; Joung, Boyoung

    2018-03-01

    The mechanisms underlying repolarization abnormalities during pregnancy are not fully understood. Although maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant for normal fetal development in mice, its role in mothers remains unclear. We evaluated the role of serotonin in ventricular repolarization in mice hearts via 5Htr3 receptor (Htr3a) and investigated the mechanism of QT-prolongation during pregnancy. We measured current amplitudes and the expression levels of voltage-gated K⁺ (Kv) channels in freshly-isolated left ventricular myocytes from wild-type non-pregnant (WT-NP), late-pregnant (WT-LP), and non-pregnant Htr3a homozygous knockout mice (Htr3a(-/-)-NP). During pregnancy, serotonin and tryptophan hydroxylase 1, a rate-limiting enzyme for the synthesis of serotonin, were markedly increased in hearts and serum. Serotonin increased Kv current densities concomitant with the shortening of the QT interval in WT-NP mice, but not in WT-LP and Htr3a(-/-)-NP mice. Ondansetron, an Htr3 antagonist, decreased Kv currents in WT-LP mice, but not in WT-NP mice. Kv4.3 directly interacted with Htr3a, and this binding was facilitated by serotonin. Serotonin increased the trafficking of Kv4.3 channels to the cellular membrane in WT-NP. Serotonin increases repolarizing currents by augmenting Kv currents. Elevated serotonin levels during pregnancy counterbalance pregnancy-related QT prolongation by facilitating Htr3-mediated Kv currents. © Copyright: Yonsei University College of Medicine 2018

  7. Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors

    International Nuclear Information System (INIS)

    Pazos, A.; Palacios, M.

    1985-01-01

    The distribution of serotonin-1 (5-HT 1 ) receptors in the rat brain was studied by light microscopic quantitative autoradiography. Receptors were labeled with [ 3 H]serotonin (5-[ 3 H]HT), 8-hydroxy-2-[N-dipropylamino- 3 H]tetralin (8-OH-[ 3 H]DPAT), [ 3 H]LSD and [ 3 H]mesulergine, and the densities quantified by microdensitometry with the aid of a computer-assisted image-analysis system. Competition experiments for 5-[ 3 H]HT binding by several serotonin-1 agonists led to the identification of brain areas enriched in each one of the three subtypes of 5-HT 1 recognition sites already described. The existence of these 'selective' areas allowed a detailed pharmacological characterization of these sites to be made in a more precise manner than has been attained in membrane-binding studies. Very high concentrations of 5-HT 1 receptors were localized in the choroid plexus, lateroseptal nucleus, globus pallidus and ventral pallidum, dentate gyrus, dorsal subiculum, olivary pretectal nucleus, substantia nigra, reticular and external layer of the entorhinal cortex. The distribution of 5-HT 1 receptors reported here is discussed in correlation with the distribution of serotoninergic neurons and fibers, the related anatomical pathways and the effects which appear to be mediated by these sites. (Auth.)

  8. MR imaging of intracellular and extracellular deoxyhemoglobin

    International Nuclear Information System (INIS)

    Janick, P.A.; Grossman, R.I.; Asakura, T.

    1989-01-01

    MR imaging was performed on varying concentrations of intracellular and extracellular deoxyhemoglobin as well as varying proportions of deoxyhemoglobin and oxyhemoglobin in vitro at 1.5T with use of standard spin-echo and gradient-refocused spin sequences. This study indicates that susceptibility-induced T2 shortening occurs over a broad range of intracellular deoxyhemoglobin concentrations (maximal at hematocrits between 20% and 45%), reflecting diffusional effects at the cellular level. T2* gradient-echo imaging enhances the observed hypointensity in images of intracellular deoxyhemoglobin. The characteristic MR appearance of acute hemotomas can be modeled by the behavior of intracellular and extracellular deoxyhemoglobin and oxyhemoglobin

  9. Serotonin syndrome:case report and current concepts.

    LENUS (Irish Health Repository)

    Fennell, J

    2005-05-01

    Selective serotonin reuptake inhibitors (SSRI\\'s) are increasingly being used as the first line therapeutic agent for the depression. It is therefore not unusual to see a case of overdose with these agents. More commonly an adverse drug reaction may be seen among the older patients who are particularly vulnerable to the serotonin syndrome due to multiple co-morbidity and polypharmacy. The clinical picture of serotonin syndrome (SS) is non-specific and there is no confirmatory test. SS may go unrecognized because it is often mistaken for a viral illness, anxiety, neurological disorder or worsening psychiatric condition.

  10. The importance of serotonin in the gastrointestinal tract

    Directory of Open Access Journals (Sweden)

    Jarosław Koza

    2017-12-01

    Description of the current knowledge and conclusions. Serotonin is responsible for some symptoms of carcinoid syndrome. It is the result of higher 5-hydroxytryptamine content in the body. Moreover disrupted serotonin system is found in different gastrointestinal disorders e.g. in gastroesophageal reflux disease, functional heartburn, hypersensitive esophagus, functional dyspepsia, irritable bowel syndrome (both diarrhoea predominant and constipation predominant as well as in inflammatory bowel diseases. Knowledge of changed mechanisms in particular diseases facilitates the optimal choice of treatment. Drugs affecting the serotonin system in gastroenterological clinical practice are useful especially in the case of abnormalities in the brain - gut axis.

  11. Moderation of antidepressant response by the serotonin transporter gene

    DEFF Research Database (Denmark)

    Huezo-Diaz, Patricia; Uher, Rudolf; Smith, Rebecca

    2009-01-01

    Background: There have been conflicting reports on whether the length polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) moderates the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs). We hypothesised that the pharmacogenetic effect of 5-HTTLPR...... the serotonin transporter gene were genotyped in 795 adults with moderate-to-severe depression treated with escitalopram or nortriptyline in the Genome Based Therapeutic Drugs for Depression (GENDEP) project. Results: The 5-HTTLPR moderated the response to escitalopram, with long-allele carriers improving more...

  12. Hippocampal volume and serotonin transporter polymorphism in major depressive disorder

    DEFF Research Database (Denmark)

    Ahdidan, Jamila; Foldager, Leslie; Rosenberg, Raben

    2013-01-01

    Objective: The main aim of the present study was to replicate a previous finding in major depressive disorder (MDD) of association between reduced hippocampal volume and the long variant of the di- and triallelic serotonin transporter polymorphism in SLC6A4 on chromosome 17q11.2. Secondarily, we...... that we aimed to replicate, and no significant associations with the serotonin transporter polymorphism were found. Conclusions: The present quantitative and morphometric MRI study was not able to replicate the previous finding of association between reduced hippocampal volume in depressed patients...... and the serotonin transporter polymorphism....

  13. Tributyltin impaired reproductive success in female zebrafish through disrupting oogenesis, reproductive behaviors and serotonin synthesis.

    Science.gov (United States)

    Xiao, Wei-Yang; Li, Ying-Wen; Chen, Qi-Liang; Liu, Zhi-Hao

    2018-07-01

    Tributyltin (TBT), an organotin acting as aromatase (Cyp19a1) inhibitor, has been found to disrupt gametogenesis and reproductive behaviors in several fish species. However, few studies addressing the mechanisms underlying the impaired gametogenesis and reproduction have been reported. In this study, female adults of zebrafish (Danio rerio) were continuously exposed to two nominal concentrations of TBT (100 and 500 ng/L, actual concentrations: 90.8 ± 1.3 ng/L and 470.3 ± 2.7 ng/L, respectively) for 28 days. After exposures, TBT decreased the total egg number, reduced the hatchability and elevated the mortality of the larvae. Decreased gonadosomatic index (GSI) and altered percentages of follicles in different developmental stages (increased early-stage follicles and reduced mid/late-stage follicles) were also observed in the ovary of TBT-treated fish. TBT also lowered the plasma level of 17β-estradiol and suppressed the expressions of cyp19a1a in the ovary. In treated fish, up-regulated expressions of aldhla2, sycp3 and dmc1 were present in the ovary, indicating an enhanced level of meiosis. The mRNA level of vtg1 was dramatically suppressed in the liver of TBT-treated fish, suggesting an insufficient synthesis of Vtg protein, consistent with the decreased percentage of mid/late-stage follicles in the ovaries. Moreover, TBT significantly suppressed the reproductive behaviors of the female fish (duration of both sexes simultaneously in spawning area, the frequency of meeting and the visit in spawning area) and down-regulated the mRNA levels of genes involved in the regulation of reproductive behaviors (cyp19a1b, gnrh-3 and kiss 2) in the brain. In addition, TBT significantly suppressed the expressions of serotonin-related genes, such as tph2 (encoding serotonin synthase), pet1 (marker of serotonin neuron) and kiss 1 (the modulator of serotonin synthesis), suggesting that TBT might disrupt the non-reproductive behaviors of zebrafish. The present

  14. The serotonin transporter: Examination of the changes in transporter affinity induced by ligand binding

    International Nuclear Information System (INIS)

    Humphreys, C.J.

    1989-01-01

    The plasmalemmal serotonin transporter uses transmembrane gradients of Na + , Cl - and K + to accumulate serotonin within blood platelets. Transport is competitively inhibited by the antidepressant imipramine. Like serotonin transport, imipramine binding requires Na + . Unlike serotonin, however, imipramine does not appear to be transported. To gain insight into the mechanism of serotonin transport the author have analyzed the influences of Na + and Cl - , the two ions cotransported with serotonin, on both serotonin transport and the interaction of imipramine and other antidepressant drugs with the plasmalemmal serotonin transporter of human platelets. Additionally, the author have synthesized, purified and characterized the binding of 2-iodoimipramine to the serotonin transporter. Finally, the author have conducted a preliminary study of the inhibition of serotonin transport and imipramine binding produced by dicyclohexylcarbodiimide. My results reveal many instances of positive heterotropic cooperativity in ligand binding to the serotonin transporter. Na + binding enhances the transporters affinity for imipramine and several other antidepressant drugs, and also increases the affinity for Cl - . Cl - enhances the transporters affinity for imipramine, as well as for Na + . At concentrations in the range of its K M for transport serotonin is a competitive inhibitor of imipramine binding. At much higher concentrations, however, serotonin also inhibits imipramines dissociation rate constant. This latter effect which is Na + -independent and species specific, is apparently produced by serotonin binding at a second, low affinity site on, or near, the transporter complex. Iodoimipramine competitively inhibit both [ 3 H]imipramine binding and [ 3 H]serotonin transport

  15. Serotonin binding in vitro by releasable proteins from human blood platelets

    International Nuclear Information System (INIS)

    Heemstra, V.L.

    1983-11-01

    Among the substances released from human blood platelets are serotonin and various proteins. It was hypothesized that one of these proteins binds serotonin and that serotonin might be important to the protein's function or that the protein might be important to serotonin's function. Two platelet-specific proteins, platelet factor 4 (PF4) and β-thromboglobulin (βTG) were found to bind serotonin in vitro. Endogenous PF4 was isolated by serotonin-affinity chromatography and was identified by radioimmunoassay. Purified [ 125 I] -PF4 and native PF4 bound to and eluted from a serotonin-affinity column similarly. Ultrafiltration of the homologous protein, βTG, with [ 14 C]-serotonin demonstrated binding of about 8 moles serotonin per mole tetrameric βTG with a dissociation constant of about 4 X 10(sup-8) M. Equilibrium dialysis of PF4 with radiolabelled serotonin was attempted, but no binding constant values were obtained because serotonin apparently bound to the dialysis membrane. Since EDTA was one of the two agents that eluted PF4 from the serotonin-affinity gel, calcium binding by PF4 was investigated by equilibrium dialysis. Evidence was obtained for positively cooperative binding of calcium ions by PF4. It is concluded that PF4 and βTG bind serotonin in vitro, that they may also bind in vivo when platelets undergo release, and that the functions of serotonin, PF4 and βTG may be mediated in part by serotonin-protein associations

  16. The serotonin transporter and early life stress : Translational perspectives

    NARCIS (Netherlands)

    Houwing, Danielle J; Buwalda, Bauke; Zee, van der Eddy; de Boer, Sietse F; Olivier, Jocelien D A

    2017-01-01

    The interaction between the serotonin transporter (SERT) linked polymorphic region (5-HTTLPR) and adverse early life stressing (ELS) events is associated with enhanced stress susceptibility and risk to develop mental disorders like major depression, anxiety, and aggressiveness. In particular, human

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

    Science.gov (United States)

    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)

  18. Cholinesterase catalyzed hydrolysis of O-acyl derivatives of serotonin

    International Nuclear Information System (INIS)

    Makhaeva, G.F.; Suvorov, N.N.; Ginodman, L.N.; Antonov, V.K.; AN SSSR, Moscow. Inst. Bioorganicheskoj Khimii)

    1977-01-01

    Hydrolysis of O acyl serotonin derivatives containing the residues of monocarbon dicarbon and amino acids under the effect of horse serum butyryl cholinesterase and bull erythrocytic acetylcholinesterase has been studied. It has been established, that acetylcholinesterase hydrolizes O acetylserotonin only; butyrylcholinesterase hydrolizes all the compounds investigated, except for 5,5'-terephthaloildioxytriptamine. The kinetic parameters of hydrolysis were determined. O acyl serotonin derivatives turned out good substrates of butylrylcholinesterase; serotonin and 5.5'-terephtaloildioxytriptamine are effective competitine inhibitors of the enzyme. Estimating of resistance of O acyl serotonin derivatines to blood cholinesterase effect under physiological conditions shows that the compounds investigated with the exception of 5,5'-terephthaloildioxytriptamine must be quickly hydrolyzed under butyrylcholinesterase action. 5,5'-terephthaloildioxytriptamine is suggested as a radioprotective preparation with the prolonged effect, which agrees with the biological test results

  19. [3]tetrahydrotrazodone binding. Association with serotonin binding sites

    International Nuclear Information System (INIS)

    Kendall, D.A.; Taylor, D.P.; Enna, S.J.

    1983-01-01

    High (17 nM) and low (603 nM) affinity binding sites for [ 3 ]tetrahydrotrazodone ([ 3 ] THT), a biologically active analogue of trazodone, have been identified in rat brain membranes. The substrate specificity, concentration, and subcellular and regional distributions of these sites suggest that they may represent a component of the serotonin transmitter system. Pharmacological analysis of [ 3 ]THT binding, coupled with brain lesion and drug treatment experiments, revealed that, unlike other antidepressants, [ 3 ] THT does not attach to either a biogenic amine transporter or serotonin binding sites. Rather, it would appear that [ 3 ]THT may be an antagonist ligand for the serotonin binding site. This probe may prove of value in defining the mechanism of action of trazodone and in further characterizing serotonin receptors

  20. Dynamics of intracellular information decoding

    International Nuclear Information System (INIS)

    Kobayashi, Tetsuya J; Kamimura, Atsushi

    2011-01-01

    A variety of cellular functions are robust even to substantial intrinsic and extrinsic noise in intracellular reactions and the environment that could be strong enough to impair or limit them. In particular, of substantial importance is cellular decision-making in which a cell chooses a fate or behavior on the basis of information conveyed in noisy external signals. For robust decoding, the crucial step is filtering out the noise inevitably added during information transmission. As a minimal and optimal implementation of such an information decoding process, the autocatalytic phosphorylation and autocatalytic dephosphorylation (aPadP) cycle was recently proposed. Here, we analyze the dynamical properties of the aPadP cycle in detail. We describe the dynamical roles of the stationary and short-term responses in determining the efficiency of information decoding and clarify the optimality of the threshold value of the stationary response and its information-theoretical meaning. Furthermore, we investigate the robustness of the aPadP cycle against the receptor inactivation time and intrinsic noise. Finally, we discuss the relationship among information decoding with information-dependent actions, bet-hedging and network modularity

  1. Dynamics of intracellular information decoding.

    Science.gov (United States)

    Kobayashi, Tetsuya J; Kamimura, Atsushi

    2011-10-01

    A variety of cellular functions are robust even to substantial intrinsic and extrinsic noise in intracellular reactions and the environment that could be strong enough to impair or limit them. In particular, of substantial importance is cellular decision-making in which a cell chooses a fate or behavior on the basis of information conveyed in noisy external signals. For robust decoding, the crucial step is filtering out the noise inevitably added during information transmission. As a minimal and optimal implementation of such an information decoding process, the autocatalytic phosphorylation and autocatalytic dephosphorylation (aPadP) cycle was recently proposed. Here, we analyze the dynamical properties of the aPadP cycle in detail. We describe the dynamical roles of the stationary and short-term responses in determining the efficiency of information decoding and clarify the optimality of the threshold value of the stationary response and its information-theoretical meaning. Furthermore, we investigate the robustness of the aPadP cycle against the receptor inactivation time and intrinsic noise. Finally, we discuss the relationship among information decoding with information-dependent actions, bet-hedging and network modularity.

  2. Secretome of obligate intracellular Rickettsia

    Science.gov (United States)

    Gillespie, Joseph J.; Kaur, Simran J.; Rahman, M. Sayeedur; Rennoll-Bankert, Kristen; Sears, Khandra T.; Beier-Sexton, Magda; Azad, Abdu F.

    2014-01-01

    The genus Rickettsia (Alphaproteobacteria, Rickettsiales, Rickettsiaceae) is comprised of obligate intracellular parasites, with virulent species of interest both as causes of emerging infectious diseases and for their potential deployment as bioterrorism agents. Currently, there are no effective commercially available vaccines, with treatment limited primarily to tetracycline antibiotics, although others (e.g. josamycin, ciprofloxacin, chloramphenicol, and azithromycin) are also effective. Much of the recent research geared toward understanding mechanisms underlying rickettsial pathogenicity has centered on characterization of secreted proteins that directly engage eukaryotic cells. Herein, we review all aspects of the Rickettsia secretome, including six secretion systems, 19 characterized secretory proteins, and potential moonlighting proteins identified on surfaces of multiple Rickettsia species. Employing bioinformatics and phylogenomics, we present novel structural and functional insight on each secretion system. Unexpectedly, our investigation revealed that the majority of characterized secretory proteins have not been assigned to their cognate secretion pathways. Furthermore, for most secretion pathways, the requisite signal sequences mediating translocation are poorly understood. As a blueprint for all known routes of protein translocation into host cells, this resource will assist research aimed at uniting characterized secreted proteins with their apposite secretion pathways. Furthermore, our work will help in the identification of novel secreted proteins involved in rickettsial ‘life on the inside’. PMID:25168200

  3. HYPERTHERMIA, INTRACELLULAR FREE CALCIUM AND CALCIUM IONOPHORES

    NARCIS (Netherlands)

    STEGE, GJJ; WIERENGA, PK; KAMPINGA, HH; KONINGS, AWT

    1993-01-01

    It is shown that heat-induced increase of intracellular calcium does not correlate with hyperthermic cell killing. Six different cell lines were investigated; in four (EAT, HeLa S3, L5178Y-R and L5178Y-S) heat treatments killing 90% of the cells did not affect the levels of intracellular free

  4. In vivo imaging of cerebral serotonin transporter and serotonin(2A) receptor binding in 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") and hallucinogen users

    DEFF Research Database (Denmark)

    Erritzoe, David; Frøkjær, Vibe; Holst, Klaus K

    2011-01-01

    Both hallucinogens and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin.......Both hallucinogens and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin....

  5. New intracellular activities of matrix metalloproteinases shine in the moonlight.

    Science.gov (United States)

    Jobin, Parker G; Butler, Georgina S; Overall, Christopher M

    2017-11-01

    Adaption of a single protein to perform multiple independent functions facilitates functional plasticity of the proteome allowing a limited number of protein-coding genes to perform a multitude of cellular processes. Multifunctionality is achievable by post-translational modifications and by modulating subcellular localization. Matrix metalloproteinases (MMPs), classically viewed as degraders of the extracellular matrix (ECM) responsible for matrix protein turnover, are more recently recognized as regulators of a range of extracellular bioactive molecules including chemokines, cytokines, and their binders. However, growing evidence has convincingly identified select MMPs in intracellular compartments with unexpected physiological and pathological roles. Intracellular MMPs have both proteolytic and non-proteolytic functions, including signal transduction and transcription factor activity thereby challenging their traditional designation as extracellular proteases. This review highlights current knowledge of subcellular location and activity of these "moonlighting" MMPs. Intracellular roles herald a new era of MMP research, rejuvenating interest in targeting these proteases in therapeutic strategies. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. SEP-225289 serotonin and dopamine transporter occupancy: a PET study.

    Science.gov (United States)

    DeLorenzo, Christine; Lichenstein, Sarah; Schaefer, Karen; Dunn, Judith; Marshall, Randall; Organisak, Lisa; Kharidia, Jahnavi; Robertson, Brigitte; Mann, J John; Parsey, Ramin V

    2011-07-01

    SEP-225289 is a novel compound that, based on in vitro potencies for transporter function, potentially inhibits reuptake at dopamine, norepinephrine, and serotonin transporters. An open-label PET study was conducted during the development of SEP-225289 to investigate its dopamine and serotonin transporter occupancy. Different single doses of SEP-225289 were administered to healthy volunteers in 3 cohorts: 8 mg (n = 7), 12 mg (n = 5), and 16 mg (n = 7). PET was performed before and approximately 24 h after oral administration of SEP-225289, to assess occupancy at trough levels. Dopamine and serotonin transporter occupancies were estimated from PET using (11)C-N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane ((11)C-PE2I) and (11)C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ((11)C-DASB), respectively. Plasma concentration of SEP-225289 was assessed before ligand injection, and subjects were monitored for adverse events. Average dopamine and serotonin transporter occupancies increased with increasing doses of SEP-225289. Mean dopamine and serotonin transporter occupancies were 33% ± 11% and 2% ± 13%, respectively, for 8 mg; 44% ± 4% and 9% ± 10%, respectively, for 12 mg; and 49% ± 7% and 14% ± 15%, respectively, for 16 mg. On the basis of the relationship between occupancy and plasma concentration, dopamine transporter IC(50) (the plasma concentration of drug at 50% occupancy) was determined (4.5 ng/mL) and maximum dopamine transporter occupancy was extrapolated (85%); however, low serotonin transporter occupancy prevented similar serotonin transporter calculations. No serious adverse events were reported. At the doses evaluated, occupancy of the dopamine transporter was significantly higher than that of the serotonin transporter, despite similar in vitro potencies, confirming that, in addition to in vitro assays, PET occupancy studies can be instrumental to the drug development process by informing early decisions about

  7. Genetics of premenstrual syndrome: investigation of specific serotonin receptor polymorphisms

    OpenAIRE

    Dhingra, Vandana

    2014-01-01

    Premenstrual dysphoric disorder (PMDD) is a distressing and disabling syndrome causing a significant degree of impairment on daily functioning and interpersonal relationships in 3-8% of the women. With the convincing evidence that PMS is inheritable and that serotonin is important in the pathogenesis of PMS, and failure of initial studies to demonstrate significant associations between key genes controlling the synthesis, reuptake and catabolism of serotonin and PMDD, the main aim of this the...

  8. Plasma serotonin in horses undergoing surgery for small intestinal colic

    OpenAIRE

    Torfs, Sara C; Maes, An A; Delesalle, Catherine J; Pardon, Bart; Croubels, Siska M; Deprez, Piet

    2015-01-01

    This study compared serotonin concentrations in platelet poor plasma (PPP) from healthy horses and horses with surgical small intestinal (SI) colic, and evaluated their association with postoperative ileus, strangulation and non-survival. Plasma samples (with EDTA) from 33 horses with surgical SI colic were collected at several pre- and post-operative time points. Serotonin concentrations were determined using liquid-chromatography tandem mass spectrometry. Results were compared with those fo...

  9. Ortholog-based screening and identification of genes related to intracellular survival.

    Science.gov (United States)

    Yang, Xiaowen; Wang, Jiawei; Bing, Guoxia; Bie, Pengfei; De, Yanyan; Lyu, Yanli; Wu, Qingmin

    2018-04-20

    Bioinformatics and comparative genomics analysis methods were used to predict unknown pathogen genes based on homology with identified or functionally clustered genes. In this study, the genes of common pathogens were analyzed to screen and identify genes associated with intracellular survival through sequence similarity, phylogenetic tree analysis and the λ-Red recombination system test method. The total 38,952 protein-coding genes of common pathogens were divided into 19,775 clusters. As demonstrated through a COG analysis, information storage and processing genes might play an important role intracellular survival. Only 19 clusters were present in facultative intracellular pathogens, and not all were present in extracellular pathogens. Construction of a phylogenetic tree selected 18 of these 19 clusters. Comparisons with the DEG database and previous research revealed that seven other clusters are considered essential gene clusters and that seven other clusters are associated with intracellular survival. Moreover, this study confirmed that clusters screened by orthologs with similar function could be replaced with an approved uvrY gene and its orthologs, and the results revealed that the usg gene is associated with intracellular survival. The study improves the current understanding of intracellular pathogens characteristics and allows further exploration of the intracellular survival-related gene modules in these pathogens. Copyright © 2018. Published by Elsevier B.V.

  10. HFE mRNA expression is responsive to intracellular and extracellular iron loading: short communication.

    Science.gov (United States)

    Mehta, Kosha J; Farnaud, Sebastien; Patel, Vinood B

    2017-10-01

    In liver hepatocytes, the HFE gene regulates cellular and systemic iron homeostasis by modulating cellular iron-uptake and producing the iron-hormone hepcidin in response to systemic iron elevation. However, the mechanism of iron-sensing in hepatocytes remain enigmatic. Therefore, to study the effect of iron on HFE and hepcidin (HAMP) expressions under distinct extracellular and intracellular iron-loading, we examined the effect of holotransferrin treatment (1, 2, 5 and 8 g/L for 6 h) on intracellular iron levels, and mRNA expressions of HFE and HAMP in wild-type HepG2 and previously characterized iron-loaded recombinant-TfR1 HepG2 cells. Gene expression was analyzed by real-time PCR and intracellular iron was measured by ferrozine assay. Data showed that in the wild-type cells, where intracellular iron content remained unchanged, HFE expression remained unaltered at low holotransferrin treatments but was upregulated upon 5 g/L (p HFE and HAMP expressions were elevated only at low 1 g/L treatment (p HFE (p HFE mRNA was independently elevated by extracellular and intracellular iron-excess. Thus, it may be involved in sensing both, extracellular and intracellular iron. Repression of HAMP expression under simultaneous intracellular and extracellular iron-loading resembles non-hereditary iron-excess pathologies.

  11. Increased hypothalamic serotonin turnover in inflammation-induced anorexia.

    Science.gov (United States)

    Dwarkasing, J T; Witkamp, R F; Boekschoten, M V; Ter Laak, M C; Heins, M S; van Norren, K

    2016-05-20

    Anorexia can occur as a serious complication of disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections between peripheral inflammation, anorexia and hypothalamic serotonin metabolism and signaling pathways. First, we investigated the response of two hypothalamic neuronal cell lines to TNFα, IL-6 and LPS. Next, we studied transcriptomic changes and serotonergic activity in the hypothalamus of mice after intraperitoneal injection with TNFα, IL-6 or a combination of TNFα and IL-6. In vitro, we showed that hypothalamic neurons responded to inflammatory mediators by releasing cytokines. This inflammatory response was associated with an increased serotonin release. Mice injected with TNFα and IL-6 showed decreased food intake, associated with altered expression of inflammation-related genes in the hypothalamus. In addition, hypothalamic serotonin turnover showed to be elevated in treated mice. Overall, our results underline that peripheral inflammation reaches the hypothalamus where it affects hypothalamic serotoninergic metabolism. These hypothalamic changes in serotonin pathways are associated with decreased food intake, providing evidence for a role of serotonin in inflammation-induced anorexia.

  12. Serotonin induces peripheral antinociception via the opioidergic system.

    Science.gov (United States)

    Diniz, Danielle Aguiar; Petrocchi, Júlia Alvarenga; Navarro, Larissa Caldeira; Souza, Tâmara Cristina; Castor, Marina Gomes Miranda E; Duarte, Igor Dimitri Gama; Romero, Thiago Roberto Lima

    2018-01-01

    Studies conducted since 1969 have shown that the release of serotonin (5-HT) in the dorsal horn of the spinal cord contributes to opioid analgesia. In the present study, the participation of the opioidergic system in antinociceptive effect serotonin at the peripheral level was examined. The paw pressure test was used with mice (Swiss, males from 35 g) which had increased pain sensitivity by intraplantar injection of PGE 2 (2 μg). Serotonin (250 ng), administered locally to the right paw of animals, produces antinociception in this model. The selective antagonists for mu, delta and kappa opioid receptors, clocinnamox clocinnamox (40 μg), naltrindole (60 μg) and nor-binaltorfimina (200 μg), respectively, inhibited the antinociceptive effect induced by serotonin. Additionally, bestatin (400 μg), an inhibitor of enkephalinases that degrade peptides opioids, enhanced the antinociceptive effect induced by serotonin (low dose of 62.5 ng). These results suggest that serotonin possibly induce peripheral antinociception through the release of endogenous opioid peptides, possible from immune cells or keratinocytes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  13. Lung damage and pulmonary uptake of serotonin in intact dogs

    International Nuclear Information System (INIS)

    Dawson, C.A.; Christensen, C.W.; Rickaby, D.A.; Linehan, J.H.; Johnston, M.R.

    1985-01-01

    The authors examined the influence of glass bead embolization and oleic acid, dextran, and imipramine infusion on the pulmonary uptake of trace doses of [ 3 H]serotonin and the extravascular volume accessible to [ 14 C]antipyrine in anesthetized dogs. Embolization and imipramine decreased serotonin uptake by 53 and 61%, respectively, but no change was observed with oleic acid or dextran infusion. The extravascular volume accessible to the antipyrine was reduced by 77% after embolization and increased by 177 and approximately 44% after oleic acid and dextran infusion, respectively. The results suggest that when the perfused endothelial surface is sufficiently reduced, as with embolization, the uptake of trace doses of serotonin will be depressed. In addition, decreases in serotonin uptake in response to imipramine in this study and in response to certain endothelial toxins in other studies suggest that serotonin uptake can reveal certain kinds of changes in endothelial function. However, the lack of a response to oleic acid-induced damage in the present study suggests that serotonin uptake is not sensitive to all forms of endothelial damage

  14. Noninvasive measurement of lung carbon-11-serotonin extraction in man

    International Nuclear Information System (INIS)

    Coates, G.; Firnau, G.; Meyer, G.J.; Gratz, K.F.

    1991-01-01

    The fraction of serotonin extracted on a single passage through the lungs is being used as an early indicator of lung endothelial damage but the existing techniques require multiple arterial blood samples. We have developed a noninvasive technique to measure lung serotonin uptake in man. We utilized the double indicator diffusion principle, a positron camera, 11 C-serotonin as the substrate, and 11 CO-erythrocytes as the vascular marker. From regions of interest around each lung, we recorded time-activity curves in 0.5-sec frames for 30 sec after a bolus injection of first the vascular marker 11 CO-erythrocytes and 10 min later 11 C-serotonin. A second uptake measurement was made after imipramine 25-35 mg was infused intravenously. In three normal volunteers, the single-pass uptake of 11 C-serotonin was 63.9% +/- 3.6%. This decreased in all subjects to a mean of 53.6% +/- 1.4% after imipramine. The rate of lung washout of 11 C was also significantly prolonged after imipramine. This noninvasive technique can be used to measure lung serotonin uptake to detect early changes in a variety of conditions that alter the integrity of the pulmonary endothelium

  15. INFLUENCE OF A SEROTONIN-RICH AND DOPAMINE-RICH DIET ON PLATELET SEROTONIN CONTENT AND URINARY-EXCRETION OF BIOGENIC-AMINES AND THEIR METABOLITES

    NARCIS (Netherlands)

    KEMA, IP; SCHELLINGS, AMJ; MEIBORG, G; HOPPENBROUWERS, CJM; MUSKIET, FAJ

    Using high-performance liquid chromatography and gas chromatography, we reevaluated the 24-h influence of a serotonin- and dopamine-rich diet on platelet serotonin and serotonin, 5-hydroxyindoleacetic acid (5-HIAA), and major catecholamine metabolites in the urine of 15 healthy adults. Although

  16. Altered serotonin transporter availability in patients with multiple sclerosis

    International Nuclear Information System (INIS)

    Hesse, Swen; Sabri, Osama; Moeller, Franziska; Thomae, Eva; Then Bergh, Florian; Petroff, David; Lobsien, Donald; Luthardt, Julia; Becker, Georg-Alexander; Patt, Marianne; Seese, Anita; Meyer, Philipp M.; Regenthal, Ralf

    2014-01-01

    Modulation of the immune system by the CNS may involve serotonergic regulation via the brain serotonin transporters (SERT). This regulation may be disturbed in patients with CNS disorders including multiple sclerosis (MS). Central serotonergic mechanisms have not been investigated in MS by in vivo imaging. The objective of the study was to assess the availability of SERT in antidepressant-naive patients with MS by means of PET. Included in this study were 23 patients with MS and 22 matched healthy volunteers who were investigated with PET and the SERT-selective marker [ 11 C]DASB, and distribution volume ratios were determined. Clinical assessment of the patients included the expanded disability status scale, the MS fatigue scale Wuerzburger Erschoepfungsinventar bei MS (WEIMuS) and the Beck Depression Inventory (BDI). The PET data were analysed with both volume-of-interest and voxel-based analyses to determine regional SERT availability. Patients had lower SERT availability in the cingulate cortex, the thalamus and the insula, and increased availability in the orbitofrontal cortex. Patients with relapsing/remitting MS tended to have lower SERT in the hippocampus, whereas patients with primary progressive disease showed increased SERT availability in prefrontal regions. There was a positive correlation between SERT availability in the insula and both depression and fatigue scores (r = 0.56 vs. BDI, p = 0.02; r = 0.49 vs. WEIMuS, p = 0.05). Serotonergic neurotransmission in MS patients is altered in limbic and paralimbic regions as well as in the frontal cortex that this appears to contribute to psychiatric symptoms of MS. (orig.)

  17. Altered serotonin transporter availability in patients with multiple sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Hesse, Swen; Sabri, Osama [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig (Germany); Moeller, Franziska; Thomae, Eva; Then Bergh, Florian [University of Leipzig, Department of Neurology, Leipzig (Germany); Petroff, David [University of Leipzig, Coordinating Centre for Clinical Studies, Leipzig (Germany); Lobsien, Donald [University of Leipzig, Department of Neuroradiology, Leipzig (Germany); Luthardt, Julia; Becker, Georg-Alexander; Patt, Marianne; Seese, Anita; Meyer, Philipp M. [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Regenthal, Ralf [University of Leipzig, Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, Leipzig (Germany)

    2014-05-15

    Modulation of the immune system by the CNS may involve serotonergic regulation via the brain serotonin transporters (SERT). This regulation may be disturbed in patients with CNS disorders including multiple sclerosis (MS). Central serotonergic mechanisms have not been investigated in MS by in vivo imaging. The objective of the study was to assess the availability of SERT in antidepressant-naive patients with MS by means of PET. Included in this study were 23 patients with MS and 22 matched healthy volunteers who were investigated with PET and the SERT-selective marker [{sup 11}C]DASB, and distribution volume ratios were determined. Clinical assessment of the patients included the expanded disability status scale, the MS fatigue scale Wuerzburger Erschoepfungsinventar bei MS (WEIMuS) and the Beck Depression Inventory (BDI). The PET data were analysed with both volume-of-interest and voxel-based analyses to determine regional SERT availability. Patients had lower SERT availability in the cingulate cortex, the thalamus and the insula, and increased availability in the orbitofrontal cortex. Patients with relapsing/remitting MS tended to have lower SERT in the hippocampus, whereas patients with primary progressive disease showed increased SERT availability in prefrontal regions. There was a positive correlation between SERT availability in the insula and both depression and fatigue scores (r = 0.56 vs. BDI, p = 0.02; r = 0.49 vs. WEIMuS, p = 0.05). Serotonergic neurotransmission in MS patients is altered in limbic and paralimbic regions as well as in the frontal cortex that this appears to contribute to psychiatric symptoms of MS. (orig.)

  18. Intracellular localization of Arabidopsis sulfurtransferases.

    Science.gov (United States)

    Bauer, Michael; Dietrich, Christof; Nowak, Katharina; Sierralta, Walter D; Papenbrock, Jutta

    2004-06-01

    Sulfurtransferases (Str) comprise a group of enzymes widely distributed in archaea, eubacteria, and eukaryota which catalyze the transfer of a sulfur atom from suitable sulfur donors to nucleophilic sulfur acceptors. In all organisms analyzed to date, small gene families encoding Str proteins have been identified. The gene products were localized to different compartments of the cells. Our interest concerns the localization of Str proteins encoded in the nuclear genome of Arabidopsis. Computer-based prediction methods revealed localization in different compartments of the cell for six putative AtStrs. Several methods were used to determine the localization of the AtStr proteins experimentally. For AtStr1, a mitochondrial localization was demonstrated by immunodetection in the proteome of isolated mitochondria resolved by one- and two-dimensional gel electrophoresis and subsequent blotting. The respective mature AtStr1 protein was identified by mass spectrometry sequencing. The same result was obtained by transient expression of fusion constructs with the green fluorescent protein in Arabidopsis protoplasts, whereas AtStr2 was exclusively localized to the cytoplasm by this method. Three members of the single-domain AtStr were localized in the chloroplasts as demonstrated by transient expression of green fluorescent protein fusions in protoplasts and stomata, whereas the single-domain AtStr18 was shown to be cytoplasmic. The remarkable subcellular distribution of AtStr15 was additionally analyzed by transmission electron immunomicroscopy using a monospecific antibody against green fluorescent protein, indicating an attachment to the thylakoid membrane. The knowledge of the intracellular localization of the members of this multiprotein family will help elucidate their specific functions in the organism.

  19. Intracellular calcium homeostasis and signaling.

    Science.gov (United States)

    Brini, Marisa; Calì, Tito; Ottolini, Denis; Carafoli, Ernesto

    2013-01-01

    Ca(2+) is a universal carrier of biological information: it controls cell life from its origin at fertilization to its end in the process of programmed cell death. Ca(2+) is a conventional diffusible second messenger released inside cells by the interaction of first messengers with plasma membrane receptors. However, it can also penetrate directly into cells to deliver information without the intermediation of first or second messengers. Even more distinctively, Ca(2+) can act as a first messenger, by interacting with a plasma membrane receptor to set in motion intracellular signaling pathways that involve Ca(2+) itself. Perhaps the most distinctive property of the Ca(2+) signal is its ambivalence: while essential to the correct functioning of cells, Ca(2+) becomes an agent that mediates cell distress, or even (toxic) cell death, if its concentration and movements inside cells are not carefully tuned. Ca(2+) is controlled by reversible complexation to specific proteins, which could be pure Ca(2+) buffers, or which, in addition to buffering Ca(2+), also decode its signal to pass it on to targets. The most important actors in the buffering of cell Ca(2+) are proteins that transport it across the plasma membrane and the membrane of the organelles: some have high Ca(2+) affinity and low transport capacity (e.g., Ca(2+) pumps), others have opposite properties (e.g., the Ca(2+) uptake system of mitochondria). Between the initial event of fertilization, and the terminal event of programmed cell death, the Ca(2+) signal regulates the most important activities of the cell, from the expression of genes, to heart and muscle contraction and other motility processes, to diverse metabolic pathways involved in the generation of cell fuels.

  20. Ecstasy use and serotonin syndrome: a neglected danger to adolescents and young adults prescribed selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Dobry, Yuriy; Rice, Timothy; Sher, Leo

    2013-01-01

    At present, there are scarce clinical and basic lab data concerning the risk of acute serotonin toxicity from selective serotonin reuptake inhibitors (SSRIs) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) co-administration. The health care community can strongly benefit from efforts to address the high risks associated with serotonin syndrome from this specific drug combination. The aim of this work is to review the risk of serotonin syndrome in adolescents and young adults prescribed with SSRIs and are concurrently using ecstasy. An electronic search of the major behavioral science bibliographic databases (Pubmed, PsycINFO, Medline) was conducted to retrieve peer-reviewed articles, which detail the clinical characteristics, biological mechanisms and social implications of SSRIs, MDMA, and their potential synergism in causing serotonin syndrome in the pediatric and young adult population. Search terms included "serotonin syndrome", "ecstasy", "MDMA", "pediatric", and "SSRI". Additional references were incorporated from the bibliographies of these retrieved articles. MDMA, in combination with the widely-prescribed SSRI antidepressant class, can lead to rapid, synergistic rise of serotonin (5-HT) concentration in the central nervous system, leading to the acute medical emergency known as serotonin syndrome. This review addresses such complication through an exploration of the theoretical mechanisms and clinical manifestations of this life-threatening pharmacological interaction. The increasing incidences of recreational ecstasy use and SSRI pharmacotherapy among multiple psychiatric disorders in the adolescent population have made this an overlooked yet increasingly relevant danger, which poses a threat to public health. This can be curbed through further research, as well as greater health care provision and attention from a regulatory body owing.

  1. Tryptase potentiates enteric nerve activation by histamine and serotonin: Relevance for the effects of mucosal biopsy supernatants from irritable bowel syndrome patients.

    Science.gov (United States)

    Ostertag, D; Annahazi, A; Krueger, D; Michel, K; Demir, I E; Ceyhan, G O; Zeller, F; Schemann, M

    2017-09-01

    We previously showed that mucosal biopsy supernatants from irritable bowel syndrome patients activated neurons despite low concentrations of tryptase, histamine, and serotonin which individually would not cause spike discharge. We studied the potentiating responses between these mediators on excitability of enteric neurons. Calcium-imaging was performed using the calcium-sensitive dye Fluo-4 AM in human submucous plexus preparations from 45 individuals. Histamine, serotonin, and tryptase were applied alone and in combinations to evaluate nerve activation which was assessed by analyzing increase in intracellular Ca 2+ ([Ca 2+ ] i ), the proportion of responding neurons and the product of both defined as Ca-neuroindex (NI). Protease activated receptor (PAR) 2 activating peptide, PAR2 antagonist and the serine protease-inhibitor FUT-175 were used to particularly investigate the role of proteases. Histamine or serotonin (1 μmol/L each) evoked only few small responses (median NI [25%/75%]: 0 [0/148]; 85 [0/705] respectively). Their combined application evoked statistically similar responses (216 [21/651]). Addition of the PAR2 activator tryptase induced a significantly higher Ca-NI (1401 [867/4075]) compared to individual application of tryptase or to coapplied histamine and serotonin. This synergistic potentiation was neither mimicked by PAR2 activating peptide nor reversed by the PAR2 antagonist GB83, but abolished by FUT-175. We observed synergistic potentiation between histamine, serotonin, and tryptase in enteric neurons, which is mediated by proteolytic activity rather than PAR2 activation. This explained neuronal activation by a cocktail of these mediators despite their low concentrations and despite a relatively small PAR2-mediated response in human submucous neurons. © 2017 John Wiley & Sons Ltd.

  2. Blockade of intracellular Zn2+ signaling in the basolateral amygdala affects object recognition memory via attenuation of dentate gyrus LTP.

    Science.gov (United States)

    Fujise, Yuki; Kubota, Mitsuyasu; Suzuki, Miki; Tamano, Haruna; Takeda, Atsushi

    2017-09-01

    Hippocampus-dependent memory is modulated by the amygdala. However, it is unknown whether intracellular Zn 2+ signaling in the amygdala is involved in hippocampus-dependent memory. On the basis of the evidence that intracellular Zn 2+ signaling in dentate granule cells (DGC) is necessary for object recognition memory via LTP at medial perforant pathway (PP)-DGC synapses, the present study examined whether intracellular Zn 2+ signaling in the amygdala influences object recognition memory via modulation of LTP at medial PP-DGC synapses. When ZnAF-2DA (100 μM, 2 μl) was injected into the basolateral amygdala (BLA), intracellular ZnAF-2 locally chelated intracellular Zn 2+ in the amygdala. Recognition memory was affected when training of object recognition test was performed 20 min after ZnAF-2DA injection into the BLA. Twenty minutes after injection of ZnAF-2DA into the BLA, LTP induction at medial PP-DGC synapses was attenuated, while LTP induction at PP-BLA synapses was potentiated and LTP induction at BLA-DGC synapses was attenuated. These results suggest that intracellular Zn 2+ signaling in the BLA is involved in BLA-associated LTP and modulates LTP at medial PP-DGC synapses, followed by modulation of object recognition memory. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system

    International Nuclear Information System (INIS)

    Passchier, J.; Waarde, A. van

    2001-01-01

    The 5-HT 1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT 1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy. Here, we review the radioligands which are available for visualisation and quantification of this important neuroreceptor in the human brain, using positron emission tomography (PET) or single-photon emission tomography (SPET). More than 20 compounds have been labelled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogues of the agonist, 8-OH-DPAT, structural analogues of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl- 11 C] WAY-100635 (WAY), [carbonyl- 11 C]desmethyl-WAY-100635 (DWAY), p-[ 18 F]MPPF and [ 11 C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT 1A receptor distribution in the brain (even the raphe nuclei are visualised), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centres within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) production of a radioiodinated or technetium-labelled ligand for SPET. (orig.)

  4. Dm5-HT2B: Pharmacological Characterization of the Fifth Serotonin Receptor Subtype of Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Wolfgang Blenau

    2017-05-01

    Full Text Available Serotonin (5-hydroxytryptamine, 5-HT is an important regulator of physiological and behavioral processes in both protostomes (e.g., insects and deuterostomes (e.g., mammals. In insects, serotonin has been found to modulate the heart rate and to control secretory processes, development, circadian rhythms, aggressive behavior, as well as to contribute to learning and memory. Serotonin exerts its activity by binding to and activating specific membrane receptors. The clear majority of these receptors belong to the superfamily of G-protein-coupled receptors. In Drosophila melanogaster, a total of five genes have been identified coding for 5-HT receptors. From this family of proteins, four have been pharmacologically examined in greater detail, so far. While Dm5-HT1A, Dm5-HT1B, and Dm5-HT7 couple to cAMP signaling cascades, the Dm5-HT2A receptor leads to Ca2+ signaling in an inositol-1,4,5-trisphosphate-dependent manner. Based on sequence similarity to homologous genes in other insects, a fifth D. melanogaster gene was uncovered coding for a Dm5-HT2B receptor. Knowledge about this receptor’s pharmacological properties is very limited. This is quite surprising because Dm5-HT2B has been attributed to distinct physiological functions based on genetic interference with its gene expression. Mutations were described reducing the response of the larval heart to 5-HT, and specific knockdown of Dm5-HT2B mRNA in hemocytes resulted in a higher susceptibility of the flies to bacterial infection. To gain deeper understanding of Dm5-HT2B’s pharmacology, we evaluated the receptor’s response to a series of established 5-HT receptor agonists and antagonists in a functional cell-based assay. Metoclopramide and mianserin were identified as two potent antagonists that may allow pharmacological interference with Dm5-HT2B signaling in vitro and in vivo.

  5. Dm5-HT2B: Pharmacological Characterization of the Fifth Serotonin Receptor Subtype of Drosophila melanogaster.

    Science.gov (United States)

    Blenau, Wolfgang; Daniel, Stöppler; Balfanz, Sabine; Thamm, Markus; Baumann, Arnd

    2017-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an important regulator of physiological and behavioral processes in both protostomes (e.g., insects) and deuterostomes (e.g., mammals). In insects, serotonin has been found to modulate the heart rate and to control secretory processes, development, circadian rhythms, aggressive behavior, as well as to contribute to learning and memory. Serotonin exerts its activity by binding to and activating specific membrane receptors. The clear majority of these receptors belong to the superfamily of G-protein-coupled receptors. In Drosophila melanogaster , a total of five genes have been identified coding for 5-HT receptors. From this family of proteins, four have been pharmacologically examined in greater detail, so far. While Dm5-HT 1A , Dm5-HT 1B , and Dm5-HT 7 couple to cAMP signaling cascades, the Dm5-HT 2A receptor leads to Ca 2+ signaling in an inositol-1,4,5-trisphosphate-dependent manner. Based on sequence similarity to homologous genes in other insects, a fifth D. melanogaster gene was uncovered coding for a Dm5-HT 2B receptor. Knowledge about this receptor's pharmacological properties is very limited. This is quite surprising because Dm5-HT 2B has been attributed to distinct physiological functions based on genetic interference with its gene expression. Mutations were described reducing the response of the larval heart to 5-HT, and specific knockdown of Dm5-HT 2B mRNA in hemocytes resulted in a higher susceptibility of the flies to bacterial infection. To gain deeper understanding of Dm5-HT 2B 's pharmacology, we evaluated the receptor's response to a series of established 5-HT receptor agonists and antagonists in a functional cell-based assay. Metoclopramide and mianserin were identified as two potent antagonists that may allow pharmacological interference with Dm5-HT 2B signaling in vitro and in vivo .

  6. Simultaneous quantification of monoamine neurotransmitters and their biogenic metabolites intracellularly and extracellularly in primary neuronal cell cultures and in sub-regions of guinea pig brain

    DEFF Research Database (Denmark)

    Schou-Pedersen, Anne Marie Voigt; Hansen, Stine Normann; Tveden-Nyborg, Pernille

    2016-01-01

    In the present paper, we describe a validated chromatographic method for the simultaneous quantification of monoamine neurotransmitters and their biogenic metabolites intracellularly and extracellularly in primary neuronal cell culture and in sub-regions of the guinea pig brain. Electrochemical...... of intracellular and extracellular amounts of monoamine neurotransmitters and their metabolites in guinea pig frontal cortex and hippocampal primary neuronal cell cultures. Noradrenaline, dopamine and serotonin were found to be in a range from 0.31 to 1.7 pmol per 2 million cells intracellularly, but only...... the biogenic metabolites could be detected extracellularly. Distinct differences in monoamine concentrations were observed when comparing concentrations in guinea pig frontal cortex and cerebellum tissue with higher amounts of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid...

  7. Biological synthesis and characterization of intracellular gold ...

    Indian Academy of Sciences (India)

    thods of reduction of metal ions using plants or microorganisms are often ... have several advantages over bacteria, they are often pre- ferred. ... in static condition for a period of 7 days. ... work was focused on the production of intracellular gold.

  8. Identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats

    Directory of Open Access Journals (Sweden)

    Nijman Isaäc J

    2010-05-01

    Full Text Available Abstract Background Genetic variation in the regulatory region of the human serotonin transporter gene (SLC6A4 has been shown to affect brain functionality and personality. However, large heterogeneity in its biological effects is observed, which is at least partially due to genetic modifiers. To gain insight into serotonin transporter (SERT-specific genetic modifiers, we studied an intercross between the Wistar SERT-/- rat and the behaviorally and genetically divergent Brown Norway rat, and performed a QTL analysis. Results In a cohort of >150 intercross SERT-/- and control (SERT+/+ rats we characterized 12 traits that were previously associated with SERT deficiency, including activity, exploratory pattern, cocaine-induced locomotor activity, and abdominal and subcutaneous fat. Using 325 genetic markers, 10 SERT-/--specific quantitative trait loci (QTLs for parameters related to activity and exploratory pattern (Chr.1,9,11,14, and cocaine-induced anxiety and locomotor activity (Chr.5,8 were identified. No significant QTLs were found for fat parameters. Using in silico approaches we explored potential causal genes within modifier QTL regions and found interesting candidates, amongst others, the 5-HT1D receptor (Chr. 5, dopamine D2 receptor (Chr. 8, cannabinoid receptor 2 (Chr. 5, and genes involved in fetal development and plasticity (across chromosomes. Conclusions We anticipate that the SERT-/--specific QTLs may lead to the identification of new modulators of serotonergic signaling, which may be targets for pharmacogenetic and therapeutic approaches.

  9. Implications of genetic research on the role of the serotonin in depression: emphasis on the serotonin type 1A receptor and the serotonin transporter.

    Science.gov (United States)

    Neumeister, Alexander; Young, Theresa; Stastny, Juergen

    2004-08-01

    Serotonin systems appear to play a key role in the pathophysiology of major depressive disorder. Consequently, ongoing research determines whether serotonin related genes account for the very robust differential behavioral and neural mechanisms that discriminate patients with depression from healthy controls. Serotonin type 1(A) receptors and the serotonin transporters are reduced in depression, and recent genetic research in animals and humans has implicated both in depression. Preclinical studies have utilized a variety of animal models that have been used to explain pathophysiological mechanisms in humans, although it is not clear at all whether these models constitute relevant models for depression in humans. However, data from preclinical studies can generate hypotheses that are tested in humans by combining genetic data with behavioral and physiological challenge paradigms and neuroimaging. These studies will enhance our understanding about combined influences from multiple interacting genes, as well as from environmental factors on brain circuits and their function, and about how these mechanisms may contribute to the pathophysiology of neuropsychiatric disorders.

  10. Voltammetric and Mathematical Evidence for Dual Transport Mediation of Serotonin Clearance In Vivo

    Science.gov (United States)

    Wood, Kevin M.; Zeqja, Anisa; Nijhout, H. Frederik; Reed, Michael C.; Best, Janet; Hashemi, Parastoo

    2014-01-01

    The neurotransmitter serotonin underlies many of the brain’s functions. Understanding serotonin neurochemistry is important for improving treatments for neuropsychiatric disorders such as depression. Antidepressants commonly target serotonin clearance via serotonin transporters (SERTs) and have variable clinical effects. Adjunctive therapies, targeting other systems including serotonin autoreceptors, also vary clinically and carry adverse consequences. Fast scan cyclic voltammetry (FSCV) is particularly well suited for studying antidepressant effects on serotonin clearance and autoreceptors by providing real-time chemical information on serotonin kinetics in vivo. However, the complex nature of in vivo serotonin responses makes it difficult to interpret experimental data with established kinetic models. Here, we electrically stimulated the mouse medial forebrain bundle (MFB) to provoke and detect terminal serotonin in the substantia nigra reticulata (SNr). In response to MFB stimulation we found three dynamically distinct serotonin signals. To interpret these signals we developed a computational model that supports two independent serotonin reuptake mechanisms (high affinity, low efficiency reuptake mechanism and low affinity, high efficiency reuptake system) and bolsters an important inhibitory role for the serotonin autoreceptors. Our data and analysis, afforded by the powerful combination of voltammetric and theoretical methods, gives new understanding of the chemical heterogeneity of serotonin dynamics in the brain. This diverse serotonergic matrix likely contributes to clinical variability of antidepressants. PMID:24702305

  11. Intracellular loop 5 is important for the transport mechanism and molecular pharmacology of the human serotonin transporter

    DEFF Research Database (Denmark)

    Said, Saida; Neubauer, Henrik Amtoft; Müller, Heidi Kaastrup

    are important drug targets in treating i.e. affective disorders such as depression and anxiety, and for drugs of abuse such as ecstasy and cocaine. The normal function of the SERT relies on large conformational changes and its inhibition by antidepressants represents a conformational lock. Understanding...

  12. Mycobacterium intracellulare Infection Mimicking Progression of Scleroderma

    DEFF Research Database (Denmark)

    Krabbe, Simon; Engelhart, Merete; Thybo, Sören

    2017-01-01

    This case report describes a patient with scleroderma who developed Mycobacterium intracellulare infection, which for more than a year mimicked worsening of her connective tissue disorder. The patient was diagnosed with scleroderma based on puffy fingers that developed into sclerodactyly, abnormal......, unfortunately with significant scarring. Immunodeficiency testing was unremarkable. In summary, an infection with Mycobacterium intracellulare was mistaken for an unusually severe progression of scleroderma....

  13. A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System.

    Science.gov (United States)

    Beliveau, Vincent; Ganz, Melanie; Feng, Ling; Ozenne, Brice; Højgaard, Liselotte; Fisher, Patrick M; Svarer, Claus; Greve, Douglas N; Knudsen, Gitte M

    2017-01-04

    The serotonin (5-hydroxytryptamine, 5-HT) system modulates many important brain functions and is critically involved in many neuropsychiatric disorders. Here, we present a high-resolution, multidimensional, in vivo atlas of four of the human brain's 5-HT receptors (5-HT 1A , 5-HT 1B , 5-HT 2A , and 5-HT 4 ) and the 5-HT transporter (5-HTT). The atlas is created from molecular and structural high-resolution neuroimaging data consisting of positron emission tomography (PET) and magnetic resonance imaging (MRI) scans acquired in a total of 210 healthy individuals. Comparison of the regional PET binding measures with postmortem human brain autoradiography outcomes showed a high correlation for the five 5-HT targets and this enabled us to transform the atlas to represent protein densities (in picomoles per milliliter). We also assessed the regional association between protein concentration and mRNA expression in the human brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor- and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system of the human brain. We present a high-resolution positron emission tomography (PET)- and magnetic resonance imaging-based human brain atlas of important serotonin receptors and the transporter. The regional PET-derived binding measures correlate strongly with the corresponding autoradiography protein levels. The strong correlation enables the transformation of the PET-derived human brain atlas into a protein density map of the serotonin (5-hydroxytryptamine, 5-HT) system. Next, we compared the regional receptor/transporter protein densities with mRNA levels and uncovered unique associations between protein expression and density at high detail. This new in vivo neuroimaging atlas of the 5-HT system not only provides insight in the human brain's regional protein

  14. Serotonin inhibits low-threshold spike interneurons in the striatum

    Science.gov (United States)

    Cains, Sarah; Blomeley, Craig P; Bracci, Enrico

    2012-01-01

    Low-threshold spike interneurons (LTSIs) are important elements of the striatal architecture and the only known source of nitric oxide in this nucleus, but their rarity has so far prevented systematic studies. Here, we used transgenic mice in which green fluorescent protein is expressed under control of the neuropeptide Y (NPY) promoter and striatal NPY-expressing LTSIs can be easily identified, to investigate the effects of serotonin on these neurons. In sharp contrast with its excitatory action on other striatal interneurons, serotonin (30 μm) strongly inhibited LTSIs, reducing or abolishing their spontaneous firing activity and causing membrane hyperpolarisations. These hyperpolarisations persisted in the presence of tetrodotoxin, were mimicked by 5-HT2C receptor agonists and reversed by 5-HT2C antagonists. Voltage-clamp slow-ramp experiments showed that serotonin caused a strong increase in an outward current activated by depolarisations that was blocked by the specific M current blocker XE 991. In current-clamp experiments, XE 991 per se caused membrane depolarisations in LTSIs and subsequent application of serotonin (in the presence of XE 991) failed to affect these neurons. We concluded that serotonin strongly inhibits striatal LTSIs acting through postsynaptic 5-HT2C receptors and increasing an M type current. PMID:22495583

  15. Effects of Junk Foods on Brain Neurotransmitters (Dopamine and Serotonin) and some Biochemical Parameters in Albino Rats

    International Nuclear Information System (INIS)

    Abd Elmonem, H.A.; Ali, E.A.

    2011-01-01

    Nutritional Habits have changed significantly and junk foods have become widely popular, in recent years. The present study aimed to shed the light on the effect of potato chips and / or ketchup consumption on some biochemical parameters. Sixty four male and female albino rats were used in the study. Animals were maintained on 0.25 g potato chips/ rat and / or 0.125 g ketchup / rat, 5 days a week for 4 weeks. Potato chips showed the lowest body wt gain in the male rats after 4 weeks but, ketchup modulated this negative effect of the potato chips in the group of male animals fed on potato chips plus ketchup. Potato chips significantly decreased brain serotonin, liver glutathione (GSH) and catalase (CAT) in both sexes; brain dopamine, serum total proteins, albumin, total globulins, α 2 - and β 1 -globulins in the females and serum thyroxine (T 4 ) in the male rats. Ketchup apparently affected serum T 4 and A / G ratio in both sexes, brain dopamine and liver GSH in the males in addition to brain serotonin, serum total globulins and ?1-globulin in the female rats. Potato chips plus ketchup significantly changed T 4 , dopamine, GSH, CAT, α 1 and α 2 -globulins in both sexes; serotonin and β 1 -globulin in the male rats, total proteins and albumin in the females. It could be concluded that potato chips consumption might induce numerous adverse effects in various body organs

  16. Characterization of the 5-HT1A receptor of the honeybee (Apis mellifera) and involvement of serotonin in phototactic behavior.

    Science.gov (United States)

    Thamm, Markus; Balfanz, Sabine; Scheiner, Ricarda; Baumann, Arnd; Blenau, Wolfgang

    2010-07-01

    Serotonin plays a key role in modulating various physiological and behavioral processes in both protostomes and deuterostomes. The vast majority of serotonin receptors belong to the superfamily of G-protein-coupled receptors. We report the cloning of a cDNA from the honeybee (Am5-ht1A) sharing high similarity with members of the 5-HT(1) receptor class. Activation of Am5-HT(1A) by serotonin inhibited the production of cAMP in a dose-dependent manner (EC(50) = 16.9 nM). Am5-HT(1A) was highly expressed in brain regions known to be involved in visual information processing. Using in vivo pharmacology, we could demonstrate that Am5-HT(1A) receptor ligands had a strong impact on the phototactic behavior of individual bees. The data presented here mark the first comprehensive study-from gene to behavior-of a 5-HT(1A) receptor in the honeybee, paving the way for the eventual elucidation of additional roles of this receptor subtype in the physiology and behavior of this social insect.

  17. Transient Serotonin Toxicity Evoked by Combination of Electroconvulsive Therapy and Fluoxetine

    Directory of Open Access Journals (Sweden)

    René Klysner

    2014-01-01

    Full Text Available The serotonin syndrome has been described only in rare instances for electroconvulsive therapy combined with an antidepressant medication. We describe a case of serotonin toxicity induced by electroconvulsive therapy in combination with fluoxetine.

  18. 3H-spiroperidol labels serotonin receptors in rat cerebral cortex and hippocampus

    International Nuclear Information System (INIS)

    Creese, I.; Snyder, S.H.

    1978-01-01

    It is found that in the cerebral cortex, butaclamol displaceable 3 H-spiroperidol binding labels both dopamine and serotonin receptors. In the hippocampus it is probable that 3 H-spiroperidol binding involves serotonin receptors exclusively. (Auth.)

  19. Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats

    NARCIS (Netherlands)

    Olivier, J D A; Jans, L A W; Korte-Bouws, G A H; Korte, S M; Deen, P M T; Cools, A R; Ellenbroek, B A; Blokland, A

    2008-01-01

    RATIONALE: Acute tryptophan depletion (ATD) transiently lowers central serotonin levels and can induce depressive mood states and cognitive defects. Previous studies have shown that ATD impairs object recognition in rats. OBJECTIVES: As individual differences exist in central serotonin

  20. Plasma serotonin level is a predictor for recurrence and poor prognosis in colorectal cancer patients.

    Science.gov (United States)

    Xia, Yan; Wang, Dawei; Zhang, Nan; Wang, Zhihao; Pang, Li

    2018-02-01

    To investigate the prognostic value of plasma serotonin levels in colorectal cancer (CRC). Preoperative plasma serotonin levels of 150 healthy control (HC) cases, 150 benign colorectal polyp (BCP) cases, and 176 CRC cases were determined using radioimmunoassay assay. Serotonin levels were compared between HC, BCP, and CRC cases, and those in CRC patients were related to 5-year outcome. Plasma serotonin levels were markedly higher in CRC patients than in either HCs or BCP cases. An elevated serotonin level was significantly associated with advanced tumor node metastasis. Receiver operating characteristic curve analysis showed that the level of serotonin had a high predictive value for disease recurrence and mortality. Multivariate analysis revealed that high serotonin level was significantly associated with poor recurrence-free survival and overall survival. Our results suggest that a high peri-operative plasma serotonin level is useful as a prognostic biomarker for CRC recurrence and poor survival. © 2017 Wiley Periodicals, Inc.

  1. 17β-Estradiol augments antidepressant efficacy of escitalopram in ovariectomized rats: Neuroprotective and serotonin reuptake transporter modulatory effects.

    Science.gov (United States)

    Ibrahim, Weam W; Safar, Marwa M; Khattab, Mahmoud M; Agha, Azza M

    2016-12-01

    The prevalence or recurrence of depression is seriously increased in women during the transition to and after menopause. The chronic hypo-estrogenic state of menopause may reduce the response to antidepressants; however the influence of estrogen therapy on their efficacy is still controversial. This study aimed at investigating the effects of combining escitalopram with 17β-estradiol on depression and cognitive impairment induced by ovariectomy, an experimental model of human menopause. Young adult female Wistar rats were subjected to either sham operation or ovariectomy. Ovariectomized animals were treated chronically with escitalopram (10mg/kg/day, i.p) alone or with four doses of 17β-estradiol (40μg/kg, s.c) given prior to the behavioral tests. Co-administration of 17β-estradiol improved escitalopram-induced antidepressant effect in forced swimming test verified as more prominent decrease in the immobility time without opposing its memory enhancing effect in Morris water maze. 17β-estradiol augmented the modulatory effects of escitalopram on the hippocampal levels of brain-derived neurotrophic factor and serotonin reuptake transporter as well as tumor necrosis factor-alpha without altering its effects on the gene expressions of serotonin receptor 1A, estrogen receptors alpha and beta, or acetylcholinestearase content. This combined therapy afforded synergistic protective effects on the brain histopathological architecture, particularly, the hippocampus. The antidepressant effect of 17β-estradiol was abolished by pretreatment with estrogen receptor antagonist, tamoxifen (10mg/kg, p.o). In conclusion, 17β-estradiol-induced antidepressant effect was confined to intracellular estrogen receptors activation. Moreover, 17β-estradiol enhanced escitalopram's efficiency in ameliorating menopausal-like depression, via exerting synergistic neuroprotective and serotonin reuptake transporter modulatory effects, without impeding escitalopram-mediated cognitive

  2. Comparison of the neurobiological effects of attribution retraining group therapy with those of selective serotonin reuptake inhibitors

    Directory of Open Access Journals (Sweden)

    C. Wang

    2013-03-01

    Full Text Available The aim of this study was to compare the effectiveness of attribution retraining group therapy (ARGT with selective serotonin reuptake inhibitors (SSRIs in the treatment of major depressive disorder (MDD, generalized anxiety disorder (GAD, and obsessive-compulsive disorder (OCD. Subjects were sequentially recruited and randomized into two groups, one receiving ARGT (n = 63 and the other SSRIs (n = 66 for 8 weeks. Fifty-four ARGT outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 16 and 55 SSRI outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 17 completed the study. All subjects were assessed using the Hamilton Depression Scale and Hamilton Anxiety Scale before and after treatment. The 10-item Yale-Brown Obsessive Compulsive Scale was employed only for OCD subjects. Plasma levels of serotonin, norepinephrine, cortisol, and adrenocorticotropic hormone were also measured at baseline and 8 weeks after completion of treatment. Symptom scores were significantly reduced (P < 0.001 in both the ARGT and SSRI groups at the end of treatment. However, MDD, GAD and OCD patients in the ARGT group had significantly lower plasma cortisol concentrations compared to baseline (P < 0.05, whereas MDD and OCD patients receiving SSRIs showed significantly increased plasma levels of serotonin (P < 0.05. These findings suggest that ARGT may modulate plasma cortisol levels and affect the hypothalamus-pituitary-adrenal axis as opposed to SSRIs, which may up-regulate plasma serotonin levels via a different pathway to produce an overall improvement in the clinical condition of the patients.

  3. Comparison of the neurobiological effects of attribution retraining group therapy with those of selective serotonin reuptake inhibitors

    Directory of Open Access Journals (Sweden)

    C. Wang

    Full Text Available The aim of this study was to compare the effectiveness of attribution retraining group therapy (ARGT with selective serotonin reuptake inhibitors (SSRIs in the treatment of major depressive disorder (MDD, generalized anxiety disorder (GAD, and obsessive-compulsive disorder (OCD. Subjects were sequentially recruited and randomized into two groups, one receiving ARGT (n = 63 and the other SSRIs (n = 66 for 8 weeks. Fifty-four ARGT outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 16 and 55 SSRI outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 17 completed the study. All subjects were assessed using the Hamilton Depression Scale and Hamilton Anxiety Scale before and after treatment. The 10-item Yale-Brown Obsessive Compulsive Scale was employed only for OCD subjects. Plasma levels of serotonin, norepinephrine, cortisol, and adrenocorticotropic hormone were also measured at baseline and 8 weeks after completion of treatment. Symptom scores were significantly reduced (P < 0.001 in both the ARGT and SSRI groups at the end of treatment. However, MDD, GAD and OCD patients in the ARGT group had significantly lower plasma cortisol concentrations compared to baseline (P < 0.05, whereas MDD and OCD patients receiving SSRIs showed significantly increased plasma levels of serotonin (P < 0.05. These findings suggest that ARGT may modulate plasma cortisol levels and affect the hypothalamus-pituitary-adrenal axis as opposed to SSRIs, which may up-regulate plasma serotonin levels via a different pathway to produce an overall improvement in the clinical condition of the patients.

  4. Review article: the many potential roles of intestinal serotonin (5-hydroxytryptamine, 5-HT) signalling in inflammatory bowel disease.

    Science.gov (United States)

    Coates, M D; Tekin, I; Vrana, K E; Mawe, G M

    2017-09-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an important mediator of every major gut-related function. Recent investigations also suggest that 5-HT can influence the development and severity of inflammation within the gut, particularly in the setting of inflammatory bowel disease (IBD). To review the roles that the intestinal serotonin signalling system plays in gut function, with a specific focus on IBD. We reviewed manuscripts from 1952 to 2017 that investigated and discussed roles for 5-HT signalling in gastrointestinal function and IBD, as well as the influence of inflammation on 5-HT signalling elements within the gut. Inflammation appears to affect every major element of intestinal 5-HT signalling, including 5-HT synthesis, release, receptor expression and reuptake capacity. Importantly, many studies (most utilising animal models) also demonstrate that modulation of selective serotonergic receptors (via agonism of 5-HT 4 R and antagonism of 5-HT 3 R) or 5-HT signal termination (via serotonin reuptake inhibitors) can alter the likelihood and severity of intestinal inflammation and/or its complicating symptoms. However, there are few human studies that have studied these relationships in a targeted manner. Insights discussed in this review have strong potential to lead to new diagnostic and therapeutic tools to improve the management of IBD and other related disorders. Specifically, strategies that focus on modifying the activity of selective serotonin receptors and reuptake transporters in the gut could be effective for controlling disease activity and/or its associated symptoms. Further studies in humans are required, however, to more completely understand the pathophysiological mechanisms underlying the roles of 5-HT in this setting. © 2017 John Wiley & Sons Ltd.

  5. Effects of ageing on serotonin transporters in healthy females

    International Nuclear Information System (INIS)

    Kuikka, J.T.; Tammela, L.; Karhunen, L.; Uusitupa, M.; Bergstroem, K.A.; Tiihonen, J.

    2001-01-01

    The effect of ageing on brain serotonin transporters was evaluated in 19 healthy female volunteers (age range 22-74 years) using single-photon emission tomography and [ 123 I] nor-β-CIT. The study subjects were scanned 0.3, 3, 6 and 23 h after injection of 185 MBq of [ 123 I] nor-β-CIT. The ratio of the distribution volume for tracer in the midbrain to that in the cerebellum minus 1 was used as an index for serotonin transporter binding. An age-related decline of 2% per decade (r=-0.47; P 123 I] nor-β-CIT binding in the serotonin transporter-rich area is much less than that in dopamine transporters in the striatum (6% per decade). (orig.)

  6. How the cerebral serotonin homeostasis predicts environmental changes

    DEFF Research Database (Denmark)

    Kalbitzer, Jan; Kalbitzer, Urs; Knudsen, Gitte Moos

    2013-01-01

    Molecular imaging studies with positron emission tomography have revealed that the availability of serotonin transporter (5-HTT) in the human brain fluctuates over the course of the year. This effect is most pronounced in carriers of the short allele of the 5-HTT promoter region (5-HTTLPR), which...... has in several previous studies been linked to an increased risk to develop mood disorders. We argue that long-lasting fluctuations in the cerebral serotonin transmission, which is regulated via the 5-HTT, are responsible for mediating responses to environmental changes based on an assessment...... of cerebral serotonin transmission to seasonal and other forms of environmental change imparts greater behavioral flexibility, at the expense of increased vulnerability to stress. This model may explain the somewhat higher prevalence of the s-allele in some human populations dwelling at geographic latitudes...

  7. Radioimmunoassays for serotonin and 5-hydroxyindole acetic acid

    International Nuclear Information System (INIS)

    Delaage, M.A.; Puizillout, J.J.

    1981-01-01

    Radioimmunoassays for serotonin and 5-hydroxyindole acetic acid were developed. High titer antibodies, having a well-defined high specificity, have been raised by coupling the side-chain of both molecules to human serum albumin. Serotonin is first converted into N-hemisuccinate, and then treated like 5-HIAA, namely, conjugated with HSA for the immunogen. Synthesis of 125 I iodinated analogues was performed by coupling 5-HIAA or N-succinyl serotonin to glycyltyrosine, without any contact between both molecules and the oxidizing reagents. Chemical conversions of biological samples (by succinylation for 5-HT and amidation for 5-HIAA) were carried out. This critical step makes the antigen molecules resemble the immunogen more closely, thus allowing an appreciable gain in specificity and sensitivity. These assays allow the rapid determination of 5-HT and 5-HIAA in small amounts of tissue, blood, cerebral spinal fluid or perfusate without any purification, with a sensitivity threshold of 50 pg

  8. Protonated serotonin: Geometry, electronic structures and photophysical properties

    Science.gov (United States)

    Omidyan, Reza; Amanollahi, Zohreh; Azimi, Gholamhassan

    2017-07-01

    The geometry and electronic structures of protonated serotonin have been investigated by the aim of MP2 and CC2 methods. The relative stabilities, transition energies and geometry of sixteen different protonated isomers of serotonin have been presented. It has been predicted that protonation does not exhibit essential alteration on the S1 ← S0 electronic transition energy of serotonin. Instead, more complicated photophysical nature in respect to its neutral analogue is suggested for protonated system owing to radiative and non-radiative deactivation pathways. In addition to hydrogen detachment (HD), hydrogen/proton transfer (H/PT) processes from ammonium to indole ring along the NH+⋯ π hydrogen bond have been predicted as the most important photophysical consequences of SERH+ at S1 excited state. The PT processes is suggested to be responsible for fluorescence of SERH+ while the HD driving coordinate is proposed for elucidation of its nonradiative deactivation mechanism.

  9. Serotonin transporter gene polymorphisms and brain function during emotional distraction from cognitive processing in posttraumatic stress disorder

    Directory of Open Access Journals (Sweden)

    Hauser Michael A

    2011-05-01

    Full Text Available Abstract Background Serotonergic system dysfunction has been implicated in posttraumatic stress disorder (PTSD. Genetic polymorphisms associated with serotonin signaling may predict differences in brain circuitry involved in emotion processing and deficits associated with PTSD. In healthy individuals, common functional polymorphisms in the serotonin transporter gene (SLC6A4 have been shown to modulate amygdala and prefrontal cortex (PFC activity in response to salient emotional stimuli. Similar patterns of differential neural responses to emotional stimuli have been demonstrated in PTSD but genetic factors influencing these activations have yet to be examined. Methods We investigated whether SLC6A4 promoter polymorphisms (5-HTTLPR, rs25531 and several downstream single nucleotide polymorphisms (SNPs modulated activity of brain regions involved in the cognitive control of emotion in post-9/11 veterans with PTSD. We used functional MRI to examine neural activity in a PTSD group (n = 22 and a trauma-exposed control group (n = 20 in response to trauma-related images presented as task-irrelevant distractors during the active maintenance period of a delayed-response working memory task. Regions of interest were derived by contrasting activation for the most distracting and least distracting conditions across participants. Results In patients with PTSD, when compared to trauma-exposed controls, rs16965628 (associated with serotonin transporter gene expression modulated task-related ventrolateral PFC activation and 5-HTTLPR tended to modulate left amygdala activation. Subsequent to combat-related trauma, these SLC6A4 polymorphisms may bias serotonin signaling and the neural circuitry mediating cognitive control of emotion in patients with PTSD. Conclusions The SLC6A4 SNP rs16965628 and 5-HTTLPR are associated with a bias in neural responses to traumatic reminders and cognitive control of emotions in patients with PTSD. Functional MRI may help identify

  10. Allosteric Binding in the Serotonin Transporter - Pharmacology, Structure, Function and Potential Use as a Novel Drug Target

    DEFF Research Database (Denmark)

    Loland, Claus J.; Sanchez, Connie; Plenge, Per

    2017-01-01

    The serotonin transporter (SERT) is an important drug target and the majority of currently used antidepressants are potent inhibitors of SERT, binding primarily to the substrate binding site. However, even though the existence of an allosteric modulator site was realized more than 30 years ago......, the research into this mechanism is still in its early days. The current knowledge about the allosteric site with respect to pharmacology, structure and function, and pharmacological tool compounds, is reviewed and a perspective is given on its potential as a drug target....

  11. Transient Serotonin Toxicity Evoked by Combination of Electroconvulsive Therapy and Fluoxetine

    DEFF Research Database (Denmark)

    Klysner, René; Bjerg Bendsen, Birgitte; Hansen, Maja Soon

    2014-01-01

    The serotonin syndrome has been described only in rare instances for electroconvulsive therapy combined with an antidepressant medication. We describe a case of serotonin toxicity induced by electroconvulsive therapy in combination with fluoxetine.......The serotonin syndrome has been described only in rare instances for electroconvulsive therapy combined with an antidepressant medication. We describe a case of serotonin toxicity induced by electroconvulsive therapy in combination with fluoxetine....

  12. Evidence for the effect of serotonin receptor 1A gene (HTR1A) polymorphism on tractability in Thoroughbred horses.

    Science.gov (United States)

    Hori, Y; Tozaki, T; Nambo, Y; Sato, F; Ishimaru, M; Inoue-Murayama, M; Fujita, K

    2016-02-01

    Tractability, or how easily animals can be trained and controlled, is an important behavioural trait for the management and training of domestic animals, but its genetic basis remains unclear. Polymorphisms in the serotonin receptor 1A gene (HTR1A) have been associated with individual variability in anxiety-related traits in several species. In this study, we examined the association between HTR1A polymorphisms and tractability in Thoroughbred horses. We assessed the tractability of 167 one-year-old horses reared at a training centre for racehorses using a questionnaire consisting of 17 items. A principal components analysis of answers contracted the data to five principal component (PC) scores. We genotyped two non-synonymous single nucleotide polymorphisms (SNPs) in the horse HTR1A coding region. We found that one of the two SNPs, c.709G>A, which causes an amino acid change at the intracellular region of the receptor, was significantly associated with scores of four of five PCs in fillies (all Ps Horses carrying an A allele at c.709G>A showed lower tractability. This result provides the first evidence that a polymorphism in a serotonin-related gene may affect tractability in horses with the effect partially different depending on sex. © 2015 Stichting International Foundation for Animal Genetics.

  13. Effects of delayed laboratory processing on platelet serotonin levels.

    Science.gov (United States)

    Sanner, Jennifer E; Frazier, Lorraine; Udtha, Malini

    2013-01-01

    Despite the availability of established guidelines for measuring platelet serotonin, these guidelines may be difficult to follow in a hospital setting where time to processing may vary from sample to sample. The purpose of this study was to evaluate the effect of the time to processing of human blood samples on the stability of the enzyme-linked immunosorbent assay (ELISA) for the determination of platelet serotonin levels in human plasma. Human blood samples collected from a convenience sample of eight healthy volunteers were analyzed to determine platelet serotonin levels from plasma collected in ethylene diamine tetra acetic acid (EDTA) tubes and stored at 4°C for 3 hr, 5 hr, 8 hr, and 12 hr. Refrigeration storage at 4°C for 3 hr, 5 hr, 8 hr, and 12 hr altered the platelet serotonin measurement when compared to immediate processing. The bias for the samples stored at 4°C for 3 hr was 102.3 (±217.39 ng/10(9) platelets), for 5 hr was 200.1 (±132.76 ng/10(9) platelets), for 8 hr was 146.9 (±221.41 ng/10(9) platelets), and for 12 hr was -67.6 (±349.60 ng/10(9) platelets). Results from this study show that accurate measurement of platelet serotonin levels is dependent on time to processing. Researchers should therefore follow a standardized laboratory guideline for obtaining immediate platelet serotonin levels after blood sample collection.

  14. Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors

    International Nuclear Information System (INIS)

    Pazos, A.; Cortes, R.; Palacios, J.M.

    1985-01-01

    The distribution of serotonin-2 (5-HT 2 ) receptors in the rat brain was studied by light microscopic quantitative autoradiography. Receptors were labeled with four ligands: [ 3 H]ketanserin, [ 3 H]mesulergine, [ 3 H]LSD and [ 3 H]spiperone, which are reported to show high affinity for 5-HT 2 receptors. Very high concentrations were localized in the claustrum, olfactory tubercle and layer IV of the neocortex. The anterior olfactory nucleus, piriform cortex and layer I of neocortex were also rich in 5-HT 2 receptors. The specificity of the different ligands used is discussed in terms of the other populations of sites recognized by them. The distribution of 5-HT 2 receptors here reported is discussed in correlation with (a) the known distribution of serotoninergic terminals, (b) the specific anatomical systems and (c) the central effects reported to be mediated by 5-HT 2 -selective drugs. (Auth.)

  15. Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer's and Parkinson's diseases.

    Science.gov (United States)

    Cheng, A V; Ferrier, I N; Morris, C M; Jabeen, S; Sahgal, A; McKeith, I G; Edwardson, J A; Perry, R H; Perry, E K

    1991-11-01

    The binding of the selective 5-HT2 antagonist [3H]ketanserin has been investigated in the temporal cortex of patients with Alzheimer's disease (SDAT), Parkinson's disease (PD), senile dementia of Lewy body type (SDLT) and neuropathologically normal subjects (control). 5-HT2 binding was reduced in SDAT, PD with dementia and SDLT. SDAT showed a 5-HT2 receptor deficit across most of the cortical layers. A significant decrease in 5-HT2 binding in the deep cortical layers was found in those SDLT cases without hallucinations. SDLT cases with hallucinations only showed a deficit in one upper layer. There was a significant difference in cortical layers III and V between SDLT without hallucinations and SDLT with hallucinations. The results confirm an abnormality of serotonin binding in various forms of dementia and suggest that preservation of 5-HT2 receptor in the temporal cortex may differentiate hallucinating from non-hallucinating cases of SDLT.

  16. Serotonin transporter evolution and impact of polymorphic transcriptional regulation

    DEFF Research Database (Denmark)

    Søeby, Karen; Larsen, Svend Ask; Olsen, Line

    2005-01-01

    The serotonin transporter (SERT) is the primary drug target in the current antidepressant therapy. A functional polymorphism in the 2nd intron of the 5HTT gene encoding the SERT has been identified and associated with susceptibility to affective disorders and treatment response to antidepressants...... in the VNTRs of all mammalian SERT genes. The number of these putative binding sites varies proportionally to the length of the VNTR. We propose that the intronic VNTR have been selectively targeted through mammalian evolution to finetune transcriptional regulation of the serotonin expression....

  17. Coaction of Stress and Serotonin Transporter Genotype in Predicting Aggression at the Transition to Adulthood

    Science.gov (United States)

    Conway, Christopher C.; Keenan-Miller, Danielle; Hammen, Constance; Lind, Penelope A.; Najman, Jake M.; Brennan, Patricia A.

    2012-01-01

    Despite consistent evidence that serotonin functioning affects stress reactivity and vulnerability to aggression, research on serotonin gene-stress interactions (G x E) in the development of aggression remains limited. The present study investigated variation in the promoter region of the serotonin transporter gene (5-HTTLPR) as a moderator of the…

  18. Effect of serotonin on the yield of UV-induced thymine dimers in DNA

    International Nuclear Information System (INIS)

    Frajkin, G.Ya.; Strakhovskaya, M.G.; Ivanova, Eh.V.

    1985-01-01

    Using fluorescence method serotonin interaction with DNA is studied and bond constant Ksub(c)=4.2x10 4 M -1 is defined. It is shown that bound serotonin reduces yield of UV-induced thymine dimers. Value of efficient distance of protective serotonin effect constituting part of DNA chain of 4 base pairs, is determined

  19. 21 CFR 862.1390 - 5-Hydroxyindole acetic acid/serotonin test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false 5-Hydroxyindole acetic acid/serotonin test system... Test Systems § 862.1390 5-Hydroxyindole acetic acid/serotonin test system. (a) Identification. A 5-hydroxyindole acetic acid/serotonin test system is a device intended to measure 5-hydroxyindole acetic acid...

  20. Acute and delayed effect of (-) deprenyl and (-) 1-phenyl-2-propylaminopentane (PPAP) on the serotonin content of peritoneal cells (white blood cells and mast cells).

    Science.gov (United States)

    Csaba, G; Kovács, P; Pállinger, Eva

    2006-01-01

    Acute and delayed (hormonal imprinting) effect of (-) deprenyl and its derivative without MAO-B inhibitory activity (-) PPAP, were studied on cells of the peritoneal fluid (lymphocytes, monocytes, granulocytes and mast cells) by flow cytometric and confocal microscopic analysis. Thirty minutes after treatment of 6-week-old female animals, deprenyl was ineffective while PPAP significantly increased the serotonin level of these cells. Three weeks after treatment at weaning, deprenyl drastically decreased the serotonin level of each cell type, while PPAP moderately but significantly increased the serotonin level of monocytes, granulocytes and mast cells. This means that the two related molecules have different effects on the immune cells, which seem to be independent of MAO-B inhibition. The experiments emphasize the necessity of studying the prolonged effects of biologically active molecules, even if they are without acute effects. As serotonin is a modulator of the immune system, the influence on immune cells of the molecules studied can contribute to their enhancing effect. Copyright 2004 John Wiley & Sons, Ltd.

  1. Transient fluctuations of intracellular zinc ions in cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yuan [Division of Human Nutrition, Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, TX 77555 (United States); Maret, Wolfgang, E-mail: womaret@utmb.edu [Division of Human Nutrition, Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, TX 77555 (United States); Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX 77555 (United States)

    2009-08-15

    Zinc is essential for cell proliferation, differentiation, and viability. When zinc becomes limited for cultured cells, DNA synthesis ceases and the cell cycle is arrested. The molecular mechanisms of actions of zinc are believed to involve changes in the availability of zinc(II) ions (Zn{sup 2+}). By employing a fluorescent Zn{sup 2+} probe, FluoZin-3 acetoxymethyl ester, intracellular Zn{sup 2+} concentrations were measured in undifferentiated and in nerve growth factor (NGF)-differentiated rat pheochromocytoma (PC12) cells. Intracellular Zn{sup 2+} concentrations are pico- to nanomolar in PC12 cells and are higher in the differentiated than in the undifferentiated cells. When following cellular Zn{sup 2+} concentrations for 48 h after the removal of serum, a condition that is known to cause cell cycle arrest, Zn{sup 2+} concentrations decrease after 30 min but, remarkably, increase after 1 h, and then decrease again to about one half of the initial concentration. Cell proliferation, measured by an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, decreases after both serum starvation and zinc chelation. Two peaks of Zn{sup 2+} concentrations occur within one cell cycle: one early in the G1 phase and the other in the late G1/S phase. Thus, fluctuations of intracellular Zn{sup 2+} concentrations and established modulation of phosphorylation signaling, via an inhibition of protein tyrosine phosphatases at commensurately low Zn{sup 2+} concentrations, suggest a role for Zn{sup 2+} in the control of the cell cycle. Interventions targeted at these picomolar Zn{sup 2+} fluctuations may be a way of controlling cell growth in hyperplasia, neoplasia, and diseases associated with aberrant differentiation.

  2. Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function.

    Science.gov (United States)

    Spencer, William C; Deneris, Evan S

    2017-01-01

    The brain serotonin (5-hydroxytryptamine; 5-HT) system has been extensively studied for its role in normal physiology and behavior, as well as, neuropsychiatric disorders. The broad influence of 5-HT on brain function, is in part due to the vast connectivity pattern of 5-HT-producing neurons throughout the CNS. 5-HT neurons are born and terminally specified midway through embryogenesis, then enter a protracted period of maturation, where they functionally integrate into CNS circuitry and then are maintained throughout life. The transcriptional regulatory networks controlling progenitor cell generation and terminal specification of 5-HT neurons are relatively well-understood, yet the factors controlling 5-HT neuron maturation are only recently coming to light. In this review, we first provide an update on the regulatory network controlling 5-HT neuron development, then delve deeper into the properties and regulatory strategies governing 5-HT neuron maturation. In particular, we discuss the role of the 5-HT neuron terminal selector transcription factor (TF) Pet-1 as a key regulator of 5-HT neuron maturation. Pet-1 was originally shown to positively regulate genes needed for 5-HT synthesis, reuptake and vesicular transport, hence 5-HT neuron-type transmitter identity. It has now been shown to regulate, both positively and negatively, many other categories of genes in 5-HT neurons including ion channels, GPCRs, transporters, neuropeptides, and other transcription factors. Its function as a terminal selector results in the maturation of 5-HT neuron excitability, firing characteristics, and synaptic modulation by several neurotransmitters. Furthermore, there is a temporal requirement for Pet-1 in the control of postmitotic gene expression trajectories thus indicating a direct role in 5-HT neuron maturation. Proper regulation of the maturation of cellular identity is critical for normal neuronal functioning and perturbations in the gene regulatory networks controlling

  3. Decreased uptake of 3H-serotonin and endogenous content of serotonin in blood platelets in hypertensive patients

    International Nuclear Information System (INIS)

    Kamal, L.A.; Le Quan-Bui, K.H.; Meyer, P.

    1984-01-01

    The uptake and content of serotonin in blood platelets were studied in patients with essential hypertension and in five families in which at least one member was hypertensive. Blood was obtained from male and female normotensive volunteers and hypertensive patients who were free of medication. Lineweaver-Burk plots of 3H-serotonin uptake from both control subjects and hypertensive patients were linear, which suggested simple Michaelis-Menten uptake kinetics. The maximal uptake velocity (Vmax) in hypertensive patients was significantly lower than in control subjects (control . 41.7 +/- 3.3 pmol/min/10(8) platelets, n . 17; hypertensive . 26.6 +/- 3.0 pmol/min/10(8) platelets, n . 16; p less than 0.005). The affinity constant (Km) was slightly but significantly lower in hypertensive patients (control . 0.70 +/- 0.08 microM; hypertensive . 0.46 +/- 0.08 microM; p less than 0.05). The serotonin content in blood platelets determined by high pressure liquid chromatography with electrochemical detection was significantly lower in hypertensive patients (control . 165.0 +/- 12.9 nmol/10(11) platelets, n . 29; hypertensive . 105.9 +/- 10.4 nmol/10(11) platelets, n . 27; p less than 0.001). In the five families investigated, the lowered serotonin content was observed in some normotensive members. The reduced number of carriers of serotonin uptake and the slight decrease in the affinity constant observed in platelets of patients with essential hypertension suggest that serotonin metabolism is altered in essential hypertension and that blood platelets may be a useful model in studying the serotonergic modifications at the molecular level

  4. Efficient intracellular delivery and improved biocompatibility of colloidal silver nanoparticles towards intracellular SERS immuno-sensing.

    Science.gov (United States)

    Bhardwaj, Vinay; Srinivasan, Supriya; McGoron, Anthony J

    2015-06-21

    High throughput intracellular delivery strategies, electroporation, passive and TATHA2 facilitated diffusion of colloidal silver nanoparticles (AgNPs) are investigated for cellular toxicity and uptake using state-of-art analytical techniques. The TATHA2 facilitated approach efficiently delivered high payload with no toxicity, pre-requisites for intracellular applications of plasmonic metal nanoparticles (PMNPs) in sensing and therapeutics.

  5. Investigating Internalization and Intracellular Trafficking of GPCRs

    DEFF Research Database (Denmark)

    Foster, Simon R; Bräuner-Osborne, Hans

    2017-01-01

    for signal transduction. One of the major mechanisms for GPCR regulation involves their endocytic trafficking, which serves to internalize the receptors from the plasma membrane and thereby attenuate G protein-dependent signaling. However, there is accumulating evidence to suggest that GPCRs can signal...... independently of G proteins, as well as from intracellular compartments including endosomes. It is in this context that receptor internalization and intracellular trafficking have attracted renewed interest within the GPCR field. In this chapter, we will review the current understanding and methodologies...

  6. Potential of [11C]DASB for measuring endogenous serotonin with PET: binding studies

    International Nuclear Information System (INIS)

    Lundquist, Pinelopi; Wilking, Helena; Hoeglund, A. Urban; Sandell, Johan; Bergstroem, Mats; Hartvig, Per; Langstroem, Bengt

    2005-01-01

    The serotonin transporter radioligand [ 11 C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, or [ 11 C]DASB, was examined in order to assess its potential for measuring fluctuations in endogenous serotonin concentrations with positron emission tomography. Binding characteristics of [ 11 C]DASB and the propensity for serotonin to displace the tracer were explored in rat brain homogenates. Experiments showed that serotonin displaced [ 11 C]DASB in vitro. Ex vivo experiments performed after tranylcypromine injection (3 or 15 mg/kg) showed a dose-dependent trend in radioactivity uptake and suggested that serotonin may compete with [ 11 C]DASB for transporter binding

  7. The electrophysiological effects of the serotonin 1A receptor agonist buspirone in emotional face processing.

    Science.gov (United States)

    Bernasconi, Fosco; Kometer, Michael; Pokorny, Thomas; Seifritz, Erich; Vollenweider, Franz X

    2015-04-01

    Emotional face processing is critically modulated by the serotonergic system, and serotonin (5-HT) receptor agonists impair emotional face processing. However, the specific contribution of the 5-HT1A receptor remains poorly understood. Here we investigated the spatiotemporal brain mechanisms underpinning the modulation of emotional face processing induced by buspirone, a partial 5-HT1A receptor agonist. In a psychophysical discrimination of emotional faces task, we observed that the discrimination fearful versus neutral faces were reduced, but not happy versus neutral faces. Electrical neuroimaging analyses were applied to visual evoked potentials elicited by emotional face images, after placebo and buspirone administration. Buspirone modulated response strength (i.e., global field power) in the interval 230-248ms after stimulus onset. Distributed source estimation over this time interval revealed that buspirone decreased the neural activity in the right dorsolateral prefrontal cortex that was evoked by fearful faces. These results indicate temporal and valence-specific effects of buspirone on the neuronal correlates of emotional face processing. Furthermore, the reduced neural activity in the dorsolateral prefrontal cortex in response to fearful faces suggests a reduced attention to fearful faces. Collectively, these findings provide new insights into the role of 5-HT1A receptors in emotional face processing and have implications for affective disorders that are characterized by an increased attention to negative stimuli. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  8. Serotonin: A mediator of the gut-brain axis in multiple sclerosis.

    Science.gov (United States)

    Malinova, Tsveta S; Dijkstra, Christine D; de Vries, Helga E

    2017-11-01

    The significance of the gut microbiome for the pathogenesis of multiple sclerosis (MS) has been established, although the underlying signaling mechanisms of this interaction have not been sufficiently explored. We address this point and use serotonin (5-hydroxytryptamine (5-HT))-a microbial-modulated neurotransmitter (NT) as a showcase to demonstrate that NTs regulated by the gut microbiome are potent candidates for mediators of the gut-brain axis in demyelinating disorders. Methods, Results, and Conclusion: Our comprehensive overview of literature provides evidence that 5-HT levels in the gut are controlled by the microbiome, both via secretion and through regulation of metabolites. In addition, we demonstrate that the gut microbiome can influence the formation of the serotonergic system (SS) in the brain. We also show that SS alterations have been related to MS directly-altered expression of 5-HT transporters in central nervous system (CNS) and indirectly-beneficial effects of 5-HT modulating drugs on the course of the disease and higher prevalence of depression in patients with MS. Finally, we discuss briefly the role of other microbiome-modulated NTs such as γ-aminobutyric acid and dopamine in MS to highlight a new direction for future research aiming to relate microbiome-regulated NTs to demyelinating disorders.

  9. Serotonin syndrome and rhabdomyolysis in venlafaxine poisoning : a case report

    NARCIS (Netherlands)

    Hanekamp, BB; Zijlstra, JG; Tulleken, JE; Ligtenberg, JJM; van der Werf, TS; Hofstra, LS

    Newer, more selective, antidepressant agents are increasingly being used as first-line treatment. However, clinical experience in patients after a deliberate overdose is limited. We present a case of venlafaxine intoxication complicated by a late rise in creatine kinase, seizures and serotonin

  10. Tall Fescue Alkaloids Bind Serotonin Receptors in Cattle

    Science.gov (United States)

    The serotonin (5HT) receptor 5HT2A is involved in the tall fescue alkaloid-induced vascular contraction in the bovine periphery. This was determined by evaluating the contractile responses of lateral saphenous veins biopsied from cattle grazing different tall fescue/endophyte combinations. The contr...

  11. Acute serotonin depletion releases motivated inhibition of response vigour.

    Science.gov (United States)

    den Ouden, Hanneke E M; Swart, Jennifer C; Schmidt, Kristin; Fekkes, Durk; Geurts, Dirk E M; Cools, Roshan

    2015-04-01

    The neurotransmitter serotonin has long been implicated in the motivational control of behaviour. Recent theories propose that the role of serotonin can be understood in terms of an interaction between a motivational and a behavioural activation axis. Experimental support for these ideas, however, has been mixed. In the current study, we aimed to investigate the role of serotonin (5HT) in behavioural vigour as a function of incentive motivation. We employed dietary acute tryptophan depletion (ATD) to lower the 5HT precursor tryptophan during the performance of a speeded visual discrimination task. Feedback valence and feedback probability were manipulated independently and cued prior to target onset. On feedback trials, fast correct responses led to either reward or avoidance of punishment, while slow or incorrect responses led to reward omission or punishment. We show that behavioural responding is inhibited under high incentive motivation (i.e. high-feedback probability) at baseline 5HT levels and that lowering these leads to behavioural disinhibition, while leaving accuracy unaffected. Surprisingly, there were no differential effects of motivational valence, with 5HT depletion releasing behavioural inhibition under both appetitive and aversive motivation. Our findings extend current theories on the role of 5HT in behavioural inhibition by showing that reductions in serotonin lead to increased behavioural vigour only if there is a motivational drive to inhibit behaviour at baseline.

  12. Increased hypothalamic serotonin turnover in inflammation-induced anorexia

    NARCIS (Netherlands)

    Dwarkasing, J.T.; Witkamp, R.F.; Boekschoten, M.V.; Laak, ter M.C.; Heins, M.S.; Norren, van K.

    2016-01-01

    Background: Anorexia can occur as a serious complication of disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections

  13. Binding-Induced Fluorescence of Serotonin Transporter Ligands

    DEFF Research Database (Denmark)

    Wilson, James; Ladefoged, Lucy Kate; Babinchak, Michael

    2014-01-01

    The binding-induced fluorescence of 4-(4-(dimethylamino)-phenyl)-1-methylpyridinium (APP(+)) and two new serotonin transporter (SERT)-binding fluorescent analogues, 1-butyl-4-[4-(1-dimethylamino)phenyl]-pyridinium bromide (BPP(+)) and 1-methyl-4-[4-(1-piperidinyl)phenyl]-pyridinium (PPP(+)), has...

  14. Serotonin and noradrenaline reuptake inhibitors improve micturition control in mice.

    Directory of Open Access Journals (Sweden)

    Marco Redaelli

    Full Text Available Poor micturition control may cause profound distress, because proper voiding is mandatory for an active social life. Micturition results from the subtle interplay of central and peripheral components. It involves the coordination of autonomic and neuromuscular activity at the brainstem level, under the executive control of the prefrontal cortex. We tested the hypothesis that administration of molecules acting as reuptake inhibitors of serotonin, noradrenaline or both may exert a strong effect on the control of urine release, in a mouse model of overactive bladder. Mice were injected with cyclophosphamide (40 mg/kg, to increase micturition acts. Mice were then given one of four molecules: the serotonin reuptake inhibitor imipramine, its metabolite desipramine that acts on noradrenaline reuptake, the serotonin and noradrenaline reuptake inhibitor duloxetine or its active metabolite 4-hydroxy-duloxetine. Cyclophosphamide increased urine release without inducing overt toxicity or inflammation, except for increase in urothelium thickness. All the antidepressants were able to decrease the cyclophosphamide effects, as apparent from longer latency to the first micturition act, decreased number of urine spots and volume of released urine. These results suggest that serotonin and noradrenaline reuptake inhibitors exert a strong and effective modulatory effect on the control of urine release and prompt to additional studies on their central effects on brain areas involved in the social and behavioral control of micturition.

  15. Use of selective serotonin reuptake inhibitors reduces fertility in men

    DEFF Research Database (Denmark)

    Nørr, L; Bennedsen, Birgit; Fedder, Jens

    2016-01-01

    Clinical review of the present data on the effects of selective serotonin reuptake inhibitors (SSRIs) on male fertility was the objective of the study. PubMed and Scopus were searched for publications in English or Danish and reviewed. Human trials, animal studies and in vitro studies were included...

  16. Pathophysiological and pharmacotherapeutic aspects of serotonin and serotonergic drugs

    NARCIS (Netherlands)

    van Zwieten, P. A.; Blauw, G. J.; van Brummelen, P.

    1990-01-01

    A survey shall be given on the physiological, pathophysiological and pharmacotherapeutic backgrounds of the biogenic amine 5-hydroxytryptamine (serotonin; 5HT), to be preceded by a few historical remarks. 5HT is biosynthesized from L-tryptophan via hydroxylation and subsequent decarboxylation. 5HT

  17. Purification and fluorescent labeling of the human serotonin transporter

    DEFF Research Database (Denmark)

    Rasmussen, Søren G F; Gether, Ulrik

    2005-01-01

    To establish a purification procedure for the human serotonin transporter (hSERT) we expressed in Sf9 insect cells an epitope-tagged version of the transporter containing a FLAG epitope at the N-terminus and a polyhistidine tail at the C-terminus (FLAG-hSERT-12H). For purification, the transporter...

  18. High brain serotonin levels in migraine between attacks

    DEFF Research Database (Denmark)

    Deen, Marie; Hansen, Hanne D; Hougaard, Anders

    2018-01-01

    Migraine has been hypothesized to be a syndrome of chronic low serotonin (5-HT) levels, but investigations of brain 5-HT levels have given equivocal results. Here, we used positron emission tomography (PET) imaging of the 5-HT4receptor as a proxy for brain 5-HT levels. Given that the 5-HT4receptor...

  19. Effects of Postnatal Serotonin Agonism on Fear Response and Memory

    Science.gov (United States)

    The neurotransmitter serotonin (5-HT) also acts as a neurogenic compound in the developing brain. Early administration of a 5-HT agonist could alter the development of the serotonergic circuitry, altering behaviors mediated by 5-HT signaling, such as memory, fear and aggression. White leghorn chicks...

  20. Brief Report: Platelet-Poor Plasma Serotonin in Autism

    Science.gov (United States)

    Anderson, George M.; Hertzig, Margaret E.; McBride, P. A.

    2012-01-01

    Possible explanations for the well-replicated platelet hyperserotonemia of autism include an alteration in the platelet's handling of serotonin (5-hydroxyserotonin, 5-HT) or an increased exposure of the platelet to 5-HT. Measurement of platelet-poor plasma (PPP) levels of 5-HT appears to provide the best available index of in vivo exposure of the…

  1. A role for serotonin in piglet preweaning mortality

    Science.gov (United States)

    Improving piglet survivability rate is of high priority for swine production as well as for piglet well-being. Dysfunction in the serotonin system has been associated with growth deficiencies, infant mortality or failure to thrive (FTT) in human infants. The aim of this study was to examine the role...

  2. Serotonin transporter genotype, salivary cortisol, neuroticism and life events

    DEFF Research Database (Denmark)

    Vinberg, Maj; Miskowiak, Kamilla; Kessing, Lars Vedel

    2014-01-01

    OBJECTIVE: To investigate if cortisol alone or in interaction with other risk factors (familial risk, the serotonin transporter genotype, neuroticism and life events (LEs)) predicts onset of psychiatric disorder in healthy individuals at heritable risk. MATRIAL AND METHODS: In a high-risk study...

  3. Serotonin synthesis studied with positron emission tomography, (PET)

    DEFF Research Database (Denmark)

    Honoré, Per Gustaf Hartvig; Lundquist, Pinelopi

    Positron emission tomography (PET) has the potential to study the biosynthesis and release of serotonin (5HT) at brain serotonergic neurons. PET requires probe compounds with specific attributes to enable imaging and quantification of biological processes. This section focuses on probes to measure...

  4. Alterations to embryonic serotonin change aggression and fearfulness

    Science.gov (United States)

    Prenatal environment, including maternal hormones, affects the development of the serotonin (5-HT) system, with long-lasting effects on mood and behavioral exhibition in children and adults. The chicken provides a unique animal model to study the effects of embryonic development on childhood and ado...

  5. Plasma serotonin in horses undergoing surgery for small intestinal colic

    NARCIS (Netherlands)

    Torfs, Sara C; Maes, An A; Delesalle, Catherine J; Pardon, Bart; Croubels, Siska M; Deprez, Piet

    This study compared serotonin concentrations in platelet poor plasma (PPP) from healthy horses and horses with surgical small intestinal (SI) colic, and evaluated their association with postoperative ileus, strangulation and non-survival. Plasma samples (with EDTA) from 33 horses with surgical SI

  6. Serotonin and calcium homeostasis during the transition period.

    Science.gov (United States)

    Weaver, S R; Laporta, J; Moore, S A E; Hernandez, L L

    2016-07-01

    The transition from pregnancy to lactation puts significant, sudden demands on maternal energy and calcium reserves. Although most mammals are able to effectively manage these metabolic adaptations, the lactating dairy cow is acutely susceptible to transition-related disorders because of the high amounts of milk being produced. Hypocalcemia is a common metabolic disorder that occurs at the onset of lactation. Hypocalcemia is also known to result in poor animal welfare conditions. In addition, cows that develop hypocalcemia are more susceptible to a host of other negative health outcomes. Different feeding tactics, including manipulating the dietary cation-anion difference and administering low-calcium diets, are commonly used preventative strategies. Despite these interventions, the incidence of hypocalcemia in the subclinical form is still as high as 25% to 30% in the United States dairy cow population, with a 5% to 10% incidence of clinical hypocalcemia. In addition, although there are various effective treatments in place, they are administered only after the cow has become noticeably ill, at which point there is already significant metabolic damage. This emphasizes the need for developing alternative prevention strategies, with the monoamine serotonin implicated as a potential therapeutic target. Our research in rodents has shown that serotonin is critical for the induction of mammary parathyroid hormone-related protein, which is necessary for the mobilization of bone tissue and subsequent restoration of maternal calcium stores during lactation. We have shown that circulating serotonin concentrations are positively correlated with serum total calcium on the first day of lactation in dairy cattle. Administration of serotonin's immediate precursor through feeding, injection, or infusion to various mammalian species has been shown to increase circulating serotonin concentrations, with positive effects on other components of maternal metabolism. Most recently

  7. Therapeutic Application of Diacylglycerol Oil for Obesity: Serotonin Hypothesis

    Directory of Open Access Journals (Sweden)

    Yuji Hirowatari

    2012-01-01

    Full Text Available ABSTRACT: Characteristics for the serum lipid abnormalities in the obesity/metabolic syndrome are elevated fasting, postprandial triglyceride (TG, and decreased high-density lipoprotein-cholesterol (HDL-C. Diacylglycerol (DAG oil ingestion has been reported to ameliorate postprandial hyperlipidemia and prevent obesity by increasing energy expenditure, due to the intestinal physiochemical dynamics that differ from triacylglycerol (TAG. Our study demonstrated that DAG suppresses postprandial increase in TG-rich lipoprotein, very low-density lipoprotein (VLDL, and insulin, as compared with TAG in young, healthy individuals. Interestingly, our study also presented that DAG significantly increases plasma serotonin, which is mostly present in the intestine, and mediates thermogenesis, proposing a possible mechanism for a postprandial increase in energy expenditure by DAG. Our other study demonstrated that DAG suppresses postprandial increase in TG, VLDL-C, and remnant-like particle-cholesterol, in comparison with TAG in an apolipoprotein C-II deficient subject, suggesting that DAG suppresses postprandial TG-rich lipoprotein independently of lipoprotein lipase. Further, to understand the molecular mechanisms for DAG-mediated increase in serotonin and energy expenditure, we studied the effects of 1-monoacylglycerol and 2(1:1-10 2-monoacylglycerol, distinct digestive products of DAG and TAG, respectively, on serotonin release from the Caco-2 cells, the human intestinal cell line. We also studied effects of 1- and 2-monoacylglycerol, and serotonin on the expression of mRNA associated with â-oxidation, fatty acids metabolism, and thermogenesis, in the Caco-2 cells. 1-monoacylglycerol significantly increased serotonin release from the Caco-2 cells, compared with 2-monoacylglycerol by approximately 40%. The expression of mRNA of acyl-CoA oxidase (ACO, fatty acid translocase (FAT, and uncoupling protein-2 (UCP-2, was significantly higher in 1-MOG

  8. Selective serotonin reuptake inhibitor (SSRI antidepressants, prolactin and breast cancer

    Directory of Open Access Journals (Sweden)

    Janet eAshbury

    2012-12-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are a widely prescribed class of anti-depressants. Laboratory and epidemiologic evidence suggests that a prolactin-mediated mechanism secondary to increased serotonin levels at neuronal synapses could lead to a potentially carcinogenic effect of SSRIs. In this population-based case-control study, we evaluated the association between SSRI use and breast cancer risk as a function of their relative degree of inhibition of serotonin reuptake as a proxy for their impact on prolactin levels. Cases were 2,129 women with primary invasive breast cancer diagnosed from 2003-2007, and controls were 21,297 women randomly selected from the population registry. Detailed information for each SSRI prescription dispensed was compiled using the Saskatchewan prescription database. Logistic regression was used to evaluate the impact of use of high and lower inhibitors of serotonin reuptake and duration of use, as well as to assess the effect of individual high inhibitors on the risk of breast cancer. Exclusive users of high or lower inhibitors of serotonin reuptake were not at increased risk for breast cancer compared with nonusers of SSRIs (OR = 1.01, CI = 0.88-1.17 and OR = 0.91, CI = 0.67-1.25 respectively, regardless of their duration of use or menopausal status. While we cannot rule out the possibility of a clinically important risk increase (OR = 1.83, CI = 0.99-3.40 for long-term users of sertraline (≥24 prescriptions, given the small number of exposed cases (n=12, the borderline statistical significance and the wide confidence interval, these results need to be interpreted cautiously. In this large population-based case-control study, we found no conclusive evidence of breast cancer risk associated with the use of SSRIs even after assessing the degree of serotonin reuptake inhibition and duration of use. Our results do not support the serotonin-mediated pathway for the prolactin-breast cancer hypothesis.

  9. In Vivo Imaging of Cerebral Serotonin Transporter and Serotonin(2A) Receptor Binding in 3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") and Hallucinogen Users

    DEFF Research Database (Denmark)

    Erritzoe, David; Frokjaer, Vibe G.; Holst, Klaus K.

    2011-01-01

    Context: Both hallucinogens and 3,4-methylenedioxy-methamphetamine( MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin.Objective: ......Context: Both hallucinogens and 3,4-methylenedioxy-methamphetamine( MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin...

  10. Action potential-independent and pharmacologically unique vesicular serotonin release from dendrites

    Science.gov (United States)

    Colgan, Lesley A.; Cavolo, Samantha L.; Commons, Kathryn G.; Levitan, Edwin S.

    2012-01-01

    Serotonin released within the dorsal raphe nucleus (DR) induces feedback inhibition of serotonin neuron activity and consequently regulates mood-controlling serotonin release throughout the forebrain. Serotonin packaged in vesicles is released in response to action potentials by the serotonin neuron soma and terminals, but the potential for release by dendrites is unknown. Here three-photon (3P) microscopy imaging of endogenous serotonin in living rat brain slice, immunofluorescence and immuno-gold electron microscopy detection of VMAT2 (vesicular monoamine transporter 2) establish the presence of vesicular serotonin within DR dendrites. Furthermore, activation of glutamate receptors is shown to induce vesicular serotonin release from dendrites. However, unlike release from the soma and terminals, dendritic serotonin release is independent of action potentials, relies on L-type Ca2+ channels, is induced preferentially by NMDA, and displays distinct sensitivity to the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine. The unique control of dendritic serotonin release has important implications for DR physiology and the antidepressant action of SSRIs, dihydropyridines and NMDA receptor antagonists. PMID:23136413

  11. Non-conventional features of peripheral serotonin signalling - the gut and beyond.

    Science.gov (United States)

    Spohn, Stephanie N; Mawe, Gary M

    2017-07-01

    Serotonin was first discovered in the gut, and its conventional actions as an intercellular signalling molecule in the intrinsic and extrinsic enteric reflexes are well recognized, as are a number of serotonin signalling pharmacotherapeutic targets for treatment of nausea, diarrhoea or constipation. The latest discoveries have greatly broadened our understanding of non-conventional actions of peripheral serotonin within the gastrointestinal tract and in a number of other tissues. For example, it is now clear that bacteria within the lumen of the bowel influence serotonin synthesis and release by enterochromaffin cells. Also, serotonin can act both as a pro-inflammatory and anti-inflammatory signalling molecule in the intestinal mucosa via activation of serotonin receptors (5-HT 7 or 5-HT 4 receptors, respectively). For decades, serotonin receptors have been known to exist in a variety of tissues other than the gut, but studies have now provided strong evidence for physiological roles of serotonin in several important processes, including haematopoiesis, metabolic homeostasis and bone metabolism. Furthermore, evidence for serotonin synthesis in peripheral tissues outside of the gut is emerging. In this Review, we expand the discussion beyond gastrointestinal functions to highlight the roles of peripheral serotonin in colitis, haematopoiesis, energy and bone metabolism, and how serotonin is influenced by the gut microbiota.

  12. Exercise and sleep in aging: emphasis on serotonin.

    Science.gov (United States)

    Melancon, M O; Lorrain, D; Dionne, I J

    2014-10-01

    Reductions in central serotonin activity with aging might be involved in sleep-related disorders in later life. Although the beneficial effects of aerobic exercise on sleep are not new, sleep represents a complex recurring state of unconsciousness involving many lines of transmitters which remains only partly clear despite intense ongoing research. It is known that serotonin released into diencephalon and cerebrum might play a key inhibitory role to help promote sleep, likely through an active inhibition of supraspinal neural networks. Several lines of evidence support the stimulatory effects of exercise on higher serotonergic pathways. Hence, exercise has proved to elicit acute elevations in forebrain serotonin concentrations, an effect that waned upon cessation of exercise. While adequate exercise training might lead to adaptations in higher serotonergic networks (desensitization of forebrain receptors), excessive training has been linked to serious brain serotonergic maladaptations accompanied by insomnia. Dietary supplementation of tryptophan (the only serotonin precursor) is known to stimulate serotonergic activity and promote sleep, whereas acute tryptophan depletion causes deleterious effects on sleep. Regarding sleep-wake regulation, exercise has proved to accelerate resynchronization of the biological clock to new light-dark cycles following imposition of phase shifts in laboratory animals. Noteworthy, the effect of increased serotonergic transmission on wake state appears to be biphasic, i.e. promote wake and thereafter drowsiness. Therefore, it might be possible that acute aerobic exercise would act on sleep by increasing activity of ascending brain serotonergic projections, though additional work is warranted to better understand the implication of serotonin in the exercise-sleep axis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  13. Cationic polymers for intracellular delivery of proteins

    NARCIS (Netherlands)

    Coué, G.M.J.P.C.; Engbersen, Johannes F.J.; Samal, Sangram; Dubruel, Peter

    2015-01-01

    Many therapeutic proteins exert their pharmaceutical action inside the cytoplasm or onto individual organelles inside the cell. Intracellular protein delivery is considered to be the most direct, fastest and safest approach for curing gene-deficiency diseases, enhancing vaccination and triggering

  14. Molecular detection and characterization of sustainable intracellular ...

    African Journals Online (AJOL)

    3Centre for Biopolymer and Bio-Molecular Research, Athlone College of Technology, Republic of Ireland. ... cells was associated with the elongation of micro-villar extension that ... Keywords: Intracellular contaminants, cell cultures, bacteria culture, pre-clinical studies. ... production work involving culture technology.

  15. Spatial Cytoskeleton Organization Supports Targeted Intracellular Transport

    Science.gov (United States)

    Hafner, Anne E.; Rieger, Heiko

    2018-03-01

    The efficiency of intracellular cargo transport from specific source to target locations is strongly dependent upon molecular motor-assisted motion along the cytoskeleton. Radial transport along microtubules and lateral transport along the filaments of the actin cortex underneath the cell membrane are characteristic for cells with a centrosome. The interplay between the specific cytoskeleton organization and the motor performance realizes a spatially inhomogeneous intermittent search strategy. In order to analyze the efficiency of such intracellular search strategies we formulate a random velocity model with intermittent arrest states. We evaluate efficiency in terms of mean first passage times for three different, frequently encountered intracellular transport tasks: i) the narrow escape problem, which emerges during cargo transport to a synapse or other specific region of the cell membrane, ii) the reaction problem, which considers the binding time of two particles within the cell, and iii) the reaction-escape problem, which arises when cargo must be released at a synapse only after pairing with another particle. Our results indicate that cells are able to realize efficient search strategies for various intracellular transport tasks economically through a spatial cytoskeleton organization that involves only a narrow actin cortex rather than a cell body filled with randomly oriented actin filaments.

  16. Biological synthesis and characterization of intracellular gold ...

    Indian Academy of Sciences (India)

    In the present study, Aspergillus fumigatus was used for the intracellular synthesis of gold nanoparticles. Stable nanoparticles were produced when an aqueous solution of chloroauric acid (HAuCl4) was reduced by A. fumigatus biomass as the reducing agent. Production of nanoparticles was confirmed by the colour ...

  17. Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice.

    Science.gov (United States)

    Kalueff, A V; Fox, M A; Gallagher, P S; Murphy, D L

    2007-06-01

    Although mice with a targeted disruption of the serotonin transporter (SERT) have been studied extensively using various tests, their complex behavioral phenotype is not yet fully understood. Here we assess in detail the behavior of adult female SERT wild type (+/+), heterozygous (+/-) and knockout (-/-) mice on an isogenic C57BL/6J background subjected to a battery of behavioral paradigms. Overall, there were no differences in the ability to find food or a novel object, nest-building, self-grooming and its sequencing, and horizontal rod balancing, indicating unimpaired sensory functions, motor co-ordination and behavioral sequencing. In contrast, there were striking reductions in exploration and activity in novelty-based tests (novel object, sticky label and open field tests), accompanied by pronounced thigmotaxis, suggesting that combined hypolocomotion and anxiety (rather than purely anxiety) influence the SERT -/- behavioral phenotype. Social interaction behaviors were also markedly reduced. In addition, SERT -/- mice tended to move close to the ground, frequently displayed spontaneous Straub tail, tics, tremor and backward gait - a phenotype generally consistent with 'serotonin syndrome'-like behavior. In line with replicated evidence of much enhanced serotonin availability in SERT -/- mice, this serotonin syndrome-like state may represent a third factor contributing to their behavioral profile. An understanding of the emerging complexity of SERT -/- mouse behavior is crucial for a detailed dissection of their phenotype and for developing further neurobehavioral models using these mice.

  18. Optimizing Nanoelectrode Arrays for Scalable Intracellular Electrophysiology.

    Science.gov (United States)

    Abbott, Jeffrey; Ye, Tianyang; Ham, Donhee; Park, Hongkun

    2018-03-20

    Electrode technology for electrophysiology has a long history of innovation, with some decisive steps including the development of the voltage-clamp measurement technique by Hodgkin and Huxley in the 1940s and the invention of the patch clamp electrode by Neher and Sakmann in the 1970s. The high-precision intracellular recording enabled by the patch clamp electrode has since been a gold standard in studying the fundamental cellular processes underlying the electrical activities of neurons and other excitable cells. One logical next step would then be to parallelize these intracellular electrodes, since simultaneous intracellular recording from a large number of cells will benefit the study of complex neuronal networks and will increase the throughput of electrophysiological screening from basic neurobiology laboratories to the pharmaceutical industry. Patch clamp electrodes, however, are not built for parallelization; as for now, only ∼10 patch measurements in parallel are possible. It has long been envisioned that nanoscale electrodes may help meet this challenge. First, nanoscale electrodes were shown to enable intracellular access. Second, because their size scale is within the normal reach of the standard top-down fabrication, the nanoelectrodes can be scaled into a large array for parallelization. Third, such a nanoelectrode array can be monolithically integrated with complementary metal-oxide semiconductor (CMOS) electronics to facilitate the large array operation and the recording of the signals from a massive number of cells. These are some of the central ideas that have motivated the research activity into nanoelectrode electrophysiology, and these past years have seen fruitful developments. This Account aims to synthesize these findings so as to provide a useful reference. Summing up from the recent studies, we will first elucidate the morphology and associated electrical properties of the interface between a nanoelectrode and a cellular membrane

  19. Getting “Inside” Type I IFNs: Type I IFNs in Intracellular Bacterial Infections

    Directory of Open Access Journals (Sweden)

    Deann T. Snyder

    2017-01-01

    Full Text Available Type I interferons represent a unique and complex group of cytokines, serving many purposes during innate and adaptive immunity. Discovered in the context of viral infections, type I IFNs are now known to have myriad effects in infectious and autoimmune disease settings. Type I IFN signaling during bacterial infections is dependent on many factors including whether the infecting bacterium is intracellular or extracellular, as different signaling pathways are activated. As such, the repercussions of type I IFN induction can positively or negatively impact the disease outcome. This review focuses on type I IFN induction and downstream consequences during infection with the following intracellular bacteria: Chlamydia trachomatis, Listeria monocytogenes, Mycobacterium tuberculosis, Salmonella enterica serovar Typhimurium, Francisella tularensis, Brucella abortus, Legionella pneumophila, and Coxiella burnetii. Intracellular bacterial infections are unique because the bacteria must avoid, circumvent, and even co-opt microbial “sensing” mechanisms in order to reside and replicate within a host cell. Furthermore, life inside a host cell makes intracellular bacteria more difficult to target with antibiotics. Because type I IFNs are important immune effectors, modulating this pathway may improve disease outcomes. But first, it is critical to understand the context-dependent effects of the type I IFN pathway in intracellular bacterial infections.

  20. The role of serotonin in personality inference: tryptophan depletion impairs the identification of neuroticism in the face.

    Science.gov (United States)

    Ward, Robert; Sreenivas, Shubha; Read, Judi; Saunders, Kate E A; Rogers, Robert D

    2017-07-01

    Serotonergic mechanisms mediate the expression of personality traits (such as impulsivity, aggression and anxiety) that are linked to vulnerability to psychological illnesses, and modulate the identification of emotional expressions in the face as well as learning about broader classes of appetitive and aversive signals. Faces with neutral expressions signal a variety of socially relevant information, such that inferences about the big five personality traits, including Neuroticism, Extraversion and Agreeableness, can be accurately made on the basis of emotionally neutral facial photographs. Given the close link between Neuroticism and psychological distress, we investigated the effects of diminished central serotonin activity (achieved by tryptophan depletion) upon the accuracy of 52 healthy (non-clinical) adults' discriminations of personality from facial characteristics. All participants were able to discriminate reliably four of the big five traits. However, the tryptophan-depleted participants were specifically less accurate in discriminating Neuroticism than the matched non-depleted participants. These data suggest that central serotonin activity modulates the identification of not only negative facial emotional expression but also a broader class of signals about personality characteristics linked to psychological distress.

  1. Intracellular pH regulation in unstimulated Calliphora salivary glands is Na+ dependent and requires V-ATPase activity.

    Science.gov (United States)

    Schewe, Bettina; Blenau, Wolfgang; Walz, Bernd

    2012-04-15

    Salivary gland cells of the blowfly Calliphora vicina have a vacuolar-type H(+)-ATPase (V-ATPase) that lies in their apical membrane and energizes the secretion of a KCl-rich primary saliva upon stimulation with serotonin (5-hydroxytryptamine). Whether and to what extent V-ATPase contributes to intracellular pH (pH(i)) regulation in unstimulated gland cells is unknown. We used the fluorescent dye BCECF to study intracellular pH(i) regulation microfluorometrically and show that: (1) under resting conditions, the application of Na(+)-free physiological saline induces an intracellular alkalinization attributable to the inhibition of the activity of a Na(+)-dependent glutamate transporter; (2) the maintenance of resting pH(i) is Na(+), Cl(-), concanamycin A and DIDS sensitive; (3) recovery from an intracellular acid load is Na(+) sensitive and requires V-ATPase activity; (4) the Na(+)/H(+) antiporter is not involved in pH(i) recovery after a NH(4)Cl prepulse; and (5) at least one Na(+)-dependent transporter and the V-ATPase maintain recovery from an intracellular acid load. Thus, under resting conditions, the V-ATPase and at least one Na(+)-dependent transporter maintain normal pH(i) values of pH 7.5. We have also detected the presence of a Na(+)-dependent glutamate transporter, which seems to act as an acid loader. Despite this not being a common pH(i)-regulating transporter, its activity affects steady-state pH(i) in C. vicina salivary gland cells.

  2. Neurodegeneration in Alzheimer Disease: Role of Amyloid Precursor Protein and Presenilin 1 Intracellular Signaling

    Directory of Open Access Journals (Sweden)

    Mario Nizzari

    2012-01-01

    Full Text Available Alzheimer disease (AD is a heterogeneous neurodegenerative disorder characterized by (1 progressive loss of synapses and neurons, (2 intracellular neurofibrillary tangles, composed of hyperphosphorylated Tau protein, and (3 amyloid plaques. Genetically, AD is linked to mutations in few proteins amyloid precursor protein (APP and presenilin 1 and 2 (PS1 and PS2. The molecular mechanisms underlying neurodegeneration in AD as well as the physiological function of APP are not yet known. A recent theory has proposed that APP and PS1 modulate intracellular signals to induce cell-cycle abnormalities responsible for neuronal death and possibly amyloid deposition. This hypothesis is supported by the presence of a complex network of proteins, clearly involved in the regulation of signal transduction mechanisms that interact with both APP and PS1. In this review we discuss the significance of novel finding related to cell-signaling events modulated by APP and PS1 in the development of neurodegeneration.

  3. The Role of Intracellular Calcium for the Development and Treatment of Neuroblastoma

    International Nuclear Information System (INIS)

    Satheesh, Noothan Jyothi; Büsselberg, Dietrich

    2015-01-01

    Neuroblastoma is the second most common paediatric cancer. It develops from undifferentiated simpatico-adrenal lineage cells and is mostly sporadic; however, the aetiology behind the development of neuroblastoma is still not fully understood. Intracellular calcium ([Ca 2+ ] i ) is a secondary messenger which regulates numerous cellular processes and, therefore, its concentration is tightly regulated. This review focuses on the role of [Ca 2+ ] i in differentiation, apoptosis and proliferation in neuroblastoma. It describes the mechanisms by which [Ca 2+ ] i is regulated and how it modulates intracellular pathways. Furthermore, the importance of [Ca 2+ ] i for the function of anti-cancer drugs is illuminated in this review as [Ca 2+ ] i could be a target to improve the outcome of anti-cancer treatment in neuroblastoma. Overall, modulations of [Ca 2+ ] i could be a key target to induce apoptosis in cancer cells leading to a more efficient and effective treatment of neuroblastoma

  4. Ontogeny of serotonin and serotonin2A receptors in rat auditory cortex.

    Science.gov (United States)

    Basura, Gregory J; Abbas, Atheir I; O'Donohue, Heather; Lauder, Jean M; Roth, Bryan L; Walker, Paul D; Manis, Paul B

    2008-10-01

    Maturation of the mammalian cerebral cortex is, in part, dependent upon multiple coordinated afferent neurotransmitter systems and receptor-mediated cellular linkages during early postnatal development. Given that serotonin (5-HT) is one such system, the present study was designed to specifically evaluate 5-HT tissue content as well as 5-HT(2A) receptor protein levels within the developing auditory cortex (AC). Using high performance liquid chromatography (HPLC), 5-HT and the metabolite, 5-hydroxyindoleacetic acid (5-HIAA), was measured in isolated AC, which demonstrated a developmental dynamic, reaching young adult levels early during the second week of postnatal development. Radioligand binding of 5-HT(2A) receptors with the 5-HT(2A/2C) receptor agonist, (125)I-DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl; in the presence of SB206553, a selective 5-HT(2C) receptor antagonist, also demonstrated a developmental trend, whereby receptor protein levels reached young adult levels at the end of the first postnatal week (P8), significantly increased at P10 and at P17, and decreased back to levels not significantly different from P8 thereafter. Immunocytochemical labeling of 5-HT(2A) receptors and confocal microscopy revealed that 5-HT(2A) receptors are largely localized on layer II/III pyramidal cell bodies and apical dendrites within AC. When considered together, the results of the present study suggest that 5-HT, likely through 5-HT(2A) receptors, may play an important role in early postnatal AC development.

  5. Escitalopram, an antidepressant with an allosteric effect at the serotonin transporter--a review of current understanding of its mechanism of action.

    Science.gov (United States)

    Zhong, Huailing; Haddjeri, Nasser; Sánchez, Connie

    2012-01-01

    Escitalopram is a widely used antidepressant for the treatment of patients with major depression. It is the pure S-enantiomer of racemic citalopram. Several clinical trials and meta-analyses indicate that escitalopram is quantitatively more efficacious than many other antidepressants with a faster onset of action. This paper reviews current knowledge about the mechanism of action of escitalopram. The primary target for escitalopram is the serotonin transporter (SERT), which is responsible for serotonin (or 5-hydroxytryptamine [5-HT]) reuptake at the terminals and cell bodies of serotonergic neurons. Escitalopram and selective serotonin reuptake inhibitors bind with high affinity to the 5-HT binding site (orthosteric site) on the transporter. This leads to antidepressant effects by increasing extracellular 5-HT levels which enhance 5-HT neurotransmission. SERT also has one or more allosteric sites, binding to which modulates activity at the orthosteric binding site but does not directly affect 5-HT reuptake by the transporter. In vitro studies have shown that through allosteric binding, escitalopram decreases its own dissociation rate from the orthosteric site on the SERT. R-citalopram, the nontherapeutic enantiomer in citalopram, is also an allosteric modulator of SERT but can inhibit the actions of escitalopram by interfering negatively with its binding. Both nonclinical studies and some clinical investigations have demonstrated the cellular, neurochemical, neuroadaptive, and neuroplastic changes induced by escitalopram with acute and chronic administration. The findings from binding, neurochemical, and neurophysiological studies may provide a mechanistic rationale for the clinical difference observed with escitalopram compared to other antidepressant therapies.

  6. Endocrine and metabolic changes in transition dairy cows are affected by prepartum infusions of a serotonin precursor

    DEFF Research Database (Denmark)

    Hernandez Castellano, Lorenzo E; Hernandez, Laura L.; Sauerwein, Helga

    2017-01-01

    Serotonin (5-HT) has been shown to be involved in calcium homeostasis, modulating calcium concentration in blood. In addition, 5-HT participates in a variety of metabolic pathways, mainly through the modulation of glucose and lipid metabolism. The hypothesis of the present study...... was that the prepartum administration of 5-hydroxy-l-tryptophan (5-HTP), a 5-HT precursor, would affect endocrine systems related to calcium homeostasis, and interact with other endocrine and metabolic pathways during the transition period. In this study, 20 Holstein dairy cows were randomly assigned to 2 experimental...... homeostasis independent of PTH. The lack of treatment effects on IgG and on other hormones and metabolites indicates that 5-HTP did not affect these other metabolic pathways and the IgG concentration during the transition period....

  7. An intracellular interaction network regulates conformational transitions in the dopamine transporter

    DEFF Research Database (Denmark)

    Kniazeff, Julie; Shi, Lei; Løland, Claus Juul

    2008-01-01

    Neurotransmitter:sodium symporters (NSS)(1) mediate sodium-dependent reuptake of neurotransmitters from the synaptic cleft and are targets for many psychoactive drugs. The crystal structure of the prokaryotic NSS protein, LeuT, was recently solved at high resolution; however, the mechanistic...... and the intracellular milieu. The mechanism that emerges from these findings may be unique to the NSS family, where the local disruption of ionic interactions modulates the transition of the transporter between the outward- and inward-facing conformations....

  8. Selective serotonin reuptake inhibitors for fibromyalgia syndrome

    Science.gov (United States)

    Walitt, Brian; Urrútia, Gerard; Nishishinya, María Betina; Cantrell, Sarah E; Häuser, Winfried

    2016-01-01

    Background Fibromyalgia is a clinically well-defined chronic condition with a biopsychosocial aetiology. Fibromyalgia is characterized by chronic widespread musculoskeletal pain, sleep problems, cognitive dysfunction, and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of fibromyalgia, drug therapy focuses on pain reduction and improvement of other aversive symptoms. Objectives The objective was to assess the benefits and harms of selective serotonin reuptake inhibitors (SSRIs) in the treatment of fibromyalgia. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 5), MEDLINE (1966 to June 2014), EMBASE (1946 to June 2014), and the reference lists of reviewed articles. Selection criteria We selected all randomized, double-blind trials of SSRIs used for the treatment of fibromyalgia symptoms in adult participants. We considered the following SSRIs in this review: citalopram, fluoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline. Data collection and analysis Three authors extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. Main results The quality of evidence was very low for each outcome. We downgraded the quality of evidence to very low due to concerns about risk of bias and studies with few participants. We included seven placebo-controlled studies, two with citalopram, three with fluoxetine and two with paroxetine, with a median study duration of eight weeks (4 to 16 weeks) and 383 participants, who were pooled together. All studies had one or more sources of potential major bias. There was a small (10%) difference in patients who reported a 30% pain reduction between SSRIs (56/172 (32.6%)) and placebo (39/171 (22.8%)) risk difference (RD) 0.10, 95% confidence interval (CI) 0.01 to 0.20; number needed to treat for an additional

  9. Selective serotonin reuptake inhibitors for fibromyalgia syndrome

    Directory of Open Access Journals (Sweden)

    Brian Walitt

    Full Text Available ABSTRACT BACKGROUND: Fibromyalgia is a clinically well-defined chronic condition with a biopsychosocial aetiology. Fibromyalgia is characterized by chronic widespread musculoskeletal pain, sleep problems, cognitive dysfunction, and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of fibromyalgia, drug therapy focuses on pain reduction and improvement of other aversive symptoms. OBJECTIVES: To assess the benefits and harms of selective serotonin reuptake inhibitors (SSRIs in the treatment of fibromyalgia. METHODS: Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 5, MEDLINE (1966 to June 2014, EMBASE (1946 to June 2014, and the reference lists of reviewed articles. Selection criteria: We selected all randomized, double-blind trials of SSRIs used for the treatment of fibromyalgia symptoms in adult participants. We considered the following SSRIs in this review: citalopram, fluoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline. Data collection and analysis: Three authors extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. MAIN RESULTS: The quality of evidence was very low for each outcome. We downgraded the quality of evidence to very low due to concerns about risk of bias and studies with few participants. We included seven placebo-controlled studies, two with citalopram, three with fluoxetine and two with paroxetine, with a median study duration of eight weeks (4 to 16 weeks and 383 participants, who were pooled together. All studies had one or more sources of potential major bias. There was a small (10% difference in patients who reported a 30% pain reduction between SSRIs (56/172 (32.6% and placebo (39/171 (22.8% risk difference (RD 0.10, 95% confidence interval (CI 0.01 to 0.20; number needed to treat for an

  10. Serotonin noradrenaline reuptake inhibitors: New hope for the treatment of chronic pain.

    Science.gov (United States)

    Delgado, Pedro L

    2006-01-01

    than selective inhibitors of serotonin reuptake. Wherever valid comparisons have been made the newer dual action drugs appear to be as effective as the tricyclic and considerably better tolerated. Dual action antidepressants may thus soon become the new standard treatment of chronic pain whether it is associated with depression or not. In addition, these agents may also have a role in modulating neurogenesis and other neuroplastic changes in the central nervous system, thereby leading to more complete recovery in patients suffering from the symptoms of depression or chronic pain.

  11. Ethanol intake and 3H-serotonin uptake I: A study in Fawn-Hooded rats

    International Nuclear Information System (INIS)

    Daoust, M.; Compagnon, P.; Legrand, E.; Boucly, P.

    1991-01-01

    Ethanol intake and synaptosomal 3 H-serotonin uptake were studied in male Fawn-Hooded and Sprague-Dawley rats. Fawn-Hooded rats consumed more alcohol and more water than Sprague-Dawley rats. Plasma alcohol levels of Sprague-Dawley rats were not detectable but were about 5 mg/dl in Fawn-Hooded rats. Ethanol intake increased the Vmax of serotonin uptake in Fawn-Hooded rats in hippocampus and cortex, but not in thalamus. In Fawn-Hooded rats, serotonin uptake (Vmax) was higher than in Sprague-Dawley rats cortex. Ethanol intake reduced the Vmax of serotonin uptake in Fawn-Hooded rats in hippocampus and cortex. In cortex, the carrier affinity for serotonin was increased in alcoholized Fawn-Hooded rats. These results indicate that synaptosomal 3 H-serotonin uptake is affected by ethanol intake. In Fawn-Hooded rats, high ethanol consumption is associated with high serotonin uptake. In rats presenting high serotonin uptake, alcoholization reduces 3 H-serotonin internalization in synaptosomes, indicating a specific sensitivity to alcohol intake of serotonin uptake system

  12. Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice

    Science.gov (United States)

    Suidan, Georgette L.; Demers, Melanie; Herr, Nadine; Carbo, Carla; Brill, Alexander; Cifuni, Stephen M.; Mauler, Maximilian; Cicko, Sanja; Bader, Michael; Idzko, Marco; Bode, Christoph

    2013-01-01

    The majority of peripheral serotonin is stored in platelets, which secrete it on activation. Serotonin releases Weibel-Palade bodies (WPBs) and we asked whether absence of platelet serotonin affects neutrophil recruitment in inflammatory responses. Tryptophan hydroxylase (Tph)1–deficient mice, lacking non-neuronal serotonin, showed mild leukocytosis compared with wild-type (WT), primarily driven by an elevated neutrophil count. Despite this, 50% fewer leukocytes rolled on unstimulated mesenteric venous endothelium of Tph1−/− mice. The velocity of rolling leukocytes was higher in Tph1−/− mice, indicating fewer selectin-mediated interactions with endothelium. Stimulation of endothelium with histamine, a secretagogue of WPBs, or injection of serotonin normalized the rolling in Tph1−/− mice. Diminished rolling in Tph1−/− mice resulted in reduced firm adhesion of leukocytes after lipopolysaccharide treatment. Blocking platelet serotonin uptake with fluoxetine in WT mice reduced serum serotonin by > 80% and similarly reduced leukocyte rolling and adhesion. Four hours after inflammatory stimulation, neutrophil extravasation into lung, peritoneum, and skin wounds was reduced in Tph1−/− mice, whereas in vitro neutrophil chemotaxis was independent of serotonin. Survival of lipopolysaccharide-induced endotoxic shock was improved in Tph1−/− mice. In conclusion, platelet serotonin promotes the recruitment of neutrophils in acute inflammation, supporting an important role for platelet serotonin in innate immunity. PMID:23243271

  13. Serotonin potentiates transforming growth factor-beta3 induced biomechanical remodeling in avian embryonic atrioventricular valves.

    Directory of Open Access Journals (Sweden)

    Philip R Buskohl

    Full Text Available Embryonic heart valve primordia (cushions maintain unidirectional blood flow during development despite an increasingly demanding mechanical environment. Recent studies demonstrate that atrioventricular (AV cushions stiffen over gestation, but the molecular mechanisms of this process are unknown. Transforming growth factor-beta (TGFβ and serotonin (5-HT signaling modulate tissue biomechanics of postnatal valves, but less is known of their role in the biomechanical remodeling of embryonic valves. In this study, we demonstrate that exogenous TGFβ3 increases AV cushion biomechanical stiffness and residual stress, but paradoxically reduces matrix compaction. We then show that TGFβ3 induces contractile gene expression (RhoA, aSMA and extracellular matrix expression (col1α2 in cushion mesenchyme, while simultaneously stimulating a two-fold increase in proliferation. Local compaction increased due to an elevated contractile phenotype, but global compaction appeared reduced due to proliferation and ECM synthesis. Blockade of TGFβ type I receptors via SB431542 inhibited the TGFβ3 effects. We next showed that exogenous 5-HT does not influence cushion stiffness by itself, but synergistically increases cushion stiffness with TGFβ3 co-treatment. 5-HT increased TGFβ3 gene expression and also potentiated TGFβ3 induced gene expression in a dose-dependent manner. Blockade of the 5HT2b receptor, but not 5-HT2a receptor or serotonin transporter (SERT, resulted in complete cessation of TGFβ3 induced mechanical strengthening. Finally, systemic 5-HT administration in ovo induced cushion remodeling related defects, including thinned/atretic AV valves, ventricular septal defects, and outflow rotation defects. Elevated 5-HT in ovo resulted in elevated remodeling gene expression and increased TGFβ signaling activity, supporting our ex-vivo findings. Collectively, these results highlight TGFβ/5-HT signaling as a potent mechanism for control of biomechanical

  14. Chronic Enhancement of Serotonin Facilitates Excitatory Transcranial Direct Current Stimulation-Induced Neuroplasticity.

    Science.gov (United States)

    Kuo, Hsiao-I; Paulus, Walter; Batsikadze, Giorgi; Jamil, Asif; Kuo, Min-Fang; Nitsche, Michael A

    2016-04-01

    Serotonin affects memory formation via modulating long-term potentiation (LTP) and depression (LTD). Accordingly, acute selective serotonin reuptake inhibitor (SSRI) administration enhanced LTP-like plasticity induced by transcranial direct current stimulation (tDCS) in humans. However, it usually takes some time for SSRI to reduce clinical symptoms such as anxiety, negative mood, and related symptoms of depression and anxiety disorders. This might be related to an at least partially different effect of chronic serotonergic enhancement on plasticity, as compared with single-dose medication. Here we explored the impact of chronic application of the SSRI citalopram (CIT) on plasticity induced by tDCS in healthy humans in a partially double-blinded, placebo (PLC)-controlled, randomized crossover study. Furthermore, we explored the dependency of plasticity induction from the glutamatergic system via N-methyl-D-aspartate receptor antagonism. Twelve healthy subjects received PLC medication, combined with anodal or cathodal tDCS of the primary motor cortex. Afterwards, the same subjects took CIT (20 mg/day) consecutively for 35 days. During this period, four additional interventions were performed (CIT and PLC medication with anodal/cathodal tDCS, CIT and dextromethorphan (150 mg) with anodal/cathodal tDCS). Plasticity was monitored by motor-evoked potential amplitudes elicited by transcranial magnetic stimulation. Chronic application of CIT increased and prolonged the LTP-like plasticity induced by anodal tDCS for over 24 h, and converted cathodal tDCS-induced LTD-like plasticity into facilitation. These effects were abolished by dextromethorphan. Chronic serotonergic enhancement results in a strengthening of LTP-like glutamatergic plasticity, which might partially explain the therapeutic impact of SSRIs in depression and other neuropsychiatric diseases.

  15. Investigation of serotonin-1A receptor function in the human psychopharmacology of MDMA.

    Science.gov (United States)

    Hasler, F; Studerus, E; Lindner, K; Ludewig, S; Vollenweider, F X

    2009-11-01

    Serotonin (5-HT) release is the primary pharmacological mechanism of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') action in the primate brain. Dopamine release and direct stimulation of dopamine D2 and serotonin 5-HT2A receptors also contributes to the overall action of MDMA. The role of 5-HT1A receptors in the human psychopharmacology of MDMA, however, has not yet been elucidated. In order to reveal the consequences of manipulation at the 5-HT1A receptor system on cognitive and subjective effects of MDMA, a receptor blocking study using the mixed beta-adrenoreceptor blocker/5-HT1A antagonist pindolol was performed. Using a double-blind, placebo-controlled within-subject design, 15 healthy male subjects were examined under placebo (PL), 20 mg pindolol (PIN), MDMA (1.6 mg/kg b.wt.), MDMA following pre-treatment with pindolol (PIN-MDMA). Tasks from the Cambridge Neuropsychological Test Automated Battery were used for the assessment of cognitive performance. Psychometric questionnaires were applied to measure effects of treatment on core dimensions of Altered States of Consciousness, mood and state anxiety. Compared with PL, MDMA significantly impaired sustained attention and visual-spatial memory, but did not affect executive functions. Pre-treatment with PIN did not significantly alter MDMA-induced impairment of cognitive performance and only exerted a minor modulating effect on two psychometric scales affected by MDMA treatment ('positive derealization' and 'dreaminess'). Our findings suggest that MDMA differentially affects higher cognitive functions, but does not support the hypothesis from animal studies, that some of the MDMA effects are causally mediated through action at the 5-HT1A receptor system.

  16. The serotonin system in autism spectrum disorder: from biomarker to animal models

    Science.gov (United States)

    Muller, Christopher L.; Anacker, Allison M.J.; Veenstra-VanderWeele, Jeremy

    2015-01-01

    Elevated whole blood serotonin, or hyperserotonemia, was the first biomarker identified in autism spectrum disorder (ASD) and is present in more than 25% of affected children. The serotonin system is a logical candidate for involvement in ASD due to its pleiotropic role across multiple brain systems both dynamically and across development. Tantalizing clues connect this peripheral biomarker with changes in brain and behavior in ASD, but the contribution of the serotonin system to ASD pathophysiology remains incompletely understood. Studies of whole blood serotonin levels in ASD and in a large founder population indicate greater heritability than for the disorder itself and suggest an association with recurrence risk. Emerging data from both neuroimaging and postmortem samples also indicate changes in the brain serotonin system in ASD. Genetic linkage and association studies of both whole blood serotonin levels and of ASD risk point to the chromosomal region containing the serotonin transporter (SERT) gene in males but not in females. In ASD families with evidence of linkage to this region, multiple rare SERT amino acid variants lead to a convergent increase in serotonin uptake in cell models. A knock-in mouse model of one of these variants, SERT Gly56Ala, recapitulates the hyperserotonemia biomarker and shows increased brain serotonin clearance, increased serotonin receptor sensitivity, and altered social, communication, and repetitive behaviors. Data from other rodent models also suggest an important role for the serotonin system in social behavior, in cognitive flexibility, and in sensory development. Recent work indicates that reciprocal interactions between serotonin and other systems, such as oxytocin, may be particularly important for social behavior. Collectively, these data point to the serotonin system as a prime candidate for treatment development in a subgroup of children defined by a robust, heritable biomarker. PMID:26577932

  17. Dynamics of gradient formation by intracellular shuttling

    Energy Technology Data Exchange (ETDEWEB)

    Berezhkovskii, Alexander M. [Mathematical and Statistical Computing Laboratory, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, Maryland 20892 (United States); Shvartsman, Stanislav Y. [Department of Chemical and Biological Engineering and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544 (United States)

    2015-08-21

    A number of important cellular functions rely on the formation of intracellular protein concentration gradients. Experimental studies discovered a number of mechanisms for the formation of such gradients. One of the mechanisms relies on the intracellular shuttling of a protein that interconverts between the two states with different diffusivities, under the action of two enzymes, one of which is localized to the plasma membrane, whereas the second is uniformly distributed in the cytoplasm. Recent work reported an analytical solution for the steady state gradient in this mechanism, obtained in the framework of a one-dimensional reaction-diffusion model. Here, we study the dynamics in this model and derive analytical expressions for the Laplace transforms of the time-dependent concentration profiles in terms of elementary transcendental functions. Inverting these transforms numerically, one can obtain time-dependent concentration profiles of the two forms of the protein.

  18. Leishmania hijacking of the macrophage intracellular compartments.

    Science.gov (United States)

    Liévin-Le Moal, Vanessa; Loiseau, Philippe M

    2016-02-01

    Leishmania spp., transmitted to humans by the bite of the sandfly vector, are responsible for the three major forms of leishmaniasis, cutaneous, diffuse mucocutaneous and visceral. Leishmania spp. interact with membrane receptors of neutrophils and macrophages. In macrophages, the parasite is internalized within a parasitophorous vacuole and engages in a particular intracellular lifestyle in which the flagellated, motile Leishmania promastigote metacyclic form differentiates into non-motile, metacyclic amastigote form. This phenomenon is induced by Leishmania-triggered events leading to the fusion of the parasitophorous vacuole with vesicular members of the host cell endocytic pathway including recycling endosomes, late endosomes and the endoplasmic reticulum. Maturation of the parasitophorous vacuole leads to the intracellular proliferation of the Leishmania amastigote forms by acquisition of host cell nutrients while escaping host defense responses. © 2015 FEBS.

  19. Reduction of intracellular glutathione content and radiosensitivity

    International Nuclear Information System (INIS)

    Vos, O.; Schans, G.P. van der; Roos-Verheij, W.S.D.

    1986-05-01

    The intracellular glutathione (GSH) content in HeLa, CHO and V79 cells was reduced by incubating the cells in growth medium containing buthionine sulfoximine (BSO) or diethyl maleate (DEM). Clonogenicity, single strand DNA breaks (ssb) and double strand DNA breaks (dsb) were used as criteria for radiation induced damage after X- or γ irradiation. In survival experiments DEM gave a slightly larger sensitization although it gave a smaller reduction of the intracellular GSH. In general, sensitization was larger for dsb than for ssb, also the reduction of the OER was generally larger for dsb than for ssb. This may be due to the higher dose rate in case of dsb experiments resulting in a higher rate of radiochemical oxygen consumption. In general, no effect was found on post-irradiation repair of ssb and dsb. (Auth.)

  20. Reduction of intracellular glutathione content and radiosensitivity

    International Nuclear Information System (INIS)

    Vos, O.; Schans, G.P. van der; Roos-Verheij, W.S.D.

    1986-01-01

    The intracellular glutathione (GSH) content of HeLa, CHO and V79 cells was reduced by incubating the cells in growth medium containing buthionine sulphoximine or diethyl maleate (DEM). Clonogenicity, single-strand DNA breaks (ssb) and double-strand DNA breaks (dsb) were used as criteria for radiation-induced damage after X- or γ-irradiation. In survival experiments, DEM gave a slightly larger sensitization although it gave a smaller reduction of the intracellular GSH. In general, sensitization was larger for dsb than for ssb, also the reduction of the o.e.r. was generally larger for dsb than for ssb. This may be due to the higher dose rate in case of dsb experiments resulting in a higher rate of radiochemical oxygen consumption. In general, no effect was found on post-irradiation repair of ssb and dsb. (author)

  1. Intracellular mechanisms of solar water disinfection

    Science.gov (United States)

    Castro-Alférez, María; Polo-López, María Inmaculada; Fernández-Ibáñez, Pilar

    2016-12-01

    Solar water disinfection (SODIS) is a zero-cost intervention measure to disinfect drinking water in areas of poor access to improved water sources, used by more than 6 million people in the world. The bactericidal action of solar radiation in water has been widely proven, nevertheless the causes for this remain still unclear. Scientific literature points out that generation of reactive oxygen species (ROS) inside microorganisms promoted by solar light absorption is the main reason. For the first time, this work reports on the experimental measurement of accumulated intracellular ROS in E. coli during solar irradiation. For this experimental achievement, a modified protocol based on the fluorescent probe dichlorodihydrofluorescein diacetate (DCFH-DA), widely used for oxidative stress in eukaryotic cells, has been tested and validated for E. coli. Our results demonstrate that ROS and their accumulated oxidative damages at intracellular level are key in solar water disinfection.

  2. Intracellular serpins, firewalls and tissue necrosis.

    Science.gov (United States)

    Marciniak, Stefan J; Lomas, David A

    2008-02-01

    Luke and colleagues have recently attributed a new role to a member of the serpin superfamily of serine proteinase inhibitors. They have used Caenorhabditis elegans to show that an intracellular serpin is crucial for maintaining lysosomal integrity. We examine the role of this firewall in preventing necrosis and attempt to integrate this with current theories of stress-induced protein degradation. We discuss how mutant serpins cause disease either through polymerization or now, perhaps, by unleashing necrosis.

  3. Rationality and emotionality: serotonin transporter genotype influences reasoning bias.

    Science.gov (United States)

    Stollstorff, Melanie; Bean, Stephanie E; Anderson, Lindsay M; Devaney, Joseph M; Vaidya, Chandan J

    2013-04-01

    Reasoning often occurs under emotionally charged, opinion-laden circumstances. The belief-bias effect indexes the extent to which reasoning is based upon beliefs rather than logical structure. We examined whether emotional content increases this effect, particularly for adults genetically predisposed to be more emotionally reactive. SS/SL(G) carriers of the serotonin transporter genotype (5-HTTLPR) were less accurate selectively for evaluating emotional relational reasoning problems with belief-logic conflict relative to L(A)L(A) carriers. Trait anxiety was positively associated with emotional belief-bias, and the 5-HTTLPR genotype significantly accounted for the variance in this association. Thus, deductive reasoning, a higher cognitive ability, is sensitive to differences in emotionality rooted in serotonin neurotransmitter function.

  4. Unifying concept of serotonin transporter-associated currents.

    Science.gov (United States)

    Schicker, Klaus; Uzelac, Zeljko; Gesmonde, Joan; Bulling, Simon; Stockner, Thomas; Freissmuth, Michael; Boehm, Stefan; Rudnick, Gary; Sitte, Harald H; Sandtner, Walter

    2012-01-02

    Serotonin (5-HT) uptake by the human serotonin transporter (hSERT) is driven by ion gradients. The stoichiometry of transported 5-HT and ions is predicted to result in electroneutral charge movement. However, hSERT mediates a current when challenged with 5-HT. This discrepancy can be accounted for by an uncoupled ion flux. Here, we investigated the mechanistic basis of the uncoupled currents and its relation to the conformational cycle of hSERT. Our observations support the conclusion that the conducting state underlying the uncoupled ion flux is in equilibrium with an inward facing state of the transporter with K+ bound. We identified conditions associated with accumulation of the transporter in inward facing conformations. Manipulations that increased the abundance of inward facing states resulted in enhanced steady-state currents. We present a comprehensive kinetic model of the transport cycle, which recapitulates salient features of the recorded currents. This study provides a framework for exploring transporter-associated currents.

  5. Divergent Roles of Central Serotonin in Adult Hippocampal Neurogenesis

    Directory of Open Access Journals (Sweden)

    Ning-Ning Song

    2017-06-01

    Full Text Available The central serotonin (5-HT system is the main target of selective serotonin reuptake inhibitors (SSRIs, the first-line antidepressants widely used in current general practice. One of the prominent features of chronic SSRI treatment in rodents is the enhanced adult neurogenesis in the hippocampus, which has been proposed to contribute to antidepressant effects. Therefore, tremendous effort has been made to decipher how central 5-HT regulates adult hippocampal neurogenesis. In this paper, we review how changes in the central serotonergic system alter adult hippocampal neurogenesis. We focus on data obtained from three categories of genetically engineered mouse models: (1 mice with altered central 5-HT levels from embryonic stages, (2 mice with deletion of 5-HT receptors from embryonic stages, and (3 mice with altered central 5-HT system exclusively in adulthood. These recent findings provide unique insights to interpret the multifaceted roles of central 5-HT on adult hippocampal neurogenesis and its associated effects on depression.

  6. Expression analysis for inverted effects of serotonin transporter inactivation

    International Nuclear Information System (INIS)

    Ichikawa, Manabu; Okamura-Oho, Yuko; Shimokawa, Kazuro; Kondo, Shinji; Nakamura, Sakiko; Yokota, Hideo; Himeno, Ryutaro; Lesch, Klaus-Peter; Hayashizaki, Yoshihide

    2008-01-01

    Inactivation of serotonin transporter (HTT) by pharmacologically in the neonate or genetically increases risk for depression in adulthood, whereas pharmacological inhibition of HTT ameliorates symptoms in depressed patients. The differing role of HTT function during early development and in adult brain plasticity in causing or reversing depression remains an unexplained paradox. To address this we profiled the gene expression of adult Htt knockout (Htt KO) mice and HTT inhibitor-treated mice. Inverted profile changes between the two experimental conditions were seen in 30 genes. Consistent results of the upstream regulatory element search and the co-localization search of these genes indicated that the regulation may be executed by Pax5, Pax7 and Gata3, known to be involved in the survival, proliferation, and migration of serotonergic neurons in the developing brain, and these factors are supposed to keep functioning to regulate downstream genes related to serotonin system in the adult brain

  7. Fluorescent nanoparticles for intracellular sensing: A review

    International Nuclear Information System (INIS)

    Ruedas-Rama, Maria J.; Walters, Jamie D.; Orte, Angel; Hall, Elizabeth A.H.

    2012-01-01

    Highlights: ► Analytical applications of fluorescent nanoparticles (NPs) in intracellular sensing. ► Critical review on performance of QDots, metal NPs, silica NPs, and polymer NPs. ► Highlighted potential of fluorescence lifetime imaging microscopy (FLIM). - Abstract: Fluorescent nanoparticles (NPs), including semiconductor NPs (Quantum Dots), metal NPs, silica NPs, polymer NPs, etc., have been a major focus of research and development during the past decade. The fluorescent nanoparticles show unique chemical and optical properties, such as brighter fluorescence, higher photostability and higher biocompatibility, compared to classical fluorescent organic dyes. Moreover, the nanoparticles can also act as multivalent scaffolds for the realization of supramolecular assemblies, since their high surface to volume ratio allow distinct spatial domains to be functionalized, which can provide a versatile synthetic platform for the implementation of different sensing schemes. Their excellent properties make them one of the most useful tools that chemistry has supplied to biomedical research, enabling the intracellular monitoring of many different species for medical and biological purposes. In this review, we focus on the developments and analytical applications of fluorescent nanoparticles in chemical and biological sensing within the intracellular environment. The review also points out the great potential of fluorescent NPs for fluorescence lifetime imaging microscopy (FLIM). Finally, we also give an overview of the current methods for delivering of fluorescent NPs into cells, where critically examine the benefits and liabilities of each strategy.

  8. Fluorescent nanoparticles for intracellular sensing: A review

    Energy Technology Data Exchange (ETDEWEB)

    Ruedas-Rama, Maria J., E-mail: mjruedas@ugr.esmailto [Department of Physical Chemistry, Faculty of Pharmacy, University of Granada, Campus Cartuja, 18071, Granada (Spain); Walters, Jamie D. [Department of Chemical Engineering and Biotechnology, University of Cambridge, Tennis Court Road, Cambridge, UK CB2 1QT (United Kingdom); Orte, Angel [Department of Physical Chemistry, Faculty of Pharmacy, University of Granada, Campus Cartuja, 18071, Granada (Spain); Hall, Elizabeth A.H., E-mail: lisa.hall@biotech.cam.ac.uk [Department of Chemical Engineering and Biotechnology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QT (United Kingdom)

    2012-11-02

    Highlights: Black-Right-Pointing-Pointer Analytical applications of fluorescent nanoparticles (NPs) in intracellular sensing. Black-Right-Pointing-Pointer Critical review on performance of QDots, metal NPs, silica NPs, and polymer NPs. Black-Right-Pointing-Pointer Highlighted potential of fluorescence lifetime imaging microscopy (FLIM). - Abstract: Fluorescent nanoparticles (NPs), including semiconductor NPs (Quantum Dots), metal NPs, silica NPs, polymer NPs, etc., have been a major focus of research and development during the past decade. The fluorescent nanoparticles show unique chemical and optical properties, such as brighter fluorescence, higher photostability and higher biocompatibility, compared to classical fluorescent organic dyes. Moreover, the nanoparticles can also act as multivalent scaffolds for the realization of supramolecular assemblies, since their high surface to volume ratio allow distinct spatial domains to be functionalized, which can provide a versatile synthetic platform for the implementation of different sensing schemes. Their excellent properties make them one of the most useful tools that chemistry has supplied to biomedical research, enabling the intracellular monitoring of many different species for medical and biological purposes. In this review, we focus on the developments and analytical applications of fluorescent nanoparticles in chemical and biological sensing within the intracellular environment. The review also points out the great potential of fluorescent NPs for fluorescence lifetime imaging microscopy (FLIM). Finally, we also give an overview of the current methods for delivering of fluorescent NPs into cells, where critically examine the benefits and liabilities of each strategy.

  9. Intracellular Cholesterol Trafficking and Impact in Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Fabian Arenas

    2017-11-01

    Full Text Available Cholesterol is a critical component of membrane bilayers where it plays key structural and functional roles by regulating the activity of diverse signaling platforms and pathways. Particularly enriched in brain, cholesterol homeostasis in this organ is singular with respect to other tissues and exhibits a heterogeneous regulation in distinct brain cell populations. Due to the key role of cholesterol in brain physiology and function, alterations in cholesterol homeostasis and levels have been linked to brain diseases and neurodegeneration. In the case of Alzheimer disease (AD, however, this association remains unclear with evidence indicating that either increased or decreased total brain cholesterol levels contribute to this major neurodegenerative disease. Here, rather than analyzing the role of total cholesterol levels in neurodegeneration, we focus on the contribution of intracellular cholesterol pools, particularly in endolysosomes and mitochondria through its trafficking via specialized membrane domains delineated by the contacts between endoplasmic reticulum and mitochondria, in the onset of prevalent neurodegenerative diseases such as AD, Parkinson disease, and Huntington disease as well as in lysosomal disorders like Niemann-Pick type C disease. We dissect molecular events associated with intracellular cholesterol accumulation, especially in mitochondria, an event that results in impaired mitochondrial antioxidant defense and function. A better understanding of the mechanisms involved in the distribution of cholesterol in intracellular compartments may shed light on the role of cholesterol homeostasis disruption in neurodegeneration and may pave the way for specific intervention opportunities.

  10. A bacteriophage endolysin that eliminates intracellular streptococci

    Science.gov (United States)

    Shen, Yang; Barros, Marilia; Vennemann, Tarek; Gallagher, D Travis; Yin, Yizhou; Linden, Sara B; Heselpoth, Ryan D; Spencer, Dennis J; Donovan, David M; Moult, John; Fischetti, Vincent A; Heinrich, Frank; Lösche, Mathias; Nelson, Daniel C

    2016-01-01

    PlyC, a bacteriophage-encoded endolysin, lyses Streptococcus pyogenes (Spy) on contact. Here, we demonstrate that PlyC is a potent agent for controlling intracellular Spy that often underlies refractory infections. We show that the PlyC holoenzyme, mediated by its PlyCB subunit, crosses epithelial cell membranes and clears intracellular Spy in a dose-dependent manner. Quantitative studies using model membranes establish that PlyCB interacts strongly with phosphatidylserine (PS), whereas its interaction with other lipids is weak, suggesting specificity for PS as its cellular receptor. Neutron reflection further substantiates that PlyC penetrates bilayers above a PS threshold concentration. Crystallography and docking studies identify key residues that mediate PlyCB–PS interactions, which are validated by site-directed mutagenesis. This is the first report that a native endolysin can traverse epithelial membranes, thus substantiating the potential of PlyC as an antimicrobial for Spy in the extracellular and intracellular milieu and as a scaffold for engineering other functionalities. DOI: http://dx.doi.org/10.7554/eLife.13152.001 PMID:26978792

  11. Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain.

    Science.gov (United States)

    Bonnin, A; Levitt, P

    2011-12-01

    In addition to its role in neurotransmission, embryonic serotonin (5-HT) has been implicated in the regulation of neurodevelopmental processes. For example, we recently showed that a subset of 5-HT1-receptors expressed in the fetal forebrain mediate a serotonergic modulation of thalamocortical axons response to axon guidance cues, both in vitro and in vivo. This influence of 5-HT signaling on fetal brain wiring raised important questions regarding the source of the ligand during pregnancy. Until recently, it was thought that 5-HT sources impacting brain development arose from maternal transport to the fetus, or from raphe neurons in the brainstem of the fetus. Using genetic mouse models, we uncovered previously unknown differences in 5-HT accumulation between the fore- and hindbrain during early and late fetal stages, through an exogenous source of 5-HT. Using additional genetic strategies, a new technology for studying placental biology ex vivo, and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source and uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor, in both mice and humans. These results implicate a new, direct role for placental metabolic pathways in modulating fetal brain development and suggest an important role for maternal-placental-fetal interactions and 5-HT in the fetal programming of adult mental disorders. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  12. Serotonin syndrome associated with sertraline use: case report

    OpenAIRE

    Bárbara Werner Griciunas; Norton Yoshiaki Kitanishi; Renata Carvalho de Souza; Daniel Azevedo Cavalcante; Leonardo Mattiolli Marini

    2017-01-01

    Case report of serotonin syndrome in patient who initiated the use of sertraline at a dose greater than twice the recommended for the treatment of psychotic depression. The patient presented contracture of the limbs, puzzled look, mutism and blood pressure 230x110 mmHg. The syndrome is increasingly common, although it is not well recognized. Many medications can cause it and this possibility should be considered in patients taking serotonergic drugs presenting autonomic or mental disorders an...

  13. APRESS: apical regulatory super system, serotonin, and dopamine interaction

    Directory of Open Access Journals (Sweden)

    Hinz M

    2011-08-01

    Full Text Available Marty Hinz1, Alvin Stein2, Thomas Uncini31Clinical Research, NeuroResearch Clinics, Inc, Cape Coral, FL, USA; 2Stein Orthopedic Associates, Plantation, FL, USA; 3DBS Labs, Duluth, MN, USABackground: The monoamines serotonin and dopamine are known to exist in two separate states: the endogenous state and the competitive inhibition state. The presence of the competitive inhibition state has been known to science for many years, but from a functional standpoint it has been noted in the literature as being "meaningless."Methods: A large database of monoamine transporter response to amino acid precursor administration variations with clinical outcomes was accumulated. In the process, a new organic cation transporter (OCT model has been published, and OCT functional status determination along with amino acid precursor manipulation methods have been invented and refined.Results: Methodology was developed whereby manipulation of the OCT, in the competitive inhibition state, is carried out in a predictable manner. This, in turn, has disproved the long-held assertion that the monoamine competitive inhibition state is functionally meaningless.Conclusion: The most significant aspect of this paper is the documentation of newly recognized relationships between serotonin and dopamine. When transport of serotonin and dopamine are both in the competitive inhibition state, manipulation of the concentrations of one will lead to predictable changes in concentrations of the other. From a functional standpoint, processes regulated and controlled by changes to only serotonin can now be controlled by changes to dopamine, and vice versa, in a predictable manner.Keywords: catecholamine, monoamine, competitive inhibition state

  14. Serotonin Signal Transduction in Two Groups of Autistic Patients

    Science.gov (United States)

    2013-12-01

    behavioral, and now molecular genetic evidence implicate dysfunction of the serotonin system in autism spectrum disorders (ASD), and specifically in...validationin individuals with autism spectrum disorders . 2007 J Autism Dev Disord . 37:855-66. Lord, C.L., Cook, E.H., Leventhal, B.L., Amaral, D.G...2000 Minireview: Autism spectrum disorders . Neuron.,28:355-363. Shao Y, Cuccaro ML, Hauser ER, Raiford KL, Menold MM, Wolpert CM, Ravan SA

  15. Rationality and emotionality: serotonin transporter genotype influences reasoning bias

    OpenAIRE

    Stollstorff, Melanie; Bean, Stephanie E.; Anderson, Lindsay M.; Devaney, Joseph M.; Vaidya, Chandan J.

    2012-01-01

    Reasoning often occurs under emotionally charged, opinion-laden circumstances. The belief-bias effect indexes the extent to which reasoning is based upon beliefs rather than logical structure. We examined whether emotional content increases this effect, particularly for adults genetically predisposed to be more emotionally reactive. SS/SLG carriers of the serotonin transporter genotype (5-HTTLPR) were less accurate selectively for evaluating emotional relational reasoning problems with belief...

  16. Molecular cloning, expression and characterization of a bovine serotonin transporter

    DEFF Research Database (Denmark)

    Mortensen, O V; Kristensen, A S; Rudnick, G

    1999-01-01

    The serotonin transporter (SERT) is a member of a highly homologous family of sodium/chloride dependent neurotransmitter transporters responsible for reuptake of biogenic amines from the extracellular fluid. SERT constitutes the pharmacological target of several clinically important antidepressan......-methylenedioxymethamphetamine (MDMA) was mainly unchanged. RT-PCR amplification of RNA from different tissues demonstrated expression of SERT in placenta, brain stem, bone marrow, kidney, lung, heart, adrenal gland, liver, parathyroid gland, thyroid gland, small intestine and pancreas....

  17. Serotonin Transporter Genotype (5-HTTLPR) Predicts Utilitarian Moral Judgments

    OpenAIRE

    Marsh, Abigail A.; Crowe, Samantha L.; Yu, Henry H.; Gorodetsky, Elena K.; Goldman, David; Blair, R. J. R.

    2011-01-01

    Background The psychological and neurobiological processes underlying moral judgment have been the focus of extensive recent research. Here we show that serotonin transporter (5-HTTLPR) genotype predicts responses to moral dilemmas featuring foreseen harm to an innocent. Methodology/Principal Findings Participants in this study judged the acceptability of actions that would unintentionally or intentionally harm an innocent victim in order to save others' lives. An analysis of variance reveale...

  18. Serotonin as a Biomarker: Stress Resilience among Battlefield Airmen Trainees

    Science.gov (United States)

    2016-05-21

    anxiety, anger, impulsivity, lethargy, sleepiness, and mood disorders [2-5,11,12]. Studies have also shown that prolonged exercise increases...are likely to abandon training on their own. These data may improve the design of biomarker performance prediction models for stress, cognitive...findings demonstrate potential for using serotonin data to identify trainees who are likely to abandon training on their own. These data may improve

  19. Crystal Structure of an LSD-Bound Human Serotonin Receptor

    Energy Technology Data Exchange (ETDEWEB)

    Wacker, Daniel; Wang, Sheng; McCorvy, John D.; Betz, Robin M.; Venkatakrishnan, A.J.; Levit, Anat; Lansu, Katherine; Schools, Zachary L.; Che, Tao; Nichols, David E.; Shoichet, Brian K.; Dror, Ron O.; Roth, Bryan L. (UNCSM); (UNC); (Stanford); (Stanford-MED); (UCSF)

    2017-01-01

    The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD’s key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR—a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD’s slow binding kinetics may be due to a “lid” formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD’s binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD’s actions at human serotonin receptors.

  20. Crystal Structure of an LSD-Bound Human Serotonin Receptor.

    Science.gov (United States)

    Wacker, Daniel; Wang, Sheng; McCorvy, John D; Betz, Robin M; Venkatakrishnan, A J; Levit, Anat; Lansu, Katherine; Schools, Zachary L; Che, Tao; Nichols, David E; Shoichet, Brian K; Dror, Ron O; Roth, Bryan L

    2017-01-26

    The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT 2B . The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD's key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT 2B R and 5-HT 2A R-a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD's slow binding kinetics may be due to a "lid" formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD's binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD's actions at human serotonin receptors. PAPERCLIP. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Regional distribution of serotonin transporter protein in postmortem human brain

    Energy Technology Data Exchange (ETDEWEB)

    Kish, Stephen J. [Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada)]. E-mail: Stephen_Kish@CAMH.net; Furukawa, Yoshiaki [Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Chang Lijan [Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Tong Junchao [Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Ginovart, Nathalie [PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Wilson, Alan [PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Houle, Sylvain [PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Meyer, Jeffrey H. [PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada)

    2005-02-01

    Introduction: The primary approach in assessing the status of brain serotonin neurons in human conditions such as major depression and exposure to the illicit drug ecstasy has been the use of neuroimaging procedures involving radiotracers that bind to the serotonin transporter (SERT). However, there has been no consistency in the selection of a 'SERT-free' reference region for the estimation of free and nonspecific binding, as occipital cortex, cerebellum and white matter have all been employed. Objective and Methods: To identify areas of human brain that might have very low SERT levels, we measured, by a semiquantitative Western blotting procedure, SERT protein immunoreactivity throughout the postmortem brain of seven normal adult subjects. Results: Serotonin transporter could be quantitated in all examined brain areas. However, the SERT concentration in cerebellar cortex and white matter were only at trace values, being approximately 20% of average cerebral cortex and 5% of average striatum values. Conclusion: Although none of the examined brain areas are completely free of SERT, human cerebellar cortex has low SERT binding as compared to other examined brain regions, with the exception of white matter. Since the cerebellar cortical SERT binding is not zero, this region will not be a suitable reference region for SERT radioligands with very low free and nonspecific binding. For SERT radioligands with reasonably high free and nonspecific binding, the cerebellar cortex should be a useful reference region, provided other necessary radioligand assumptions are met.

  2. Regional distribution of serotonin transporter protein in postmortem human brain

    International Nuclear Information System (INIS)

    Kish, Stephen J.; Furukawa, Yoshiaki; Chang Lijan; Tong Junchao; Ginovart, Nathalie; Wilson, Alan; Houle, Sylvain; Meyer, Jeffrey H.

    2005-01-01

    Introduction: The primary approach in assessing the status of brain serotonin neurons in human conditions such as major depression and exposure to the illicit drug ecstasy has been the use of neuroimaging procedures involving radiotracers that bind to the serotonin transporter (SERT). However, there has been no consistency in the selection of a 'SERT-free' reference region for the estimation of free and nonspecific binding, as occipital cortex, cerebellum and white matter have all been employed. Objective and Methods: To identify areas of human brain that might have very low SERT levels, we measured, by a semiquantitative Western blotting procedure, SERT protein immunoreactivity throughout the postmortem brain of seven normal adult subjects. Results: Serotonin transporter could be quantitated in all examined brain areas. However, the SERT concentration in cerebellar cortex and white matter were only at trace values, being approximately 20% of average cerebral cortex and 5% of average striatum values. Conclusion: Although none of the examined brain areas are completely free of SERT, human cerebellar cortex has low SERT binding as compared to other examined brain regions, with the exception of white matter. Since the cerebellar cortical SERT binding is not zero, this region will not be a suitable reference region for SERT radioligands with very low free and nonspecific binding. For SERT radioligands with reasonably high free and nonspecific binding, the cerebellar cortex should be a useful reference region, provided other necessary radioligand assumptions are met

  3. Demonstration of clomipramine and venlafaxine occupation at serotonin reuptake sites in man in vivo.

    Science.gov (United States)

    Malizia, A L; Melichar, J M; Brown, D J; Gunn, R N; Reynolds, A; Jones, T; Nutt, D J

    1997-01-01

    We describe the use of 11CRTI-55 and the Multiple Objects Coincidences Counter (MOCC) to detect in-vivo binding to peripheral serotonin reuptake sites (left chest comprising platelet and lung serotonin reuptake sites) in man. Displacement and preloading experiments with clomipramine and venlafaxine in two healthy volunteers demonstrated that 11CRTI-55 binding is decreased in a dose-dependent fashion by both these drugs which bind to the serotonin transporter. In addition parallel data from the total head curve (representing 11CRTI-55 binding to central serotonin and dopamine (DA) reuptake sites) suggest that prior blockade of the serotonin transporter may be a useful strategy to maximize radioactive counts in the head when measuring the DA transporter. The MOCC is likely to be useful to determine sequential indices of relative serotonin reuptake blockade in patients on treatment.

  4. Serotonin-promoted elevation of ROS levels may lead to cardiac pathologies in diabetic rat

    Directory of Open Access Journals (Sweden)

    Ali Tahir

    2015-01-01

    Full Text Available Patients with diabetes mellitus (DM develop tendencies toward heart disease. Hyperglycemia induces the release of serotonin from enterochromaffin cells (EC. Serotonin was observed to elevate reactive oxygen species (ROS and downregulate antioxidant enzymes. As a result, elevated levels of serotonin could contribute to diabetic complications, including cardiac hypertrophy. In the present study, diabetes mellitus was induced in rats by alloxan administration; this was followed by the administration of serotonin to experimental animals. ROS, catalase (CAT, superoxide dismutase (SOD, B-type natriuretic peptide (BNP expression, and histopathological assessments were performed. Elevated ROS concentrations and decreased antioxidant enzyme activities were detected. Further, we observed an increase in cell surface area and elevated BNP expression which suggests that events associated with cardiac hypertrophy were increased in serotonin-administered diabetic rats. We conclude that serotonin secretion in diabetes could contribute to diabetic complications, including cardiac hypertrophy, through enhanced ROS production.

  5. Photomimetic effect of serotonin on yeast cells irradiated by far-UV radiation

    International Nuclear Information System (INIS)

    Fraikin, G.Y.; Strakhovskaya, M.G.; Rubin, L.B.

    1982-01-01

    The effect of serotonin on the survival of far-UV irradiated cells of the yeast Candida guilliermondii was studied. Serotonin was found to have a photomimetic property. Preincubation of cells with serotonin results in protection against far-UV inactivation, whereas the post-radiation treatment with serotonin causes a potentiation of far-UV lethality. Both effects are similar to those produced by near-UV (334 nm) radiation. The observations provide support to the previously proposed idea that photosynthesized serotonin is the underlying cause of the two effects of near-UV radiation, photoprotection and potentiation of far-UV lethality. Experiments with an excision-deficient strain of the yeast Saccharomyces cerevisiae suggest that the effect of serotonin is by its binding to DNA. (author)

  6. Visualisation of serotonin-1A (5-HT{sub 1A}) receptors in the central nervous system

    Energy Technology Data Exchange (ETDEWEB)

    Passchier, J.; Waarde, A. van [PET Center, University Hospital Groningen (Netherlands)

    2001-01-01

    The 5-HT{sub 1A} subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT{sub 1A} receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy. Here, we review the radioligands which are available for visualisation and quantification of this important neuroreceptor in the human brain, using positron emission tomography (PET) or single-photon emission tomography (SPET). More than 20 compounds have been labelled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogues of the agonist, 8-OH-DPAT, structural analogues of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl-{sup 11}C] WAY-100635 (WAY), [carbonyl-{sup 11}C]desmethyl-WAY-100635 (DWAY), p-[{sup 18}F]MPPF and [{sup 11}C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT{sub 1A} receptor distribution in the brain (even the raphe nuclei are visualised), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centres within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) production of a radioiodinated or technetium-labelled ligand for SPET. (orig.)

  7. Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation.

    Science.gov (United States)

    Rannversson, Hafsteinn; Wilson, Pamela; Kristensen, Kristina Birch; Sinning, Steffen; Kristensen, Anders Skov; Strømgaard, Kristian; Andersen, Jacob

    2015-06-05

    The serotonin transporter (SERT) terminates serotonergic neurotransmission by performing reuptake of released serotonin, and SERT is the primary target for antidepressants. SERT mediates the reuptake of serotonin through an alternating access mechanism, implying that a central substrate site is connected to both sides of the membrane by permeation pathways, of which only one is accessible at a time. The coordinated conformational changes in SERT associated with substrate translocation are not fully understood. Here, we have identified a Leu to Glu mutation at position 406 (L406E) in the extracellular loop 4 (EL4) of human SERT, which induced a remarkable gain-of-potency (up to >40-fold) for a range of SERT inhibitors. The effects were highly specific for L406E relative to six other mutations in the same position, including the closely related L406D mutation, showing that the effects induced by L406E are not simply charge-related effects. Leu(406) is located >10 Å from the central inhibitor binding site indicating that the mutation affects inhibitor binding in an indirect manner. We found that L406E decreased accessibility to a residue in the cytoplasmic pathway. The shift in equilibrium to favor a more outward-facing conformation of SERT can explain the reduced turnover rate and increased association rate of inhibitor binding we found for L406E. Together, our findings show that EL4 allosterically can modulate inhibitor binding within the central binding site, and substantiates that EL4 has an important role in controlling the conformational equilibrium of human SERT. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation*

    Science.gov (United States)

    Rannversson, Hafsteinn; Wilson, Pamela; Kristensen, Kristina Birch; Sinning, Steffen; Kristensen, Anders Skov; Strømgaard, Kristian; Andersen, Jacob

    2015-01-01

    The serotonin transporter (SERT) terminates serotonergic neurotransmission by performing reuptake of released serotonin, and SERT is the primary target for antidepressants. SERT mediates the reuptake of serotonin through an alternating access mechanism, implying that a central substrate site is connected to both sides of the membrane by permeation pathways, of which only one is accessible at a time. The coordinated conformational changes in SERT associated with substrate translocation are not fully understood. Here, we have identified a Leu to Glu mutation at position 406 (L406E) in the extracellular loop 4 (EL4) of human SERT, which induced a remarkable gain-of-potency (up to >40-fold) for a range of SERT inhibitors. The effects were highly specific for L406E relative to six other mutations in the same position, including the closely related L406D mutation, showing that the effects induced by L406E are not simply charge-related effects. Leu406 is located >10 Å from the central inhibitor binding site indicating that the mutation affects inhibitor binding in an indirect manner. We found that L406E decreased accessibility to a residue in the cytoplasmic pathway. The shift in equilibrium to favor a more outward-facing conformation of SERT can explain the reduced turnover rate and increased association rate of inhibitor binding we found for L406E. Together, our findings show that EL4 allosterically can modulate inhibitor binding within the central binding site, and substantiates that EL4 has an important role in controlling the conformational equilibrium of human SERT. PMID:25903124

  9. Conundrums in neurology: diagnosing serotonin syndrome - a meta-analysis of cases.

    Science.gov (United States)

    Werneke, Ursula; Jamshidi, Fariba; Taylor, David M; Ott, Michael

    2016-07-12

    Serotonin syndrome is a toxic state, caused by serotonin (5HT) excess in the central nervous system. Serotonin syndrome's main feature is neuro-muscular hyperexcitability, which in many cases is mild but in some cases can become life-threatening. The diagnosis of serotonin syndrome remains challenging since it can only be made on clinical grounds. Three diagnostic criteria systems, Sternbach, Radomski and Hunter classifications, are available. Here we test the validity of four assumptions that have become widely accepted: (1) The Hunter classification performs clinically better than the Sternbach and Radomski criteria; (2) in contrast to neuroleptic malignant syndrome, the onset of serotonin syndrome is usually rapid; (3) hyperthermia is a hallmark of severe serotonin syndrome; and (4) serotonin syndrome can readily be distinguished from neuroleptic malignant syndrome on clinical grounds and on the basis of medication history. Systematic review and meta-analysis of all cases of serotonin syndrome and toxicity published between 2004 and 2014, using PubMed and Web of Science. Two of the four assumptions (1 and 2) are based on only one published study each and have not been independently validated. There is little agreement between current criteria systems for the diagnosis of serotonin syndrome. Although frequently thought to be the gold standard for the diagnosis of the serotonin syndrome, the Hunter criteria did not perform better than the Sternbach and Radomski criteria. Not all cases seem to be of rapid onset and only relatively few cases may present with hyperthermia. The 0 differential diagnosis between serotonin syndrome and neuroleptic malignant syndrome is not always clear-cut. Our findings challenge four commonly made assumptions about serotonin syndrome. We propose our meta-analysis of cases (MAC) method as a new way to systematically pool and interpret anecdotal but important clinical information concerning uncommon or emergent phenomena that cannot be

  10. The serotonin system in autism spectrum disorder: from biomarker to animal models

    OpenAIRE

    Muller, Christopher L.; Anacker, Allison M.J.; Veenstra-VanderWeele, Jeremy

    2015-01-01

    Elevated whole blood serotonin, or hyperserotonemia, was the first biomarker identified in autism spectrum disorder (ASD) and is present in more than 25% of affected children. The serotonin system is a logical candidate for involvement in ASD due to its pleiotropic role across multiple brain systems both dynamically and across development. Tantalizing clues connect this peripheral biomarker with changes in brain and behavior in ASD, but the contribution of the serotonin system to ASD pathophy...

  11. Brief Report: Whole Blood Serotonin Levels and Gastrointestinal Symptoms in Autism Spectrum Disorder

    OpenAIRE

    Marler, Sarah; Ferguson, Bradley J.; Lee, Evon Batey; Peters, Brittany; Williams, Kent C.; McDonnell, Erin; Macklin, Eric A.; Levitt, Pat; Gillespie, Catherine Hagan; Anderson, George M.; Margolis, Kara Gross; Beversdorf, David Q.; Veenstra-VanderWeele, Jeremy

    2016-01-01

    Elevated whole blood serotonin levels are observed in more than 25 % of children with autism spectrum disorder (ASD). Co-occurring gastrointestinal (GI) symptoms are also common in ASD but have not previously been examined in relationship with hyperserotonemia, despite the synthesis of serotonin in the gut. In 82 children and adolescents with ASD, we observed a correlation between a quantitative measure of lower GI symptoms and whole blood serotonin levels. No significant association was seen...

  12. Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder

    DEFF Research Database (Denmark)

    Mc Mahon, Brenda; Andersen, Sofie B.; Madsen, Martin K.

    2016-01-01

    controls with low seasonality scores and 17 patients diagnosed with seasonal affective disorder were scanned in both summer and winter to investigate differences in cerebral serotonin transporter binding across groups and across seasons. The two groups had similar cerebral serotonin transporter binding...... between summer and winter (Psex-(P = 0.02) and genotype-(P = 0.04) dependent. In the patients with seasonal affective disorder, the seasonal change in serotonin transporter binding was positively associated with change in depressive symptom...

  13. Characterization and regulation of [3H]-serotonin uptake and release in rodent spinal

    International Nuclear Information System (INIS)

    Stauderman, K.A.

    1986-01-01

    The uptake and release of [ 3 H]-serotonin were investigated in rat spinal cord synaptosomes. In the uptake experiments, sodium-dependent and sodium-independent [ 3 H]-serotonin accumulation processes were found. Sodium-dependent [ 3 H]-serotonin accumulation was: linear with sodium concentrations up to 180 mM; decreased by disruption of membrane integrity or ionic gradients; associated with purified synaptosomal fractions; and reduced after description of descending serotonergic neurons in the spinal cord. Of the uptake inhibitors tested, the most potent was fluoxetine (IC 50 75 nM), followed by desipramine (IC 50 430 nM) and nomifensine (IC 50 950 nM). The sodium-independent [ 3 H]-serotonin accumulation process was insensitive to most treatments and probably represents nonspecific membrane binding. Thus, only sodium-dependent [ 3 H]-serotonin uptake represents the uptake process of serotonergic nerve terminals in rat spinal cord homogenates. In the release experiments, K + -induced release of previously accumulated [ 3 H]-serotonin was Ca 2+ -dependent, and originated from serotonergic synaptosomes. Exogenous serotonin and 5-methyoxy-N,N-dimethyltryptamine inhibited [ 3 H]-serotonin release in a concentration-dependent way. Of the antagonists tested, only methiothepin effectively blocked the effect of serotonin. These data support the existence of presynaptic serotonin autoreceptors on serotonergic nerve terminals in the rat spinal cord that act to inhibit a voltage and Ca 2+ -sensitive process linked to serotonin release. Alteration of spinai cord serotonergic function may therefore be possible by drugs acting on presynaptic serotonin autoreceptors in the spinal cord

  14. Serotonin receptors influencing cell proliferation in the jejunal crypt epithelium and in colonic adenocarcinomas.

    Science.gov (United States)

    Tutton, P J; Barkla, D H

    1986-01-01

    Serotonin has previously been shown to stimulate cell proliferation in the jejunal crypt epithelium and in colonic tumours. The original classification of serotonin receptors into D and M groups was not conductive to the understanding of these observations. The more recent classification of serotonin receptors into 5HT1 and 5HT2 groups is considered in this report. On the balance of evidence it appears that similar receptors mediate the response to serotonin in the two tissues under consideration and that these receptors resemble those of the 5HT1 group. Such receptors are usually positively linked to adenylate cyclase.

  15. [The effect of mineral water on serotonin and insulin production (an experimental study)].

    Science.gov (United States)

    Polushina, N D

    1998-01-01

    Radioimmunoassay (DRG kits) and orthotoluidine test were conducted to measure blood serotonin, insulin and glucose in 70 intact Wistar rat males before and after a course of drinking mineral water Essentuki 17 (MW). After the MW drinking course, a single dose of mineral water increases basal levels of serotonin and insulin, sensitivity of endocrine cells to MW. Serotonin and insulin rose maximally on minute 5 after the drink while in contrast to minute 15 and 30 before initiation of the MW drinking course. A direct correlation was found between blood concentrations of serotonin and insulin.

  16. Serotonin induces ecdysteroidogenesis and methyl farnesoate synthesis in the mud crab, Scylla serrata.

    Science.gov (United States)

    Girish, B P; Swetha, C H; Reddy, P Sreenivasula

    2017-09-02

    In the current study, we have examined the role of serotonin in regulating the levels of methyl farnesoate and ecdysteroids in the giant mud crab Scylla serrata and validated that serotonin indeed is a reproductive hormone. Administration of serotonin elevated circulatory levels of methyl farnesoate and ecdysteroids in crabs. Since methyl farnesoate and ecdysteroid act through retinoid X receptor (RXR) and ecdysteroid receptor (EcR) respectively and these receptors are involved in the regulation of reproduction in crustaceans, we have determined the mRNA levels of RXR and EcR in hepatopancreas and ovary after serotonin administration. The expression levels of both RXR and EcR increased significantly in the hepatopancreas and ovary of serotonin injected crabs when compared to the controls. In vitro organ culture studies revealed that incubation of Y-orgas and mandibular organ explants in the presence of serotonin resulted in a significant increase in the secretion of ecdysteroids by Y-organs, but without alterations in MF synthesis in mandibular organs. From the above studies it is evident that serotonin stimulates Y organs resulting in increased ecdysteroidogenesis. Though the circulatory levels methyl farnesoate elevated after serotonin administration, organ culture studies revealed serotonin mediated methyl farnesaote synthesis is indirect probably by inhibiting release of mandibular organ inhibiting hormone from eyestalks. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Radioenzymatic microassay for picogram quantities of serotonin or acetylserotonin in biological fluids and tissues

    International Nuclear Information System (INIS)

    Hussain, M.N.; Benedict, C.R.

    1987-01-01

    This paper describes several modifications of the original radioenzymatic assay for serotonin which increase the sensitivity of the assay 20-fold as well as enhance its reliability. Using this method serotonin concentrations can be directly measured in biological examples without precleaning the sample. When compared to currently available methods this assay is specific and sensitive to approximately 1 pg of serotonin and can be used to measure serotonin levels in individual brain nuclei or microliter quantities of biological fluids. This assay can be easily adapted for the direct measurement of N-acetylserotonin. A large number of samples can be assayed in a single working day

  18. Azithromycin effectiveness against intracellular infections of Francisella

    Directory of Open Access Journals (Sweden)

    Mann Barbara J

    2010-04-01

    Full Text Available Abstract Background Macrolide antibiotics are commonly administered for bacterial respiratory illnesses. Azithromycin (Az is especially noted for extremely high intracellular concentrations achieved within macrophages which is far greater than the serum concentration. Clinical strains of Type B Francisella (F. tularensis have been reported to be resistant to Az, however our laboratory Francisella strains were found to be sensitive. We hypothesized that different strains/species of Francisella (including Type A may have different susceptibilities to Az, a widely used and well-tolerated antibiotic. Results In vitro susceptibility testing of Az confirmed that F. tularensis subsp. holarctica Live Vaccine Strain (LVS (Type B was not sensitive while F. philomiragia, F. novicida, and Type A F. tularensis (NIH B38 and Schu S4 strain were susceptible. In J774A.1 mouse macrophage cells infected with F. philomiragia, F. novicida, and F. tularensis LVS, 5 μg/ml Az applied extracellularly eliminated intracellular Francisella infections. A concentration of 25 μg/ml Az was required for Francisella-infected A549 human lung epithelial cells, suggesting that macrophages are more effective at concentrating Az than epithelial cells. Mutants of RND efflux components (tolC and ftlC in F. novicida demonstrated less sensitivity to Az by MIC than the parental strain, but the tolC disc-inhibition assay demonstrated increased sensitivity, indicating a complex role for the outer-membrane transporter. Mutants of acrA and acrB mutants were less sensitive to Az than the parental strain, suggesting that AcrAB is not critical for the efflux of Az in F. novicida. In contrast, F. tularensis Schu S4 mutants ΔacrB and ΔacrA were more sensitive than the parental strain, indicating that the AcrAB may be important for Az efflux in F. tularensis Schu S4. F. novicida LPS O-antigen mutants (wbtN, wbtE, wbtQ and wbtA were found to be less sensitive in vitro to Az compared to the wild

  19. Cortisol responses to chronic stress in adult macaques: moderation by a polymorphism in the serotonin transporter gene.

    Science.gov (United States)

    Qin, Dongdong; Rizak, Joshua; Feng, Xiaoli; Yang, Shangchuan; Yang, Lichuan; Fan, Xiaona; Lü, Longbao; Chen, Lin; Hu, Xintian

    2015-02-01

    Accumulating evidence has shown that a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) moderates the association between stress and depressive symptoms. However, the exact etiologies underlying this moderation are not well understood. Here it is reported that among adult female rhesus macaques, an orthologous polymorphism (rh5-HTTLPR) exerted an influence on cortisol responses to chronic stress. It was found that females with two copies of the short allele were associated with increased cortisol responses to chronic stress in comparison to their counterparts who have one or two copies of the long allele. In the absence of stress, no differences related to genotype were observed in these females. This genetic moderation was found without a genetic influence on exposure to stressful situations. Rather it was found to be a genetic modulation of cortisol responses to chronic stress. These findings indicate that the rh5-HTTLPR polymorphism is closely related to hypothalamus-pituitary-adrenal (HPA) axis reactivity, which may increase susceptibility to depression in females with low serotonin transporter efficiency and a history of stress. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. A blunted anxiolytic like effect of curcumin against acute lead induced anxiety in rat: involvement of serotonin.

    Science.gov (United States)

    Benammi, Hind; El Hiba, Omar; Romane, Abderrahmane; Gamrani, Halima

    2014-06-01

    Anxiety is one of the most common mental disorders sharing extreme or pathological anxiety states as the primary disturbance in mood or emotional tone, with increased fear and exaggerated acute stress responses. Medicinal plants are very variable, but some of them are used as a spice such as curcumin (Curcuma longa). Curcumin shows a wide range of pharmacological potentialities, however, little is known about its anxiolytic properties. The aim of our study was to assess the anti-anxiety potential of curcumin extract against experimental lead induced-anxiety in rats. Experiments were carried out on male Wistar rats intoxicated acutely with an intraperitoneal injection of Pb (25mg/kg B.W.) and/or concomitantly with administration of curcumin (30 mg/kg B.W.) for 3 days. Using immunohistochemistry and anxiety assessment tests (dark light box and elevated plus maze), we evaluated, respectively, the expression of serotonin (5HT) in the dorsal raphe nucleus (DRN) and the anxiety state in our animals. Our results showed, for the first time, a noticeable anxiolytic effect of curcumin against lead induced anxiety in rats and this may possibly result from modulation of central neuronal monoaminergic neurotransmission, especially serotonin, which has shown a significant reduction of the immunoreactivity within the DRN. Copyright © 2014 Elsevier GmbH. All rights reserved.

  1. Activation of the Serotonin Pathway is Associated with Poor Outcome in COPD Exacerbation: Results of a Long-Term Cohort Study.

    Science.gov (United States)

    Meier, Marc A; Ottiger, Manuel; Vögeli, Alaadin; Steuer, Christian; Bernasconi, Luca; Thomann, Robert; Christ-Crain, Mirjam; Henzen, Christoph; Hoess, Claus; Zimmerli, Werner; Huber, Andreas; Mueller, Beat; Schuetz, Philipp

    2017-06-01

    predictive of 18-month mortality. Whether therapeutic modulation of the serotonin pathway has positive effects on outcome needs further investigation.

  2. MDMA-induced neurotoxicity of serotonin neurons involves autophagy and rilmenidine is protective against its pathobiology.

    Science.gov (United States)

    Mercer, Linda D; Higgins, Gavin C; Lau, Chew L; Lawrence, Andrew J; Beart, Philip M

    2017-05-01

    Toxicity of 3,4-methylenedioxymethamphetamine (MDMA) towards biogenic amine neurons is well documented and in primate brain predominantly affects serotonin (5-HT) neurons. MDMA induces damage of 5-HT axons and nerve fibres and intracytoplasmic inclusions. Whilst its pathobiology involves mitochondrially-mediated oxidative stress, we hypothesised MDMA possessed the capacity to activate autophagy, a proteostatic mechanism for degradation of cellular debris. We established a culture of ventral pons from embryonic murine brain enriched in 5-HT neurons to explore mechanisms of MDMA neurotoxicity and recruitment of autophagy, and evaluated possible neuroprotective actions of the clinically approved agent rilmenidine. MDMA (100 μM-1 mM) reduced cell viability, like rapamycin (RM) and hydrogen peroxide (H 2 O 2 ), in a concentration- and time-dependent manner. Immunocytochemistry revealed dieback of 5-HT arbour: MDMA-induced injury was slower than for RM and H 2 O 2 , neuritic blebbing occurred at 48 and 72 h and Hoechst labelling revealed nuclear fragmentation with 100 μM MDMA. MDMA effected concentration-dependent inhibition of [ 3 H]5-HT uptake with 500 μM MDMA totally blocking transport. Western immunoblotting for microtubule associated protein light chain 3 (LC3) revealed autophagosome formation after treatment with MDMA. Confocal analyses and immunocytochemistry for 5-HT, Hoechst and LC3 confirmed MDMA induced autophagy with abundant LC3-positive puncta within 5-HT neurons. Rilmenidine (1 μM) protected against MDMA-induced injury and image analysis showed full preservation of 5-HT arbours. MDMA had no effect on GABA neurons, indicating specificity of action at 5-HT neurons. MDMA-induced neurotoxicity involves autophagy induction in 5-HT neurons, and rilmenidine via beneficial actions against toxic intracellular events represents a potential treatment for its pathobiology in sustained usage. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Intracellular bacteria: the origin of dinoflagellate toxicity.

    Science.gov (United States)

    Silva, E S

    1990-01-01

    Dinoflagellate blooms of the same species have been registered either as toxic or nontoxic and, in the latter case, toxicity may be of different types. A hypothesis has been formulated according to which the bacteria having in some way taken part in the toxin formation are either inside the dinoflagellate cell or in the nutritive liquid. The presence of intracellular bacteria in those microorganisms has been studied mainly in material from cultures, a few from the sea, and several strains were isolated from different species. Experiments with crossed inoculations have shown that the bacterial strain from Gonyaulax tamarensis caused the cells of some other species to become toxic. From nontoxic clonal cultures of Prorocentrum balticum, Glenodinium foliaceum, and Gyrodinium instriatum, after inoculation of that bacterial strain, cultures were obtained whose cell extracts showed the same kind of toxicity as G. tamarensis. No toxic action could be found in the extracts of the bacterial cells form the assayed strains. The interference of intracellular bacteria in the metabolism of dinoflagellates must be the main cause of their toxicity.

  4. Fluorescent nanoparticles for intracellular sensing: a review.

    Science.gov (United States)

    Ruedas-Rama, Maria J; Walters, Jamie D; Orte, Angel; Hall, Elizabeth A H

    2012-11-02

    Fluorescent nanoparticles (NPs), including semiconductor NPs (Quantum Dots), metal NPs, silica NPs, polymer NPs, etc., have been a major focus of research and development during the past decade. The fluorescent nanoparticles show unique chemical and optical properties, such as brighter fluorescence, higher photostability and higher biocompatibility, compared to classical fluorescent organic dyes. Moreover, the nanoparticles can also act as multivalent scaffolds for the realization of supramolecular assemblies, since their high surface to volume ratio allow distinct spatial domains to be functionalized, which can provide a versatile synthetic platform for the implementation of different sensing schemes. Their excellent properties make them one of the most useful tools that chemistry has supplied to biomedical research, enabling the intracellular monitoring of many different species for medical and biological purposes. In this review, we focus on the developments and analytical applications of fluorescent nanoparticles in chemical and biological sensing within the intracellular environment. The review also points out the great potential of fluorescent NPs for fluorescence lifetime imaging microscopy (FLIM). Finally, we also give an overview of the current methods for delivering of fluorescent NPs into cells, where critically examine the benefits and liabilities of each strategy. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Mechanisms of cellular invasion by intracellular parasites.

    Science.gov (United States)

    Walker, Dawn M; Oghumu, Steve; Gupta, Gaurav; McGwire, Bradford S; Drew, Mark E; Satoskar, Abhay R

    2014-04-01

    Numerous disease-causing parasites must invade host cells in order to prosper. Collectively, such pathogens are responsible for a staggering amount of human sickness and death throughout the world. Leishmaniasis, Chagas disease, toxoplasmosis, and malaria are neglected diseases and therefore are linked to socio-economical and geographical factors, affecting well-over half the world's population. Such obligate intracellular parasites have co-evolved with humans to establish a complexity of specific molecular parasite-host cell interactions, forming the basis of the parasite's cellular tropism. They make use of such interactions to invade host cells as a means to migrate through various tissues, to evade the host immune system, and to undergo intracellular replication. These cellular migration and invasion events are absolutely essential for the completion of the lifecycles of these parasites and lead to their for disease pathogenesis. This review is an overview of the molecular mechanisms of protozoan parasite invasion of host cells and discussion of therapeutic strategies, which could be developed by targeting these invasion pathways. Specifically, we focus on four species of protozoan parasites Leishmania, Trypanosoma cruzi, Plasmodium, and Toxoplasma, which are responsible for significant morbidity and mortality.

  6. 5-HT1A receptors modulate small-conductance Ca2+-activated K+ channels

    DEFF Research Database (Denmark)

    Grunnet, Morten; Jespersen, Thomas; Perrier, Jean-François

    2004-01-01

    Small-conductance calcium-activated potassium channels (SK) are responsible for the medium afterhyperpolarisation (mAHP) following action potentials in neurons. Here we tested the ability of serotonin (5-HT) to modulate the activity of SK channels by coexpressing 5-HT1A receptors with different...

  7. Mutational Mapping and Modeling of the Binding Site for (S)-Citalopram in the Human Serotonin Transporter

    DEFF Research Database (Denmark)

    Andersen, Jacob; Olsen, Lars; Hansen, Kasper B.

    2010-01-01

    The serotonin transporter (SERT) regulates extracellular levels of the neurotransmitter serotonin (5-hydroxytryptamine) in the brain by facilitating uptake of released 5-hydroxytryptamine into neuronal cells. SERT is the target for widely used antidepressant drugs, including imipramine, fluoxetine...

  8. Adaptations in pre- and postsynaptic 5-HT(1A) receptor function and cocaine supersensitivity in serotonin transporter knockout rats

    NARCIS (Netherlands)

    Homberg, Judith R; De Boer, Sietse F; Raasø, Halfdan S; Olivier, Jocelien D A; Verheul, Mark; Ronken, Eric; Cools, Alexander R; Ellenbroek, Bart A; Schoffelmeer, Anton N M; Vanderschuren, Louk J M J; De Vries, Taco J; Cuppen, Edwin

    2008-01-01

    RATIONALE: While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission, the role of serotonin is not fully understood. OBJECTIVES: To study the rewarding and motivational properties of cocaine in the serotonin transporter knockout

  9. Cognitive function is related to fronto-striatal serotonin transporter levels--a brain PET study in young healthy subjects

    DEFF Research Database (Denmark)

    Madsen, Karine; Erritzøe, David Frederik; Mortensen, Erik Lykke

    2011-01-01

    Pharmacological manipulation of serotonergic neurotransmission in healthy volunteers impacts on cognitive test performance. Specifically, markers of serotonin function are associated with attention and executive functioning, long-term memory, and general cognitive ability. The serotonin transporter...

  10. VMN hypothalamic dopamine and serotonin in anorectic septic rats.

    Science.gov (United States)

    Torelli, G F; Meguid, M M; Miyata, G; Fetissov, S O; Carter, J L; Kim, H J; Muscaritoli, M; Rossi Fanelli, F

    2000-03-01

    During sepsis, catabolism of proteins and associated changes in plasma amino acids occur. Tryptophan and tyrosine, and their derivatives serotonin (5-HT) and dopamine (DA), influence hypothalamic feeding-related areas and are associated with the onset of anorexia. We hypothesized that anorexia of sepsis is associated with changes in serotonin and dopamine in the ventromedial nucleus (VMN) of the hypothalamus. The aim of this study was to test our hypothesis by measuring intra-VMN changes of these two neurotransmitters at the onset of anorexia during sepsis. Fischer 344 male rats had an intracerebral guide cannula stereotaxically implanted into the VMN. Ten days later, in awake, overnight-food-deprived rats, a microdialysis probe was inserted through the in situ VMN cannula. Two hours thereafter, serial baseline serotonin and dopamine concentrations were measured. Then cecal ligation and puncture to induce sepsis or a control laparotomy was performed under isoflurane anesthesia. VMN microdialysis samples were serially collected every 30 min for 8 h after the surgical procedure to determine 5-HT and DA changes in response to sepsis. During the hypermetabolic response to sepsis, a strong association occurred between anorexia and a significant reduction of VMN dopamine concentration (P anorexia of sepsis. Six hours after operation, a single meal was offered for 20 min to assess the response of neurotransmitters to food ingestion. Food intake was minimal in anorectic septic rats (mean size of the after food-deprived meal in the Septic group was 0.03+/-0.01 g, that of the Control group was 1.27+/-0.14 g; P = 0.0001), while Control rats demonstrated anticipated changes in neurotransmitters in response to eating. We conclude that the onset of anorexia in septic rats is associated with a reduction in VMN dopamine.

  11. Selective serotonin reuptake inhibitor suppression of HIV infectivity and replication.

    Science.gov (United States)

    Benton, Tami; Lynch, Kevin; Dubé, Benoit; Gettes, David R; Tustin, Nancy B; Ping Lai, Jian; Metzger, David S; Blume, Joshua; Douglas, Steven D; Evans, Dwight L

    2010-11-01

    To test the hypothesis that the selective serotonin reuptake inhibitor (SSRI) citalopram would down-regulate human immunodeficiency virus (HIV) infectivity and that the greatest effects would be seen in people with depression. Depression is a risk factor for morbidity and mortality in HIV/acquired immune deficiency syndrome. Serotonin (5-HT) neurotransmission has been implicated in the pathobiology of depression, and pharmacologic therapies for depression target this system. The 5-HT transporter and 5-HT receptors are widely distributed throughout the central nervous and immune systems. Depression has been associated with suppression of natural killer cells and CD8(+) lymphocytes, key regulators of HIV infection. Ex vivo models for acute and chronic HIV infection were used to study the effects of citalopram on HIV viral infection and replication in 48 depressed and nondepressed women. For both the acute and chronic infection models, HIV reverse transcriptase activity was measured in the citalopram treatment condition and the control condition. The SSRI significantly down-regulated the reverse transcriptase response in both the acute and chronic infection models. Specifically, citalopram significantly decreased the acute HIV infectivity of macrophages. Citalopram also significantly decreased HIV viral replication in the latently infected T-cell line and in the latently infected macrophage cell line. There was no difference in down-regulation by depression status. These studies suggest that an SSRI enhances natural killer/CD8 noncytolytic HIV suppression in HIV/acquired immune deficiency syndrome and decreases HIV viral infectivity of macrophages, ex vivo, suggesting the need for in vivo studies to determine a potential role for agents targeting serotonin in the host defense against HIV.

  12. Serotonin transporter activity of imidazolidine-2,4-dione and imidazo[2,1-f]purine-2,4-dione derivatives in aspect of their acid-base properties.

    Science.gov (United States)

    Zagórska, Agnieszka; Czopek, Anna; Pawłowski, Maciej; Dybała, Małgorzata; Siwek, Agata; Nowak, Gabriel

    2012-11-01

    Affinities of arylpiperazinylalkyl derivatives of imidazo[2,1-f]purine-2,4-dione and imidazolidine-2,4-dione for serotonin transporter and their acid-base properties were evaluated. The dissociation constant (pK(a)) of compounds 1-22 were determinated by potentiometric titration and calculated using pKalc 3.1 module of the Pallas system. The data from experimental methods and computational calculations were compared and suitable conclusions were reached.

  13. Iron in intracellular infection: to provide or to deprive?

    Directory of Open Access Journals (Sweden)

    Sandro eSilva-Gomes

    2013-12-01

    Full Text Available Due to their chemical versatility, transition metals were incorporated as cofactors for several basic metabolic pathways in living organisms. This same characteristic makes them potentially harmful, since they can be engaged in deleterious reactions like Fenton chemistry. As such, organisms have evolved highly specialized mechanisms to supply their own metal needs while keeping their toxic potential in check.This dual character comes into play in host-pathogen interactions, given that the host can either deprive the pathogen of these key nutrients or exploit them to induce toxicity towards the invading agent. Iron stands as the prototypic example of how a metal can be used to limit the growth of pathogens by nutrient deprivation, a mechanism widely studied in Mycobacterium infections. However, the host can also take advantage of iron-induced toxicity to control pathogen proliferation, as observed in infections caused by Leishmania. Whether we may harness either of the two pathways for therapeutical purposes is still ill-defined.In this review, we discuss how modulation of the host iron availability impacts the course of infections, focusing on those caused by two relevant intracellular pathogens, Mycobacterium and Leishmania.

  14. The treatment of kleptomania with serotonin reuptake inhibitors.

    Science.gov (United States)

    Lepkifker, E; Dannon, P N; Ziv, R; Iancu, I; Horesh, N; Kotler, M

    1999-01-01

    Kleptomania is characterized by an irresistible impulse to steal objects not needed for personal use or for their monetary value. Several recent case reports have shown that Serotonin Specific Reuptake Inhibitors (SSRIs) could be effective in the treatment of kleptomania just as it is in other obsessive-compulsive spectrum disorders. We report five cases of kleptomania patients who were successfully treated with fluoxetine or paroxetine in combination with a psychotherapeutic intervention. In one case, the discontinuation of the medication repeatedly led to the resurgence of the kleptomanic behavior. Our case series illustrates the effectiveness of SSRIs in kleptomania. It thus supports the assumption that this syndrome involves a dysfunctional serotoninergic mechanism.

  15. The Serotonin Transporter Gene Polymorphisms and Risk of Ischemic Stroke

    DEFF Research Database (Denmark)

    Mortensen, Janne Kærgård; Kraglund, Kristian Lundsgaard; Johnsen, Søren Paaske

    2018-01-01

    may influence platelet activity, as they result in different levels of transporters and thereby different levels of serotonin in platelets. SERT gene polymorphisms have thus been associated with the risk of myocardial infarction. A similar association may exist between SERT gene polymorphisms...... and stroke. However, to our knowledge, this potential association has not previously been studied. We therefore aimed to investigate the association between polymorphisms in the SERT gene and the risk of ischemic stroke/transitory ischemic attack (TIA). MATERIALS AND METHODS: We conducted a case...

  16. Possible serotonin syndrome with carbidopa-levodopa and linezolid.

    Science.gov (United States)

    Pettit, N N; Alonso, V; Wojcik, E; Anyanwu, E C; Ebara, L; Benoit, J-L

    2016-02-01

    Serotonin syndrome (SS) can occur when linezolid is combined with other serotonergic agents. We report a case of possible SS in an elderly patient receiving linezolid in combination with carbidopa-levodopa (CL). Although certain classes of agents are commonly reported as causing SS among patients receiving linezolid, there are no specific case reports detailing this reaction with CL. Linezolid combined with CL should generally be avoided; however, if linezolid must be used, discontinuation of other agents with serotonergic activity is recommended with careful monitoring for signs and symptoms of SS. © 2016 John Wiley & Sons Ltd.

  17. Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.

    Science.gov (United States)

    Dreyfus, Nicolas; Myers, Jason K; Badescu, Valentina O; de Frutos, Oscar; de la Puente, Maria Luz; Ding, Chunjin; Filla, Sandra A; Fynboe, Karsten; Gernert, Douglas L; Heinz, Beverly A; Hemrick-Luecke, Susan K; Johnson, Kirk W; Johnson, Michael P; López, Pilar; Love, Patrick L; Martin, Laura J; Masquelin, Thierry; McCoy, Michael J; Mendiola, Javier; Morrow, Denise; Muhlhauser, Mark; Pascual, Gustavo; Perun, Thomas J; Pfeifer, Lance A; Phebus, Lee A; Richards, Simon J; Rincón, Juan Antonio; Seest, Eric P; Shah, Jikesh; Shaojuan, Jia; Simmons, Rosa Maria A; Stephenson, Gregory A; Tromiczak, Eric G; Thompson, Linda K; Walter, Magnus W; Weber, Wayne W; Zarrinmayeh, Hamideh; Thomas, Craig E; Joshi, Elizabeth; Iyengar, Smriti; Johansson, Anette M

    2013-06-13

    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.

  18. The antimalarial drug quinine interferes with serotonin biosynthesis and action

    DEFF Research Database (Denmark)

    Islahudin, Farida; Tindall, Sarah M.; Mellor, Ian R.

    2014-01-01

    The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmit......The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor...... tryptophan. The study shows that quinine disrupts both serotonin biosynthesis and function, giving important new insight to the action of quinine on mammalian cells....

  19. Serotonin transporter evolution and impact of polymorphic transcriptional regulation

    DEFF Research Database (Denmark)

    Søeby, Karen; Larsen, Svend Ask; Olsen, Line

    2005-01-01

    The serotonin transporter (SERT) is the primary drug target in the current antidepressant therapy. A functional polymorphism in the 2nd intron of the 5HTT gene encoding the SERT has been identified and associated with susceptibility to affective disorders and treatment response to antidepressants....... This study addresses the possible impact of the variable number of tandem repeats (VNTR) to behavior and disease by examining the evolutionary origin and mechanisms of differential transcriptional regulation of SERT. We trace the evolutionary origin of the VNTR and show that it is present and varies...

  20. Serotonin 6 receptor controls alzheimer?s disease and depression

    OpenAIRE

    Yun, Hyung-Mun; Park, Kyung-Ran; Kim, Eun-Cheol; Kim, Sanghyeon; Hong, Jin Tae

    2015-01-01

    Alzheimer?s disease (AD) and depression in late life are one of the most severe health problems in the world disorders. Serotonin 6 receptor (5-HT6R) has caused much interest for potential roles in AD and depression. However, a causative role of perturbed 5-HT6R function between two diseases was poorly defined. In the present study, we found that a 5-HT6R antagonist, SB271036 rescued memory impairment by attenuating the generation of A? via the inhibition of ?-secretase activity and the inact...