Science.gov

Sample records for neurotransmitter transporters focus

  1. [Axolemmal transporters for neurotransmitter uptake].

    PubMed

    García-López, M

    Neurotransmission is a fundamental process in interneuronal communication. It starts with the release of the neurotransmitter following a nerve impulse and ends either by uptake by specific specific transporters or by metabolization to an inactive compound. In this review we will consider the molecular, ion dependence and electrogenic properties of the axolemal transporters for neurotransmitters and also the pathological consequences of their impairment as well as the drugs that can interact with them. Most axolemmal transporters have been cloned and grouped into two large families according to their molecular characteristics and electrogenic properties: 1. Those dependent on Na+/Cl- include transporters of GABA, noradrenaline, dopamine, serotonin, choline, proline, betaine, glycine and taurine, and 2. Those dependent on Na+/K+, which include the transporters of glutamate, alanine, serine and cysteine. The clonation of transporters has permitted (and will continue to permit) the correlation of molecular alterations of transporters with different neuro-degenerative disorders (e.g. multiple sclerosis, Parkinson's disease, Alzheimer's disease), with brain lesions (e.g. cerebral ischemia, status epilepticus) and with psychiatric alterations (e.g. schizophrenia, depression). In this respect, chemical synthesis of new selective drugs which interact with the different systems for uptake of neurotransmitters will offer new approaches to the treatment of many disorders of the central nervous system which still have no satisfactory drug treatment.

  2. Cytoplasmic permeation pathway of neurotransmitter transporters.

    PubMed

    Rudnick, Gary

    2011-09-06

    Ion-coupled solute transporters are responsible for transporting nutrients, ions, and signaling molecules across a variety of biological membranes. Recent high-resolution crystal structures of several transporters from protein families that were previously thought to be unrelated show common structural features indicating a large structural family representing transporters from all kingdoms of life. This review describes studies that led to an understanding of the conformational changes required for solute transport in this family. The first structure in this family showed the bacterial amino acid transporter LeuT, which is homologous to neurotransmitter transporters, in an extracellularly oriented conformation with a molecule of leucine occluded at the substrate site. Studies with the mammalian serotonin transporter identified positions, buried in the LeuT structure, that defined a potential pathway leading from the cytoplasm to the substrate binding site. Modeling studies utilized an inverted structural repeat within the LeuT crystal structure to predict the conformation of LeuT in which the cytoplasmic permeation pathway, consisting of positions identified in SERT, was open for diffusion of the substrate to the cytoplasm. From the difference between the model and the crystal structures, a simple "rocking bundle" mechanism was proposed, in which a four-helix bundle changed its orientation with respect to the rest of the protein to close the extracellular pathway and open the cytoplasmic one. Subsequent crystal structures from structurally related proteins provide evidence supporting this model for transport.

  3. Neurotransmitters

    NASA Image and Video Library

    Our nerve cells (neurons) communicate with each other using little chemical messengers called neurotransmitters. These neurotransmitters are transferred from one neuron to the next within a space c...

  4. Mechanism for alternating access in neurotransmitter transporters.

    PubMed

    Forrest, Lucy R; Zhang, Yuan-Wei; Jacobs, Miriam T; Gesmonde, Joan; Xie, Li; Honig, Barry H; Rudnick, Gary

    2008-07-29

    Crystal structures of LeuT, a bacterial homologue of mammalian neurotransmitter transporters, show a molecule of bound substrate that is essentially exposed to the extracellular space but occluded from the cytoplasm. Thus, there must exist an alternate conformation for LeuT in which the substrate is accessible to the cytoplasm and a corresponding mechanism that switches accessibility from one side of the membrane to the other. Here, we identify the cytoplasmic accessibility pathway of the alternate conformation in a mammalian serotonin transporter (SERT) (a member of the same transporter family as LeuT). We also propose a model for the cytoplasmic-facing state that exploits the internal pseudosymmetry observed in the crystal structure. LeuT contains two structurally similar repeats (TMs1-5 and TMs 6-10) that are inverted with respect to the plane of the membrane. The conformational differences between them result in the formation of the extracellular pathway. Our model for the cytoplasm-facing state exchanges the conformations of the two repeats and thus exposes the substrate and ion-binding sites to the cytoplasm. The conformational change that connects the two states primarily involves the tilting of a 4-helix bundle composed of transmembrane helices 1, 2, 6, and 7. Switching the tilt angle of this bundle is essentially equivalent to switching the conformation of the two repeats. Extensive mutagenesis of SERT and accessibility measurements, using cysteine reagents, are accommodated by our model. These observations may be of relevance to other transporter families, many of which contain internal inverted repeats.

  5. Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy?

    PubMed Central

    Van Liefferinge, Joeri; Massie, Ann; Portelli, Jeanelle; Di Giovanni, Giuseppe; Smolders, Ilse

    2013-01-01

    The vesicular neurotransmitter transporters (VNTs) are small proteins responsible for packing synaptic vesicles with neurotransmitters thereby determining the amount of neurotransmitter released per vesicle through fusion in both neurons and glial cells. Each transporter subtype was classically seen as a specific neuronal marker of the respective nerve cells containing that particular neurotransmitter or structurally related neurotransmitters. More recently, however, it has become apparent that common neurotransmitters can also act as co-transmitters, adding complexity to neurotransmitter release and suggesting intriguing roles for VNTs therein. We will first describe the current knowledge on vesicular glutamate transporters (VGLUT1/2/3), the vesicular excitatory amino acid transporter (VEAT), the vesicular nucleotide transporter (VNUT), vesicular monoamine transporters (VMAT1/2), the vesicular acetylcholine transporter (VAChT) and the vesicular γ-aminobutyric acid (GABA) transporter (VGAT) in the brain. We will focus on evidence regarding transgenic mice with disruptions in VNTs in different models of seizures and epilepsy. We will also describe the known alterations and reorganizations in the expression levels of these VNTs in rodent models for temporal lobe epilepsy (TLE) and in human tissue resected for epilepsy surgery. Finally, we will discuss perspectives on opportunities and challenges for VNTs as targets for possible future epilepsy therapies. PMID:24009559

  6. Expression of neurotransmitter transporters for structural and biochemical studies.

    PubMed

    Elbaz, Yael; Danieli, Tsafi; Kanner, Baruch I; Schuldiner, Shimon

    2010-10-01

    Neurotransmitter transporters play essential roles in the process of neurotransmission. Vesicular neurotransmitter transporters mediate storage inside secretory vesicles in a process that involves the exchange of lumenal H(+) for cytoplasmic transmitter. Retrieval of the neurotransmitter from the synaptic cleft catalyzed by sodium-coupled transporters is critical for the termination of the synaptic actions of the released neurotransmitter. Our current understanding of the mechanism of these transporters is based on functional and biochemical characterization but is lacking high-resolution structural information. Very few structures of membrane transport systems from mammalian origin have been solved to atomic resolution, mainly because of the difficulty in obtaining large amounts of purified protein. Development of high yield heterologous expression systems suitable for mammalian neurotransmitter transporters is essential to enable the production of purified protein for structural studies. Such a system makes possible also the production of mutants that can be used in biochemical and biophysical studies. We describe here a screen for the expression of the vesicular monoamine transporter 2 (VMAT2) in cell-free and baculovirus expression systems and discuss the expression of VMAT2 in other systems as well (bacterial, yeast and mammalian cell lines). After screening and optimization, we achieved high yield (2-2.5 mg/l) expression of functional VMAT2 in insect cells. The system was also used for the expression of three additional plasma membrane neurotransmitter transporters. All were functional and expressed to high levels. Our results demonstrate the advantages of the baculovirus expression system for the expression of mammalian neurotransmitter transporters in a functional state.

  7. Bound to be different: neurotransmitter transporters meet their bacterial cousins.

    PubMed

    Henry, L Keith; Meiler, Jens; Blakely, Randy D

    2007-12-01

    The neurotransmitter transporters belonging to the solute carrier 6 (SLC6) family, including the gamma-aminobutyric acid (GAT), norepinephrine (NET), serotonin (SERT) and dopamine (DAT) transporters are extremely important drug targets of great clinical relevance. These Na+, Cl(-)-dependent transporters primarily function following neurotransmission to reset neuronal signaling by transporting neurotransmitter out of the synapse and back into the pre-synaptic neuron. Recent studies have tracked down an elusive binding site for Cl(-) that facilitates neurotransmitter transport using structural differences evident with bacterial family members (e.g., the Aquifex aeolicus leucine transporter LeuT Aa) that lack Cl(-) dependence. Additionally, the crystal structures of antidepressant-bound LeuT Aa reveals a surprising mode of drug interaction that may have relevance for medication development. The study of sequence and structural divergence between LeuT Aa and human SLC6 family transporters can thus inform us as to how and why neurotransmitter transporters evolved a reliance on extracellular Cl(-) to propel the transport cycle; what residue changes and helical rearrangements give rise to recognition of different substrates; and how drugs such as antidepressants, cocaine, and amphetamines halt (or reverse) the transport process.

  8. The transport of neurotransmitters into synaptic vesicles.

    PubMed

    Peter, D; Liu, Y; Brecha, N; Edwards, R H

    1995-01-01

    Using selection in the neurotoxin MPP+, we have isolated a cDNA encoding vesicular amine transport. The transporter protects against MPP+ by sequestering the toxin in vesicles, away from its primary site of action in mitochondria. Unexpectedly, two distinct but highly related genes encode vesicular amine transport in the adrenal gland and the central nervous system. The sequence of both predicts twelve transmembrane domains and weak homology to a class of bacterial antibiotic resistance proteins. The two human genes occur on different chromosomes. In addition, the two transporters show a number of differences in function, including substrate specificity and the interaction with one inhibitor and the amphetamines.

  9. A neurotransmitter transporter encoded by the Drosophila inebriated gene

    PubMed Central

    Soehnge, Holly; Huang, Xi; Becker, Marie; Whitley, Penn; Conover, Diana; Stern, Michael

    1996-01-01

    Behavioral and electrophysiological studies on mutants defective in the Drosophila inebriated (ine) gene demonstrated increased excitability of the motor neuron. In this paper, we describe the cloning and sequence analysis of ine. Mutations in ine were localized on cloned DNA by restriction mapping and restriction fragment length polymorphism (RFLP) mapping of ine mutants. DNA from the ine region was then used to isolate an ine cDNA. In situ hybridization of ine transcripts to developing embryos revealed expression of this gene in several cell types, including the posterior hindgut, Malpighian tubules, anal plate, garland cells, and a subset of cells in the central nervous system. The ine cDNA contains an open reading frame of 658 amino acids with a high degree of sequence similarity to members of the Na+/Cl−-dependent neurotransmitter transporter family. Members of this family catalyze the rapid reuptake of neurotransmitters released into the synapse and thereby play key roles in controlling neuronal function. We conclude that ine mutations cause increased excitability of the Drosophila motor neuron by causing the defective reuptake of the substrate neurotransmitter of the ine transporter and thus overstimulation of the motor neuron by this neurotransmitter. From this observation comes a unique opportunity to perform a genetic dissection of the regulation of excitability of the Drosophila motor neuron. PMID:8917579

  10. How LeuT shapes our understanding of the mechanisms of sodium-coupled neurotransmitter transporters.

    PubMed

    Penmatsa, Aravind; Gouaux, Eric

    2014-03-01

    Neurotransmitter transporters are ion-coupled symporters that drive the uptake of neurotransmitters from neural synapses. In the past decade, the structure of a bacterial amino acid transporter, leucine transporter (LeuT), has given valuable insights into the understanding of architecture and mechanism of mammalian neurotransmitter transporters. Different conformations of LeuT, including a substrate-free state, inward-open state, and competitive and non-competitive inhibitor-bound states, have revealed a mechanistic framework for the transport and transport inhibition of neurotransmitters. The current review integrates our understanding of the mechanistic and pharmacological properties of eukaryotic neurotransmitter transporters obtained through structural snapshots of LeuT.

  11. Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

    PubMed Central

    Bermingham, Daniel P.

    2016-01-01

    Modulation of neurotransmission by the monoamines dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is critical for normal nervous system function. Precise temporal and spatial control of this signaling in mediated in large part by the actions of monoamine transporters (DAT, NET, and SERT, respectively). These transporters act to recapture their respective neurotransmitters after release, and disruption of clearance and reuptake has significant effects on physiology and behavior and has been linked to a number of neuropsychiatric disorders. To ensure adequate and dynamic control of these transporters, multiple modes of control have evolved to regulate their activity and trafficking. Central to many of these modes of control are the actions of protein kinases, whose actions can be direct or indirectly mediated by kinase-modulated protein interactions. Here, we summarize the current state of our understanding of how protein kinases regulate monoamine transporters through changes in activity, trafficking, phosphorylation state, and interacting partners. We highlight genetic, biochemical, and pharmacological evidence for kinase-linked control of DAT, NET, and SERT and, where applicable, provide evidence for endogenous activators of these pathways. We hope our discussion can lead to a more nuanced and integrated understanding of how neurotransmitter transporters are controlled and may contribute to disorders that feature perturbed monoamine signaling, with an ultimate goal of developing better therapeutic strategies. PMID:27591044

  12. Antidepressant binding site in a bacterial homologue of neurotransmitter transporters.

    PubMed

    Singh, Satinder K; Yamashita, Atsuko; Gouaux, Eric

    2007-08-23

    Sodium-coupled transporters are ubiquitous pumps that harness pre-existing sodium gradients to catalyse the thermodynamically unfavourable uptake of essential nutrients, neurotransmitters and inorganic ions across the lipid bilayer. Dysfunction of these integral membrane proteins has been implicated in glucose/galactose malabsorption, congenital hypothyroidism, Bartter's syndrome, epilepsy, depression, autism and obsessive-compulsive disorder. Sodium-coupled transporters are blocked by a number of therapeutically important compounds, including diuretics, anticonvulsants and antidepressants, many of which have also become indispensable tools in biochemical experiments designed to probe antagonist binding sites and to elucidate transport mechanisms. Steady-state kinetic data have revealed that both competitive and noncompetitive modes of inhibition exist. Antagonist dissociation experiments on the serotonin transporter (SERT) have also unveiled the existence of a low-affinity allosteric site that slows the dissociation of inhibitors from a separate high-affinity site. Despite these strides, atomic-level insights into inhibitor action have remained elusive. Here we screen a panel of molecules for their ability to inhibit LeuT, a prokaryotic homologue of mammalian neurotransmitter sodium symporters, and show that the tricyclic antidepressant (TCA) clomipramine noncompetitively inhibits substrate uptake. Cocrystal structures show that clomipramine, along with two other TCAs, binds in an extracellular-facing vestibule about 11 A above the substrate and two sodium ions, apparently stabilizing the extracellular gate in a closed conformation. Off-rate assays establish that clomipramine reduces the rate at which leucine dissociates from LeuT and reinforce our contention that this TCA inhibits LeuT by slowing substrate release. Our results represent a molecular view into noncompetitive inhibition of a sodium-coupled transporter and define principles for the rational design of

  13. Antidepressant Binding Site in a Bacterial Homologue of Neurotransmitter Transporters

    SciTech Connect

    Singh,S.; Yamashita, A.; Gouaux, E.

    2007-01-01

    Sodium-coupled transporters are ubiquitous pumps that harness pre-existing sodium gradients to catalyse the thermodynamically unfavourable uptake of essential nutrients, neurotransmitters and inorganic ions across the lipid bilayer. Dysfunction of these integral membrane proteins has been implicated in glucose/galactose malabsorption, congenital hypothyroidism, Bartter's syndrome, epilepsy, depression, autism and obsessive-compulsive disorder. Sodium-coupled transporters are blocked by a number of therapeutically important compounds, including diuretics, anticonvulsants and antidepressants, many of which have also become indispensable tools in biochemical experiments designed to probe antagonist binding sites and to elucidate transport mechanisms. Steady-state kinetic data have revealed that both competitive and noncompetitive modes of inhibition exist. Antagonist dissociation experiments on the serotonin transporter (SERT) have also unveiled the existence of a low-affinity allosteric site that slows the dissociation of inhibitors from a separate high-affinity site. Despite these strides, atomic-level insights into inhibitor action have remained elusive. Here we screen a panel of molecules for their ability to inhibit LeuT, a prokaryotic homologue of mammalian neurotransmitter sodium symporters, and show that the tricyclic antidepressant (TCA) clomipramine noncompetitively inhibits substrate uptake. Cocrystal structures show that clomipramine, along with two other TCAs, binds in an extracellular-facing vestibule about 11 {angstrom} above the substrate and two sodium ions, apparently stabilizing the extracellular gate in a closed conformation. Off-rate assays establish that clomipramine reduces the rate at which leucine dissociates from LeuT and reinforce our contention that this TCA inhibits LeuT by slowing substrate release. Our results represent a molecular view into noncompetitive inhibition of a sodium-coupled transporter and define principles for the rational

  14. Characterization of Bacterial Drug Antiporters Homologous to Mammalian Neurotransmitter Transporters

    PubMed Central

    Vardy, Eyal; Steiner-Mordoch, Sonia; Schuldiner, Shimon

    2005-01-01

    Multidrug transporters are ubiquitous proteins, and, based on amino acid sequence similarities, they have been classified into several families. Here we characterize a cluster of archaeal and bacterial proteins from the major facilitator superfamily (MFS). One member of this family, the vesicular monoamine transporter (VMAT) was previously shown to remove both neurotransmitters and toxic compounds from the cytoplasm, thereby conferring resistance to their effects. A BLAST search of the available microbial genomes against the VMAT sequence yielded sequences of novel putative multidrug transporters. The new sequences along with VMAT form a distinct cluster within the dendrogram of the MFS, drug-proton antiporters. A comparison with other proteins in the family suggests the existence of a potential ion pair in the membrane domain. Three of these genes, from Mycobacterium smegmatis, Corynebacterium glutamicum, and Halobacterium salinarum, were cloned and functionally expressed in Escherichia coli. The proteins conferred resistance to fluoroquinolones and chloramphenicol (at concentrations two to four times greater than that of the control). Measurement of antibiotic accumulation in cells revealed proton motive force-dependent transport of those compounds. PMID:16237035

  15. Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3.

    PubMed

    Duan, Haichuan; Wang, Joanne

    2010-12-01

    The plasma membrane monoamine transporter (PMAT) and organic cation transporter 3 (OCT3) are the two most prominent low-affinity, high-capacity (i.e., uptake(2)) transporters for endogenous biogenic amines. Using the Flp-in system, we expressed human PMAT (hPMAT) and human OCT3 (hOCT3) at similar levels in human embryonic kidney 293 cells. Parallel and detailed kinetics analysis revealed distinct and seemingly complementary patterns for the two transporters in transporting monoamine neurotransmitters. hPMAT is highly selective toward serotonin (5-HT) and dopamine, with the rank order of transport efficiency (V(max)/K(m)) being: dopamine, 5-HT ≫ histamine, norepinephrine, epinephrine. The substrate preference of hPMAT toward these amines is substantially driven by large (up to 15-fold) distinctions in its apparent binding affinities (K(m)). In contrast, hOCT3 is less selective than hPMAT toward the monoamines, and the V(max)/K(m) rank order for hOCT3 is: histamine > norepinephrine, epinephrine > dopamine >5-HT. It is noteworthy that hOCT3 demonstrated comparable (≤2-fold difference) K(m) toward all amines, and distinctions in V(max) played an important role in determining its differential transport efficiency toward the monoamines. Real-time reverse transcription-polymerase chain reaction revealed that hPMAT is expressed at much higher levels than hOCT3 in most human brain areas, whereas hOCT3 is selectively and highly expressed in adrenal gland and skeletal muscle. Our results suggest that hOCT3 represents a major uptake(2) transporter for histamine, epinephrine, and norepinephrine. hPMAT, on the other hand, is a major uptake(2) transporter for 5-HT and dopamine and may play a more important role in transporting these two neurotransmitters in the central nervous system.

  16. Drosophila melanogaster as a genetic model system to study neurotransmitter transporters

    PubMed Central

    Martin, Ciara A.; Krantz, David E.

    2014-01-01

    The model genetic organism Drosophila melanogaster, commonly known as the fruit fly, uses many of the same neurotransmitters as mammals and very similar mechanisms of neurotransmitter storage, release and recycling. This system offers a variety of powerful molecular-genetic methods for the study of transporters, many of which would be difficult in mammalian models. We review here progress made using Drosophila to understand the function and regulation of neurotransmitter transporters and discuss future directions for its use. PMID:24704795

  17. P2Y Purinergic Regulation of the Glycine Neurotransmitter Transporters*

    PubMed Central

    Jiménez, Esperanza; Zafra, Francisco; Pérez-Sen, Raquel; Delicado, Esmerilda G.; Miras-Portugal, Maria Teresa; Aragón, Carmen; López-Corcuera, Beatriz

    2011-01-01

    The sodium- and chloride-coupled glycine neurotransmitter transporters (GLYTs) control the availability of glycine at glycine-mediated synapses. The mainly glial GLYT1 is the key regulator of the glycine levels in glycinergic and glutamatergic pathways, whereas the neuronal GLYT2 is involved in the recycling of synaptic glycine from the inhibitory synaptic cleft. In this study, we report that stimulation of P2Y purinergic receptors with 2-methylthioadenosine 5′-diphosphate in rat brainstem/spinal cord primary neuronal cultures and adult rat synaptosomes leads to the inhibition of GLYT2 and the stimulation of GLYT1 by a paracrine regulation. These effects are mainly mediated by the ADP-preferring subtypes P2Y1 and P2Y13 because the effects are partially reversed by the specific antagonists N6-methyl-2′-deoxyadenosine-3′,5′-bisphosphate and pyridoxal-5′-phosphate-6-azo(2-chloro-5-nitrophenyl)-2,4-disulfonate and are totally blocked by suramin. P2Y12 receptor is additionally involved in GLYT1 stimulation. Using pharmacological approaches and siRNA-mediated protein knockdown methodology, we elucidate the molecular mechanisms of GLYT regulation. Modulation takes place through a signaling cascade involving phospholipase C activation, inositol 1,4,5-trisphosphate production, intracellular Ca2+ mobilization, protein kinase C stimulation, nitric oxide formation, cyclic guanosine monophosphate production, and protein kinase G-I (PKG-I) activation. GLYT1 and GLYT2 are differentially sensitive to NO/cGMP/PKG-I both in brain-derived preparations and in heterologous systems expressing the recombinant transporters and P2Y1 receptor. Sensitivity to 2-methylthioadenosine 5′-diphosphate by GLYT1 and GLYT2 was abolished by small interfering RNA (siRNA)-mediated knockdown of nitric-oxide synthase. Our data may help define the role of GLYTs in nociception and pain sensitization. PMID:21245148

  18. Neurotransmitter Transporter-Like: A Male Germline-specific SLC6 Transporter Required for Drosophila Spermiogenesis

    PubMed Central

    Chatterjee, Nabanita; Rollins, Janet; Mahowald, Anthony P.; Bazinet, Christopher

    2011-01-01

    The SLC6 class of membrane transporters, known primarily as neurotransmitter transporters, is increasingly appreciated for its roles in nutritional uptake of amino acids and other developmentally specific functions. A Drosophila SLC6 gene, Neurotransmitter transporter-like (Ntl), is expressed only in the male germline. Mobilization of a transposon inserted near the 3′ end of the Ntl coding region yields male-sterile mutants defining a single complementation group. Germline transformation with Ntl cDNAs under control of male germline-specific control elements restores Ntl/Ntl homozygotes to normal fertility, indicating that Ntl is required only in the germ cells. In mutant males, sperm morphogenesis appears normal, with elongated, individualized and coiled spermiogenic cysts accumulating at the base of the testes. However, no sperm are transferred to the seminal vesicle. The level of polyglycylation of Ntl mutant sperm tubulin appears to be significantly lower than that of wild type controls. Glycine transporters are the most closely related SLC6 transporters to Ntl, suggesting that Ntl functions as a glycine transporter in developing sperm, where augmentation of the cytosolic pool of glycine may be required for the polyglycylation of the massive amounts of tubulin in the fly's giant sperm. The male-sterile phenotype of Ntl mutants may provide a powerful genetic system for studying the function of an SLC6 transporter family in a model organism. PMID:21298005

  19. Snapshot of antidepressants at work: the structure of neurotransmitter transporter proteins.

    PubMed

    Cuboni, Serena; Hausch, Felix

    2014-05-12

    In the sweet spot: Cocrystal structures of engineered neurotransmitter transporters reveal the binding mode of commonly prescribed antidepressants, providing a basis for a rational drug design for this class of proteins. The picture shows the structure of the dopamine transporter of Drosophila melanogaster in complex with the antidepressant nortriptyline.

  20. Classical neurotransmitters and neuropeptides involved in major depression in a multi-neurotransmitter system: a focus on antidepressant drugs.

    PubMed

    Werner, Felix-Martin; Coveñas, R

    2013-01-01

    We summarize the alterations of classical neurotransmitters and neuropeptides and the corresponding subreceptors involved in major depression. Neuronal circuits in the brainstem, hippocampus and hypothalamus are developed, since they can be used to derive a multimodal pharmacotherapy. In this sense, serotonin hypoactivity could occur through a strong presynaptic inhibition of glutaminergic neurons via the subtype 5 of metabotropic glutaminergic receptors, and noradrenaline hypoactivity could be due to an enhanced presynaptic inhibition of GABAergic neurons via GABAB receptors. In the hippocampus, dopamine hypoactivity leads to a decreased positive effect. In clinical trials, the antidepressant effect of drugs interfering with the mentioned subreceptors, for example the triple reuptake inhibitor amitifadine, is being investigated. Moreover, the alterations of neuropeptides, such as corticotropin-releasing hormone, neuropeptide Y and galanin are pointed out. The additional antidepressant effect of analogs, agonists and antagonists of the mentioned neuropeptides should be examined.

  1. Co-existence of Functionally Different Vesicular Neurotransmitter Transporters

    PubMed Central

    Münster-Wandowski, Agnieszka; Zander, Johannes-Friedrich; Richter, Karin; Ahnert-Hilger, Gudrun

    2016-01-01

    The vesicular transmitter transporters VGLUT, VGAT, VMAT2 and VAChT, define phenotype and physiological properties of neuronal subtypes. VGLUTs concentrate the excitatory amino acid glutamate, VGAT the inhibitory amino acid GABA, VMAT2 monoamines, and VAChT acetylcholine (ACh) into synaptic vesicle (SV). Following membrane depolarization SV release their content into the synaptic cleft. A strict segregation of vesicular transporters is mandatory for the precise functioning of synaptic communication and of neuronal circuits. In the last years, evidence accumulates that subsets of neurons express more than one of these transporters leading to synaptic co-release of different and functionally opposing transmitters and modulation of synaptic plasticity. Synaptic co-existence of transporters may change during pathological scenarios in order to ameliorate misbalances in neuronal activity. In addition, evidence increases that transporters also co-exist on the same vesicle providing another layer of regulation. Generally, vesicular transmitter loading relies on an electrochemical gradient ΔμH+ driven by the proton ATPase rendering the lumen of the vesicle with respect to the cytosol positive (Δψ) and acidic (ΔpH). While the activity of VGLUT mainly depends on the Δψ component, VMAT, VGAT and VAChT work best at a high ΔpH. Thus, a vesicular synergy of transporters depending on the combination may increase or decrease the filling of SV with the principal transmitter. We provide an overview on synaptic co-existence of vesicular transmitter transporters including changes in the excitatory/inhibitory balance under pathological conditions. Additionally, we discuss functional aspects of vesicular synergy of transmitter transporters. PMID:26909036

  2. Co-existence of Functionally Different Vesicular Neurotransmitter Transporters.

    PubMed

    Münster-Wandowski, Agnieszka; Zander, Johannes-Friedrich; Richter, Karin; Ahnert-Hilger, Gudrun

    2016-01-01

    The vesicular transmitter transporters VGLUT, VGAT, VMAT2 and VAChT, define phenotype and physiological properties of neuronal subtypes. VGLUTs concentrate the excitatory amino acid glutamate, VGAT the inhibitory amino acid GABA, VMAT2 monoamines, and VAChT acetylcholine (ACh) into synaptic vesicle (SV). Following membrane depolarization SV release their content into the synaptic cleft. A strict segregation of vesicular transporters is mandatory for the precise functioning of synaptic communication and of neuronal circuits. In the last years, evidence accumulates that subsets of neurons express more than one of these transporters leading to synaptic co-release of different and functionally opposing transmitters and modulation of synaptic plasticity. Synaptic co-existence of transporters may change during pathological scenarios in order to ameliorate misbalances in neuronal activity. In addition, evidence increases that transporters also co-exist on the same vesicle providing another layer of regulation. Generally, vesicular transmitter loading relies on an electrochemical gradient ΔμH(+) driven by the proton ATPase rendering the lumen of the vesicle with respect to the cytosol positive (Δψ) and acidic (ΔpH). While the activity of VGLUT mainly depends on the Δψ component, VMAT, VGAT and VAChT work best at a high ΔpH. Thus, a vesicular synergy of transporters depending on the combination may increase or decrease the filling of SV with the principal transmitter. We provide an overview on synaptic co-existence of vesicular transmitter transporters including changes in the excitatory/inhibitory balance under pathological conditions. Additionally, we discuss functional aspects of vesicular synergy of transmitter transporters.

  3. Neurotransmitter and psychostimulant recognition by the dopamine transporter

    PubMed Central

    Wang, Kevin H.; Penmatsa, Aravind; Gouaux, Eric

    2015-01-01

    Na+/Cl−-coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine x-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine (DA), a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants D-amphetamine, methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters. PMID:25970245

  4. A putative vesicular transporter expressed in Drosophila mushroom bodies that mediates sexual behavior may define a novel neurotransmitter system

    PubMed Central

    Brooks, Elizabeth S.; Greer, Christina L.; Romero-Calderón, Rafael; Serway, Christine N.; Grygoruk, Anna; Haimovitz, Jasmine M.; Nguyen, Bac T.; Najibi, Rod; Tabone, Christopher J.; de Belle, J. Steven; Krantz, David E.

    2011-01-01

    Summary Storage and release of classical and amino acid neurotransmitters requires vesicular transporters. Some neurons lack known vesicular transporters, suggesting additional neurotransmitter systems remain unidentified. Insect mushroom bodies (MBs) are critical for several behaviors, including learning, but the neurotransmitters released by the intrinsic Kenyon cells (KCs) remain unknown. Likewise, KCs do not express a known vesicular transporter. We report the identification of a novel Drosophila gene portabella (prt) that is structurally similar to known vesicular transporters. Both larval and adult brains express PRT in the KCs of the MBs. Additional PRT cells project to the central complex and optic ganglia. prt mutation causes an olfactory learning deficit and an unusual defect in the male’s position during copulation that is rescued by expression in KCs. Since prt is expressed in neurons that lack other known vesicular transporters or neurotransmitters, it may define a previously unknown neurotransmitter system responsible for sexual behavior and a component of olfactory learning. PMID:22017990

  5. Structure and localisation of drug binding sites on neurotransmitter transporters.

    PubMed

    Ravna, Aina W; Sylte, Ingebrigt; Dahl, Svein G

    2009-10-01

    The dopamine (DAT), serotontin (SERT) and noradrenalin (NET) transporters are molecular targets for different classes of psychotropic drugs. The crystal structure of Aquifex aeolicus LeuT(Aa) was used as a template for molecular modeling of DAT, SERT and NET, and two putative drug binding sites (pocket 1 and 2) in each transporter were identified. Cocaine was docked into binding pocket 1 of DAT, corresponding to the leucine binding site in LeuT(Aa), which involved transmembrane helices (TMHs) 1, 3, 6 and 8. Clomipramine was docked into binding pocket 2 of DAT, involving TMHs 1, 3, 6, 10 and 11, and extracellular loops 4 and 6, corresponding to the clomipramine binding site in a crystal structure of a LeuT(Aa)-clomipramine complex. The structures of the proposed cocaine- and tricyclic antidepressant-binding sites may be of particular interest for the design of novel DAT interacting ligands.

  6. Common drugs inhibit human organic cation transporter 1 (OCT1)-mediated neurotransmitter uptake.

    PubMed

    Boxberger, Kelli H; Hagenbuch, Bruno; Lampe, Jed N

    2014-06-01

    The human organic cation transporter 1 (OCT1) is a polyspecific transporter involved in the uptake of positively charged and neutral small molecules in the liver. To date, few endogenous compounds have been identified as OCT1 substrates; more importantly, the effect of drugs on endogenous substrate transport has not been examined. In this study, we established monoamine neurotransmitters as substrates for OCT1, specifically characterizing serotonin transport in human embryonic kidney 293 cells. Kinetic analysis yielded a Km of 197 micomolar and a Vmax of 561 pmol/mg protein/minute for serotonin. Furthermore, we demonstrated that serotonin uptake was inhibited by diphenhydramine, fluoxetine, imatinib, and verapamil, with IC50 values in the low micromolar range. These results were recapitulated in primary human hepatocytes, suggesting that OCT1 plays a significant role in hepatic elimination of serotonin and that xenobiotics may alter the elimination of endogenous compounds as a result of interactions at the transporter level.

  7. Common Drugs Inhibit Human Organic Cation Transporter 1 (OCT1)-Mediated Neurotransmitter Uptake

    PubMed Central

    Boxberger, Kelli H.; Hagenbuch, Bruno

    2014-01-01

    The human organic cation transporter 1 (OCT1) is a polyspecific transporter involved in the uptake of positively charged and neutral small molecules in the liver. To date, few endogenous compounds have been identified as OCT1 substrates; more importantly, the effect of drugs on endogenous substrate transport has not been examined. In this study, we established monoamine neurotransmitters as substrates for OCT1, specifically characterizing serotonin transport in human embryonic kidney 293 cells. Kinetic analysis yielded a Km of 197 micomolar and a Vmax of 561 pmol/mg protein/minute for serotonin. Furthermore, we demonstrated that serotonin uptake was inhibited by diphenhydramine, fluoxetine, imatinib, and verapamil, with IC50 values in the low micromolar range. These results were recapitulated in primary human hepatocytes, suggesting that OCT1 plays a significant role in hepatic elimination of serotonin and that xenobiotics may alter the elimination of endogenous compounds as a result of interactions at the transporter level. PMID:24688079

  8. Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6.

    PubMed

    Chen, Nian-Hang; Reith, Maarten E A; Quick, Michael W

    2004-02-01

    The SLC6 family is a diverse set of transporters that mediate solute translocation across cell plasma membranes by coupling solute transport to the cotransport of sodium and chloride down their electrochemical gradients. These transporters probably have 12 transmembrane domains, with cytoplasmic N- and C-terminal tails, and at least some may function as homo-oligomers. Family members include the transporters for the inhibitory neurotransmitters GABA and glycine, the aminergic transmitters norepinephrine, serotonin, and dopamine, the osmolytes betaine and taurine, the amino acid proline, and the metabolic compound creatine. In addition, this family includes a system B(0+) cationic and neutral amino acid transporter, and two transporters for which the solutes are unknown. In general, SLC6 transporters act to regulate the level of extracellular solute concentrations. In the central and the peripheral nervous system, these transporters can regulate signaling among neurons, are the sites of action of various drugs of abuse, and naturally occurring mutations in several of these proteins are associated with a variety of neurological disorders. For example, transgenic animals lacking specific aminergic transporters show profoundly disturbed behavioral phenotypes and probably represent excellent systems for investigating psychiatric disease. SLC6 transporters are also found in many non-neural tissues, including kidney, intestine, and testis, consistent with their diverse physiological roles. Transporters in this family represent attractive therapeutic targets because they are subject to multiple forms of regulation by many different signaling cascades, and because a number of pharmacological agents have been identified that act specifically on these proteins.

  9. The role of SNARE proteins in trafficking and function of neurotransmitter transporters.

    PubMed

    Quick, M W

    2006-01-01

    The SNARE hypothesis of vesicle fusion proposes that a series of protein-protein interactions governs the delivery of vesicles to various membrane targets such as the Golgi network and the plasma membrane. Key players in this process include members of the syntaxin family of membrane proteins. The first member identified in this family, syntaxin 1A, plays an essential role in the docking and fusion of neurotransmitter-containing vesicles to the presynaptic membrane of neurons. Syntaxin 1A and other syntaxin family members have also been shown to interact with, and directly regulate, a variety of ion channels. More recently, the family of plasma membrane neurotransmitter transporters, proteins that function in part to control transmitter levels in brain, have been shown to be direct targets of syntaxin 1A regulation. This regulation involves both the trafficking of transporters as well as the control of ion and transmitter flux through transporters. In this chapter, the functional effects of syntaxin-transporter interactions are reviewed, and how such interactions may regulate neuronal signaling are considered.

  10. A putative vesicular transporter expressed in Drosophila mushroom bodies that mediates sexual behavior may define a neurotransmitter system.

    PubMed

    Brooks, Elizabeth S; Greer, Christina L; Romero-Calderón, Rafael; Serway, Christine N; Grygoruk, Anna; Haimovitz, Jasmine M; Nguyen, Bac T; Najibi, Rod; Tabone, Christopher J; de Belle, J Steven; Krantz, David E

    2011-10-20

    Vesicular transporters are required for the storage of all classical and amino acid neurotransmitters in synaptic vesicles. Some neurons lack known vesicular transporters, suggesting additional neurotransmitter systems remain unidentified. Insect mushroom bodies (MBs) are critical for several behaviors, including learning, but the neurotransmitters released by the intrinsic Kenyon cells (KCs) remain unknown. Likewise, KCs do not express a known vesicular transporter. We report the identification of a novel Drosophila gene portabella (prt) that is structurally similar to known vesicular transporters. Both larval and adult brains express PRT in the KCs of the MBs. Additional PRT cells project to the central complex and optic ganglia. prt mutation causes an olfactory learning deficit and an unusual defect in the male's position during copulation that is rescued by expression in KCs. Because prt is expressed in neurons that lack other known vesicular transporters or neurotransmitters, it may define a previously unknown neurotransmitter system responsible for sexual behavior and a component of olfactory learning. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Ligand Binding in the Extracellular Vestibule of the Neurotransmitter Transporter Homologue LeuT.

    PubMed

    Grouleff, Julie; Koldsø, Heidi; Miao, Yinglong; Schiøtt, Birgit

    2017-03-15

    The human monoamine transporters (MATs) facilitate the reuptake of monoamine neurotransmitters from the synaptic cleft. MATs are linked to a number of neurological diseases and are the targets of both therapeutic and illicit drugs. Until recently, no high-resolution structures of the human MATs existed, and therefore, studies of this transporter family have relied on investigations of the homologues bacterial transporters such as the leucine transporter LeuT, which has been crystallized in several conformational states. A two-substrate transport mechanism has been suggested for this transporter family, which entails that high-affinity binding of a second substrate in an extracellular site is necessary for the substrate in the central binding site to be transported. Compelling evidence for this mechanism has been presented, however, a number of equally compelling accounts suggest that the transporters function through a mechanism involving only a single substrate and a single high-affinity site. To shed light on this apparent contradiction, we have performed extensive molecular dynamics simulations of LeuT in the outward-occluded conformation with either one or two substrates bound to the transporter. We have also calculated the substrate binding affinity in each of the two proposed binding sites through rigorous free energy simulations. Results show that substrate binding is unstable in the extracellular vestibule and the substrate binding affinity within the suggested extracellular site is very low (0.2 and 3.3 M for the two dominant binding modes) compared to the central substrate binding site (14 nM). This suggests that for LeuT in the outward-occluded conformation only a single high-affinity substrate binding site exists.

  12. Substrate-modulated gating dynamics in a Na+-coupled neurotransmitter transporter homologue.

    PubMed

    Zhao, Yongfang; Terry, Daniel S; Shi, Lei; Quick, Matthias; Weinstein, Harel; Blanchard, Scott C; Javitch, Jonathan A

    2011-06-02

    Neurotransmitter/Na(+) symporters (NSSs) terminate neuronal signalling by recapturing neurotransmitter released into the synapse in a co-transport (symport) mechanism driven by the Na(+) electrochemical gradient. NSSs for dopamine, noradrenaline and serotonin are targeted by the psychostimulants cocaine and amphetamine, as well as by antidepressants. The crystal structure of LeuT, a prokaryotic NSS homologue, revealed an occluded conformation in which a leucine (Leu) and two Na(+) are bound deep within the protein. This structure has been the basis for extensive structural and computational exploration of the functional mechanisms of proteins with a LeuT-like fold. Subsequently, an 'outward-open' conformation was determined in the presence of the inhibitor tryptophan, and the Na(+)-dependent formation of a dynamic outward-facing intermediate was identified using electron paramagnetic resonance spectroscopy. In addition, single-molecule fluorescence resonance energy transfer imaging has been used to reveal reversible transitions to an inward-open LeuT conformation, which involve the movement of transmembrane helix TM1a away from the transmembrane helical bundle. We investigated how substrate binding is coupled to structural transitions in LeuT during Na(+)-coupled transport. Here we report a process whereby substrate binding from the extracellular side of LeuT facilitates intracellular gate opening and substrate release at the intracellular face of the protein. In the presence of alanine, a substrate that is transported ∼10-fold faster than leucine, we observed alanine-induced dynamics in the intracellular gate region of LeuT that directly correlate with transport efficiency. Collectively, our data reveal functionally relevant and previously hidden aspects of the NSS transport mechanism that emphasize the functional importance of a second substrate (S2) binding site within the extracellular vestibule. Substrate binding in this S2 site appears to act cooperatively

  13. Molecular characterization of the first aromatic nutrient transporter from the sodium neurotransmitter symporter family.

    PubMed

    Meleshkevitch, Ella A; Assis-Nascimento, Poincyane; Popova, Lyudmila B; Miller, Melissa M; Kohn, Andrea B; Phung, Elizabeth N; Mandal, Anita; Harvey, William R; Boudko, Dmitri Y

    2006-08-01

    Nutrient amino acid transporters (NATs, subfamily of sodium neurotransmitter symporter family SNF, a.k.a. SLC6) represent a set of phylogenetically and functionally related transport proteins, which perform intracellular absorption of neutral, predominantly essential amino acids. Functions of NATs appear to be critical for the development and survival in organisms. However, mechanisms of specific and synergetic action of various NAT members in the amino acid transport network are virtually unexplored. A new transporter, agNAT8, was cloned from the malaria vector mosquito Anopheles gambiae (SS). Upon heterologous expression in Xenopus oocytes it performs high-capacity, sodium-coupled (2:1) uptake of nutrients with a strong preference for aromatic catechol-branched substrates, especially phenylalanine and its derivatives tyrosine and L-DOPA, but not catecholamines. It represents a previously unknown SNF phenotype, and also appears to be the first sodium-dependent B(0) type transporter with a narrow selectivity for essential precursors of catecholamine synthesis pathways. It is strongly and specifically transcribed in absorptive and secretory parts of the larval alimentary canal and specific populations of central and peripheral neurons of visual-, chemo- and mechano-sensory afferents. We have identified a new SNF transporter with previously unknown phenotype and showed its important role in the accumulation and redistribution of aromatic substrates. Our results strongly suggest that agNAT8 is an important, if not the major, provider of an essential catechol group in the synthesis of catecholamines for neurochemical signaling as well as ecdysozoan melanization and sclerotization pathways, which may include cuticle hardening/coloring, wound curing, oogenesis, immune responses and melanization of pathogens.

  14. LeuT: a prokaryotic stepping stone on the way to a eukaryotic neurotransmitter transporter structure.

    PubMed

    Singh, Satinder K

    2008-01-01

    Ion-coupled secondary transport is utilized by a broad range of integral membrane proteins to catalyze the energetically unfavorable movement of solute molecules across a lipid bilayer. Members of the solute carrier 6 (SLC6) family, present in both prokaryotes and eukaryotes, are sodium-coupled symporters that play crucial roles in processes as diverse as nutrient uptake and neurotransmitter clearance. The crystal structure of LeuT, a bacterial member of this family, provided the first atomic-level glimpse into overall architecture, pinpointed the substrate and sodium binding sites and implicated candidate helices and residues in the "gating" conformational changes that accompany ion binding and release. The structure is consistent with a wealth of elegant biochemical data on the eukaryotic counterparts and has for the first time permitted the construction of accurate homology models that can be directly tested experimentally. Sequence identity is especially high near the substrate and sodium binding sites and, thus, molecular insights within these regions have been substantial. However, there are several topics relevant to transport mechanism, inhibition and regulation that structure/function studies of LeuT cannot adequately address, suggesting the need for a eukaryotic transporter crystal structure.

  15. Antibody-Conjugated Single Quantum Dot Tracking of Membrane Neurotransmitter Transporters in Primary Neuronal Cultures.

    PubMed

    Bailey, Danielle M; Kovtun, Oleg; Rosenthal, Sandra J

    2017-01-01

    Single particle tracking (SPT) experiments have provided the scientific community with invaluable single-molecule information about the dynamic regulation of individual receptors, transporters, kinases, lipids, and molecular motors. SPT is an alternative to ensemble averaging approaches, where heterogeneous modes of motion might be lost. Quantum dots (QDs) are excellent probes for SPT experiments due to their photostability, high brightness, and size-dependent, narrow emission spectra. In a typical QD-based SPT experiment, QDs are bound to the target of interest and imaged for seconds to minutes via fluorescence video microscopy. Single QD spots in individual frames are then linked to form trajectories that are analyzed to determine their mean square displacement, diffusion coefficient, confinement index, and instantaneous velocity. This chapter describes a generalizable protocol for the single particle tracking of membrane neurotransmitter transporters on cell membranes with either unmodified extracellular antibody probes and secondary antibody-conjugated quantum dots or biotinylated extracellular antibody probes and streptavidin-conjugated quantum dots in primary neuronal cultures. The neuronal cell culture, the biotinylation protocol and the quantum dot labeling procedures, as well as basic data analysis are discussed.

  16. Mefloquine and Psychotomimetics Share Neurotransmitter Receptor and Transporter Interactions In Vitro

    PubMed Central

    Janowsky, Aaron; Eshleman, Amy J.; Johnson, Robert A.; Wolfrum, Katherine M.; Hinrichs, David J.; Yang, Jongtae; Zabriskie, T. Mark; Smilkstein, Martin J.; Riscoe, Michael K.

    2014-01-01

    Rationale Mefloquine is used for the prevention and treatment of chloroquine-resistant malaria, but its use is associated with nightmares, hallucinations, and exacerbation of symptoms of post-traumatic stress disorder. We hypothesized that potential mechanisms of action for the adverse psychotropic effects of mefloquine resemble those of other known psychotomimetics. Objectives Using in vitro radioligand binding and functional assays, we examined the interaction of (+)- and (−)-mefloquine enantiomers, the non-psychotomimetic anti-malarial agent, chloroquine, and several hallucinogens and psychostimulants with recombinant human neurotransmitter receptors and transporters. Results Hallucinogens and mefloquine bound stereoselectively and with relatively high affinity (Ki = 0.71–341 nM) to serotonin (5-HT) 2A but not 5-HT1A or 5-HT2C receptors. Mefloquine but not chloroquine was a partial 5-HT2A agonist and a full 5-HT2C agonist, stimulating inositol phosphate accumulation, with similar potency and efficacy as the hallucinogen dimethyltryptamine (DMT). 5-HT receptor antagonists blocked mefloquine’s effects. Mefloquine had low or no affinity for dopamine D1, D2, D3, and D4.4 receptors, or dopamine and norepinephrine transporters. However, mefloquine was a very low potency antagonist at the D3 receptor and mefloquine but not chloroquine or hallucinogens blocked [3H]5-HT uptake by the 5-HT transporter. Conclusions Mefloquine but not chloroquine shares an in vitro receptor interaction profile with some hallucinogens and this neurochemistry may be relevant to the adverse neuropsychiatric effects associated with mefloquine use by a small percentage of patients. Additionally, evaluating interactions with this panel of receptors and transporters may be useful for characterizing effects of other psychotropic drugs and for avoiding psychotomimetic effects for new pharmacotherapies, including antimalarial quinolines. PMID:24488404

  17. Two Na+ Sites Control Conformational Change in a Neurotransmitter Transporter Homolog*

    PubMed Central

    Tavoulari, Sotiria; Margheritis, Eleonora; Nagarajan, Anu; DeWitt, David C.; Zhang, Yuan-Wei; Rosado, Edwin; Ravera, Silvia; Rhoades, Elizabeth; Forrest, Lucy R.; Rudnick, Gary

    2016-01-01

    In LeuT, a prokaryotic homolog of neurotransmitter transporters, Na+ stabilizes outward-open conformational states. We examined how each of the two LeuT Na+ binding sites contributes to Na+-dependent closure of the cytoplasmic pathway using biochemical and biophysical assays of conformation. Mutating either of two residues that contribute to the Na2 site completely prevented cytoplasmic closure in response to Na+, suggesting that Na2 is essential for this conformational change, whereas Na1 mutants retained Na+ responsiveness. However, mutation of Na1 residues also influenced the Na+-dependent conformational change in ways that varied depending on the position mutated. Computational analyses suggest those mutants influence the ability of Na1 binding to hydrate the substrate pathway and perturb an interaction network leading to the extracellular gate. Overall, the results demonstrate that occupation of Na2 stabilizes outward-facing conformations presumably through a direct interaction between Na+ and transmembrane helices 1 and 8, whereas Na+ binding at Na1 influences conformational change through a network of intermediary interactions. The results also provide evidence that N-terminal release and helix motions represent distinct steps in cytoplasmic pathway opening. PMID:26582198

  18. Two Na+ Sites Control Conformational Change in a Neurotransmitter Transporter Homolog.

    PubMed

    Tavoulari, Sotiria; Margheritis, Eleonora; Nagarajan, Anu; DeWitt, David C; Zhang, Yuan-Wei; Rosado, Edwin; Ravera, Silvia; Rhoades, Elizabeth; Forrest, Lucy R; Rudnick, Gary

    2016-01-15

    In LeuT, a prokaryotic homolog of neurotransmitter transporters, Na(+) stabilizes outward-open conformational states. We examined how each of the two LeuT Na(+) binding sites contributes to Na(+)-dependent closure of the cytoplasmic pathway using biochemical and biophysical assays of conformation. Mutating either of two residues that contribute to the Na2 site completely prevented cytoplasmic closure in response to Na(+), suggesting that Na2 is essential for this conformational change, whereas Na1 mutants retained Na(+) responsiveness. However, mutation of Na1 residues also influenced the Na(+)-dependent conformational change in ways that varied depending on the position mutated. Computational analyses suggest those mutants influence the ability of Na1 binding to hydrate the substrate pathway and perturb an interaction network leading to the extracellular gate. Overall, the results demonstrate that occupation of Na2 stabilizes outward-facing conformations presumably through a direct interaction between Na(+) and transmembrane helices 1 and 8, whereas Na(+) binding at Na1 influences conformational change through a network of intermediary interactions. The results also provide evidence that N-terminal release and helix motions represent distinct steps in cytoplasmic pathway opening.

  19. Signal focusing through active transport

    NASA Astrophysics Data System (ADS)

    Godec, Aljaž; Metzler, Ralf

    2015-07-01

    The accuracy of molecular signaling in biological cells and novel diagnostic devices is ultimately limited by the counting noise floor imposed by the thermal diffusion. Motivated by the fact that messenger RNA and vesicle-engulfed signaling molecules transiently bind to molecular motors and are actively transported in biological cells, we show here that the random active delivery of signaling particles to within a typical diffusion distance to the receptor generically reduces the correlation time of the counting noise. Considering a variety of signaling particle sizes from mRNA to vesicles and cell sizes from prokaryotic to eukaryotic cells, we show that the conditions for active focusing—faster and more precise signaling—are indeed compatible with observations in living cells. Our results improve the understanding of molecular cellular signaling and novel diagnostic devices.

  20. Draft Genome Sequences of Lactobacillus plantarum Strain 90sk and Lactobacillus brevis Strain 15f: Focusing on Neurotransmitter Genes

    PubMed Central

    Yunes, Roman A.; Klimina, Ksenia M.; Emelyanov, Kirill V.; Zakharevich, Natalia V.; Poluektova, Elena U.

    2015-01-01

    The genomes of Lactobacillus plantarum strain 90sk and Lactobacillus brevis strain 15f were isolated from human intestinal microbiota. Both strains synthesize gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter. Detailed genome analyses will help to understand the role of GABA in the interaction of bacteria with human intestinal cells. PMID:25883284

  1. Draft Genome Sequences of Lactobacillus plantarum Strain 90sk and Lactobacillus brevis Strain 15f: Focusing on Neurotransmitter Genes.

    PubMed

    Yunes, Roman A; Klimina, Ksenia M; Emelyanov, Kirill V; Zakharevich, Natalia V; Poluektova, Elena U; Danilenko, Valery N

    2015-04-16

    The genomes of Lactobacillus plantarum strain 90sk and Lactobacillus brevis strain 15f were isolated from human intestinal microbiota. Both strains synthesize gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter. Detailed genome analyses will help to understand the role of GABA in the interaction of bacteria with human intestinal cells.

  2. Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine.

    PubMed

    Busch, A E; Karbach, U; Miska, D; Gorboulev, V; Akhoundova, A; Volk, C; Arndt, P; Ulzheimer, J C; Sonders, M S; Baumann, C; Waldegger, S; Lang, F; Koepsell, H

    1998-08-01

    Recently, we cloned the human cation transporter hOCT2, a member of a new family of polyspecific transporters from kidney, and demonstrated electrogenic uptake of tetraethylammonium, choline, N1-methylnicotinamide, and 1-methyl-4-phenylpyridinium. Using polymerase chain reaction amplification, cDNA sequencing, in situ hybridization, and immunohistochemistry, we now show that hOCT2 message and protein are expressed in neurons of the cerebral cortex and in various subcortical nuclei. In Xenopus laevis oocytes expressing hOCT2, electrogenic transport of norepinephrine, histamine, dopamine, serotonin, and the antiparkinsonian drugs memantine and amantadine was demonstrated by tracer influx, tracer efflux, electrical measurements, or a combination. Apparent Km values of 1.9 +/- 0.6 mM (norepinephrine), 1.3 +/- 0.3 mM (histamine), 0.39 +/- 0.16 mM (dopamine), 80 +/- 20 microM (serotonin), 34 +/- 5 microM (memantine), and 27 +/- 3 microM (amantadine) were estimated. Measurement of trans-effects in depolarized oocytes and human embryonic kidney cells expressing hOCT2 suggests that there were different rates and specificities for cation influx and efflux. The hypothesis is raised that hOCT2 plays a physiological role in the central nervous system by regulating interstitial concentrations of monoamine neurotransmitters that have evaded high affinity uptake mechanisms. We show that amantadine does not interact with the expressed human Na+/Cl- dopamine cotransporter. However, concentrations of amantadine that are effective for the treatment of Parkinson's disease may increase the interstitial concentrations of dopamine and other aminergic neurotransmitters by competitive inhibition of hOCT2.

  3. Molecular dynamics simulations of Na+/Cl(-)-dependent neurotransmitter transporters in a membrane-aqueous system.

    PubMed

    Jørgensen, Anne Marie; Tagmose, Lena; Jørgensen, Anne Marie M; Bøgesø, Klaus P; Peters, Günther H

    2007-06-01

    We have performed molecular dynamics simulations of a homology model of the human serotonin transporter (hSERT) in a membrane environment and in complex with either the natural substrate 5-HT or the selective serotonin reuptake inhibitor escitalopram. We have also included a transporter homologue, the Aquifex aeolicus leucine transporter (LeuT), in our study to evaluate the applicability of a simple and computationally attractive membrane system. Fluctuations in LeuT extracted from simulations are in good agreement with crystallographic B factors. Furthermore, key interactions identified in the X-ray structure of LeuT are maintained throughout the simulations indicating that our simple membrane system is suitable for studying the transmembrane protein hSERT in complex with 5-HT or escitalopram. For these transporter complexes, only relatively small fluctuations are observed in the ligand-binding cleft. Specific interactions responsible for ligand recognition, are identified in the hSERT-5HT and hSERT-escitalopram complexes. Our findings are in good agreement with predictions from mutagenesis studies.

  4. Strategies for immunohistochemical protein localization using antibodies: What did we learn from neurotransmitter transporters in glial cells and neurons.

    PubMed

    Danbolt, Niels Christian; Zhou, Yun; Furness, David N; Holmseth, Silvia

    2016-12-01

    Immunocytochemistry and Western blotting are still major methods for protein localization, but they rely on the specificity of the antibodies. Validation of antibody specificity remains challenging mostly because ideal negative controls are often unavailable. Further, immunochemical labeling patterns are also influenced by a number of other factors such as postmortem changes, fixation procedures and blocking agents as well as the general assay conditions (e.g., buffers, temperature, etc.). Western blotting similarly depends on tissue collection and sample preparation as well as the electrophoretic separation, transfer to blotting membranes and the immunochemical probing of immobilized molecules. Publication of inaccurate information on protein distribution has downstream consequences for other researchers because the interpretation of physiological and pharmacological observations depends on information on where ion channels, receptors, enzymes or transporters are located. Despite numerous reports, some of which are strongly worded, erroneous localization data are being published. Here we describe the extent of the problem and illustrate the nature of the pitfalls with examples from studies of neurotransmitter transporters. We explain the importance of supplementing immunochemical observations with other measurements (e.g., mRNA levels and distribution, protein activity, mass spectrometry, electrophysiological recordings, etc.) and why quantitative considerations are integral parts of the quality control. Further, we propose a practical strategy for researchers who plan to embark on a localization study. We also share our thoughts about guidelines for quality control. GLIA 2016;64:2045-2064.

  5. Accelerated molecular dynamics and protein conformational change: a theoretical and practical guide using a membrane embedded model neurotransmitter transporter.

    PubMed

    Gedeon, Patrick C; Thomas, James R; Madura, Jeffry D

    2015-01-01

    Molecular dynamics simulation provides a powerful and accurate method to model protein conformational change, yet timescale limitations often prevent direct assessment of the kinetic properties of interest. A large number of molecular dynamic steps are necessary for rare events to occur, which allow a system to overcome energy barriers and conformationally transition from one potential energy minimum to another. For many proteins, the energy landscape is further complicated by a multitude of potential energy wells, each separated by high free-energy barriers and each potentially representative of a functionally important protein conformation. To overcome these obstacles, accelerated molecular dynamics utilizes a robust bias potential function to simulate the transition between different potential energy minima. This straightforward approach more efficiently samples conformational space in comparison to classical molecular dynamics simulation, does not require advanced knowledge of the potential energy landscape and converges to the proper canonical distribution. Here, we review the theory behind accelerated molecular dynamics and discuss the approach in the context of modeling protein conformational change. As a practical example, we provide a detailed, step-by-step explanation of how to perform an accelerated molecular dynamics simulation using a model neurotransmitter transporter embedded in a lipid cell membrane. Changes in protein conformation of relevance to the substrate transport cycle are then examined using principle component analysis.

  6. Modeling and dynamics of the inward-facing state of a Na+/Cl- dependent neurotransmitter transporter homologue.

    PubMed

    Shaikh, Saher Afshan; Tajkhorshid, Emad

    2010-08-26

    The leucine transporter (LeuT) has recently commanded exceptional attention due mainly to two distinctions; it provides the only crystal structures available for a protein homologous to the pharmacologically relevant neurotransmitter: sodium symporters (NSS), and, it exhibits a hallmark 5-TM inverted repeat ("LeuT-fold"), a fold recently discovered to also exist in several secondary transporter families, underscoring its general role in transporter function. Constructing the transport cycle of "LeuT-fold" transporters requires detailed structural and dynamic descriptions of the outward-facing (OF) and inward-facing (IF) states, as well as the intermediate states. To this end, we have modeled the structurally unknown IF state of LeuT, based on the known crystal structures of the OF state of LeuT and the IF state of vSGLT, a "LeuT-fold" transporter. The detailed methodology developed for the study combines structure-based alignment, threading, targeted MD and equilibrium MD, and can be applied to other proteins. The resulting IF-state models maintain the secondary structural features of LeuT. Water penetration and solvent accessibility calculations show that TM1, TM3, TM6 and TM8 line the substrate binding/unbinding pathway with TM10 and its pseudosymmetric partner, TM5, participating in the extracellular and intracellular halves of the lumen, respectively. We report conformational hotspots where notable changes in interactions occur between the IF and OF states. We observe Na2 exiting the LeuT-substrate- complex in the IF state, mainly due to TM1 bending. Inducing a transition in only one of the two pseudosymmetric domains, while allowing the second to respond dynamically, is found to be sufficient to induce the formation of the IF state. We also propose that TM2 and TM7 may be facilitators of TM1 and TM6 motion. Thus, this study not only presents a novel modeling methodology applied to obtain the IF state of LeuT, but also describes structural elements involved in

  7. Lobeline esters as novel ligands for neuronal nicotinic acetylcholine receptors and neurotransmitter transporters

    PubMed Central

    Hojahmat, Marhaba; Horton, David B.; Norrholm, Seth D.; Miller, Dennis K.; Grinevich, Vladimir P.; Deaciuc, Agripina Gabriela; Dwoskin, Linda P.; Crooks, Peter A.

    2013-01-01

    Vescular monoamine transporter-2 (VMAT2) is a viable target for development of pharmacotherapies for psychostimulant abuse. Lobeline (1) is a potent antagonist at α4β2* nicotinic acetylcholine receptors, has moderate affinity (Ki=5.46 μM) for VMAT2, and is being investigated currently as a clinical candidate for treatment of psychostimulant abuse. A series of carboxylic acid and sulfonic acid ester analogs 2–20 of lobeline were synthesized and evaluated for interaction with α4β2* and α7* neuronal nicotinic acetylcholine receptors (nAChRs), the dopamine transporter (DAT), serotonin transporter (SERT) and VMAT2. Both carboxylic acid and sulfonic acid esters had low affinity at α7* nAChRs. Similar to lobeline (Ki=4 nM), sulfonic acid esters had high affinity at α4β2* (Ki=5–17 nM). Aromatic carboxylic acid ester analogs of lobeline (2–4) were 100–1000-fold less potent than lobeline at α4β2* nAChRs, whereas aliphatic carboxylic acid ester analogs were 10–100-fold less potent than lobeline at α4β2*. Two representative lobeline esters, the 10-O-benzoate (2) and the 10-O-benzenesulfonate (10) were evaluated in the 36Rb+ efflux assay using rat thalamic synaptosomes, and were shown to be antagonists with IC50 values of 0.85 μM and 1.60 μM, respectively. Both carboxylic and sulfonic acid esters exhibited a range of potencies (equipotent to 13–45-fold greater potency compared to lobeline) for inhibiting DAT and SERT, respectively, and like lobeline, had moderate affinity (Ki=1.98–10.8 μM) for VMAT2. One of the more interesting analogs, p-methoxybenzoic acid ester 4, had low affinity at α4β2* nAChRs (Ki=19.3 μM) and was equipotent with lobeline, at VMAT2 (Ki=2.98 μM), exhibiting a 6.5-fold selectivity for VMAT2 over α4β2 nAChRs. Thus, esterification of the lobeline molecule may be a useful structural modification for the development of lobeline analogs with improved selectivity at VMAT2. PMID:20036131

  8. Azidobupramine, an Antidepressant-Derived Bifunctional Neurotransmitter Transporter Ligand Allowing Covalent Labeling and Attachment of Fluorophores

    PubMed Central

    Werner, Anna M.; Cuboni, Serena; Rudolf, Georg C.; Höfner, Georg; Wanner, Klaus T.; Sieber, Stephan A.; Schmidt, Ulrike; Holsboer, Florian; Rein, Theo; Hausch, Felix

    2016-01-01

    The aim of this study was to design, synthesize and validate a multifunctional antidepressant probe that is modified at two distinct positions. The purpose of these modifications was to allow covalent linkage of the probe to interaction partners, and decoration of probe-target complexes with fluorescent reporter molecules. The strategy for the design of such a probe (i.e., azidobupramine) was guided by the need for the introduction of additional functional groups, conveying the required properties while keeping the additional moieties as small as possible. This should minimize the risk of changing antidepressant-like properties of the new probe azidobupramine. To control for this, we evaluated the binding parameters of azidobupramine to known target sites such as the transporters for serotonin (SERT), norepinephrine (NET), and dopamine (DAT). The binding affinities of azidobupramine to SERT, NET, and DAT were in the range of structurally related and clinically active antidepressants. Furthermore, we successfully visualized azidobupramine-SERT complexes not only in SERT-enriched protein material but also in living cells stably overexpressing SERT. To our knowledge, azidobupramine is the first structural analogue of a tricyclic antidepressant that can be covalently linked to target structures and further attached to reporter molecules while preserving antidepressant-like properties and avoiding radioactive isotopes. PMID:26863431

  9. Transport of biogenic amine neurotransmitters at the mouse blood-retina and blood-brain barriers by uptake1 and uptake2.

    PubMed

    André, Pascal; Saubaméa, Bruno; Cochois-Guégan, Véronique; Marie-Claire, Cynthia; Cattelotte, Julie; Smirnova, Maria; Schinkel, Alfred H; Scherrmann, Jean-Michel; Cisternino, Salvatore

    2012-11-01

    Uptake1 and uptake2 transporters are involved in the extracellular clearance of biogenic amine neurotransmitters at synaptic clefts. We looked for them at the blood-brain barrier (BBB) and blood-retina barriers (BRB), where they could be involved in regulating the neurotransmitter concentration and modulate/terminate receptor-mediated effects within the neurovascular unit (NVU). Uptake2 (Oct1-3/Slc22a1-3, Pmat/Slc29a4) and Mate1/Slc47a1 transporters are also involved in the transport of xenobiotics. We used in situ carotid perfusion of prototypic substrates like [(3)H]-1-methyl-4-phenylpyridinium ([(3)H]-MPP(+)), [(3)H]-histamine, [(3)H]-serotonin, and [(3)H]-dopamine, changes in ionic composition and genetic deletion of Oct1-3 carriers to detect uptake1 and uptake2 at the BBB and BRB. We showed that uptake1 and uptake2 are involved in the transport of [(3)H]-dopamine and [(3)H]-MPP(+) at the blood luminal BRB, but not at the BBB. These functional studies, together with quantitative RT-PCR and confocal imaging, suggest that the mouse BBB lacks uptake1 (Net/Slc6a2, Dat/Slc6a3, Sert/Slc6a4), uptake2, and Mate1 on both the luminal and abluminal sides. However, we found evidence for functional Net and Oct1 transporters at the luminal BRB. These heterogeneous transport properties of the brain and retina NVUs suggest that the BBB helps protect the brain against biogenic amine neurotransmitters in the plasma while the BRB has more of a metabolic/endocrine role.

  10. Improved alternating gradient transport and focusing of neutral molecules

    SciTech Connect

    Kalnins, Juris; Lambertson, Glen; Gould, Harvey

    2001-12-02

    Polar molecules, in strong-field seeking states, can be transported and focused by an alternating sequence of electric field gradients that focus in one transverse direction while defocusing in the other. We show by calculation and numerical simulation, how one may greatly improve the alternating gradient transport and focusing of molecules. We use a new optimized multipole lens design, a FODO lattice beam transport line, and lenses to match the beam transport line to the beam source and the final focus. We derive analytic expressions for the potentials, fields, and gradients that may be used to design these lenses. We describe a simple lens optimization procedure and derive the equations of motion for tracking molecules through a beam transport line. As an example, we model a straight beamline that transports a 560 m/s jet-source beam of methyl fluoride molecules 15 m from its source and focuses it to 2 mm diameter. We calculate the beam transport line acceptance and transmission, for a beam with velocity spread, and estimate the transmitted intensity for specified source conditions. Possible applications are discussed.

  11. Dendritic Release of Neurotransmitters.

    PubMed

    Ludwig, Mike; Apps, David; Menzies, John; Patel, Jyoti C; Rice, Margaret E

    2016-12-06

    Release of neuroactive substances by exocytosis from dendrites is surprisingly widespread and is not confined to a particular class of transmitters: it occurs in multiple brain regions, and includes a range of neuropeptides, classical neurotransmitters, and signaling molecules, such as nitric oxide, carbon monoxide, ATP, and arachidonic acid. This review is focused on hypothalamic neuroendocrine cells that release vasopressin and oxytocin and midbrain neurons that release dopamine. For these two model systems, the stimuli, mechanisms, and physiological functions of dendritic release have been explored in greater detail than is yet available for other neurons and neuroactive substances. © 2017 American Physiological Society. Compr Physiol 7:235-252, 2017.

  12. Neuroactivity of detonation nanodiamonds: dose-dependent changes in transporter-mediated uptake and ambient level of excitatory/inhibitory neurotransmitters in brain nerve terminals.

    PubMed

    Pozdnyakova, Natalia; Pastukhov, Artem; Dudarenko, Marina; Galkin, Maxim; Borysov, Arsenii; Borisova, Tatiana

    2016-03-31

    Nanodiamonds are one of the most perspective nano-sized particles with superb physical and chemical properties, which are mainly composed of carbon sp(3) structures in the core with sp(2) and disorder/defect carbons on the surface. The research team recently demonstrated neuromodulatory properties of carbon nanodots with other than nanodiamonds hybridization types, i.e., sp(2) hybridized graphene islands and diamond-like sp(3) hybridized elements. In this study, neuroactive properties of uncoated nanodiamonds produced by detonation synthesis were assessed basing on their effects on transporter-mediated uptake and the ambient level of excitatory and inhibitory neurotransmitters, glutamate and γ-aminobutyric acid (GABA), in isolated rat brain nerve terminals. It was shown that nanodiamonds in a dose-dependent manner attenuated the initial velocity of Na(+)-dependent transporter-mediated uptake and accumulation of L-[(14)C]glutamate and [(3)H]GABA by nerve terminals and increased the ambient level of these neurotransmitters. Also, nanodiamonds caused a weak reduction in acidification of synaptic vesicles and depolarization of the plasma membrane of nerve terminals. Therefore, despite different types of hybridization in nanodiamonds and carbon dots, they exhibit very similar effects on glutamate and GABA transport in nerve terminals and this common feature of both nanoparticles is presumably associated with their nanoscale size. Observed neuroactive properties of pure nanodiamonds can be used in neurotheranostics for simultaneous labeling/visualization of nerve terminals and modulation of key processes of glutamate- and GABAergic neurotransmission. In comparison with carbon dots, wider medical application involving hypo/hyperthermia, external magnetic fields, and radiolabel techniques can be perspective for nanodiamonds.

  13. Quantitative profiling of neurotransmitter abnormalities in the hippocampus of rats treated with lipopolysaccharide: Focusing on kynurenine pathway and implications for depression.

    PubMed

    Guo, Yujin; Cai, Hualin; Chen, Lei; Liang, Donglou; Yang, Ranyao; Dang, Ruili; Jiang, Pei

    2016-06-15

    Peripheral administration of lipopolysaccharide (LPS) can induce the rodents to a depression-like state accompanied with remarkable changes of neurotransmitter systems. In this study, the effect of an intraperitoneal LPS injection (3mg/kg) on the concentrations of neurotransmitters was investigated by in vivo microdialysis in rat hippocampus. To further explore dysregulation pattern of the neurotransmitters following continuous inflammatory process, we then analyzed the neurotransmitters in the hippocampus of rats after 2-week LPS exposure (500μg/kg every other day). Acute treatment of LPS quickly enhanced glutamate release and increased the extracellular levels of dopamine, serotonin and their metabolites. Elevated glutamate status was also found in the chronic inflamed hippocampus, whereas dopamine and serotonin was decreased following prolonged LPS exposure. Interestingly, both acute and chronic treatment of LPS significantly elevated hippocampal kynurenine concentrations and altered the balance between the serotonin and kynurenine branches of tryptophan metabolism-increasing kynurenine/tryptophan ratio, but decreasing serotonin/tryptophan ratio. Additionally, kynurenic acid, the endogenous NMDA receptor antagonist, and the ratio of kynurenic acid/kynurenine were significantly decreased by acute treatment of LPS, which may further strengthen NMDA receptor activation. Since that NMDA activation can exacerbate inflammatory and neurodegenerative process, the enhanced glutamate release and dysregulated kynurenine pathway might constitute a vicious cycle playing a pivotal role in the neuropsychiatric disorders associated with inflammation, such as depression. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Methionine uptake in Corynebacterium glutamicum by MetQNI and by MetPS, a novel methionine and alanine importer of the NSS neurotransmitter transporter family.

    PubMed

    Trötschel, Christian; Follmann, Martin; Nettekoven, Jeannine A; Mohrbach, Tobias; Forrest, Lucy R; Burkovski, Andreas; Marin, Kay; Krämer, Reinhard

    2008-12-02

    The soil bacterium Corynebacterium glutamicum is a model organism in amino acid biotechnology. Here we present the identification of two different L-methionine uptake systems including the first characterization of a bacterial secondary methionine carrier. The primary carrier MetQNI is a high affinity ABC-type transporter specific for l-methionine. Its expression is under the control of the transcription factor McbR, the global regulator of sulfur metabolism in C. glutamicum. Besides MetQNI, a novel secondary methionine uptake system of the NSS (neurotransmitter:sodium symporter) family was identified and named MetP. The MetP system is characterized by a lower affinity for methionine and uses Na(+) ions for energetic coupling. It is also the main alanine transporter in C. glutamicum and is expressed constitutively. These observations are consistent with models of methionine, alanine, and leucine bound to MetP, derived from the X-ray crystal structure of the LeuT transporter from Aquifex aeolicus. Complementation studies show that MetP consists of two components, a large subunit with 12 predicted transmembrane segments and, surprisingly, an additional subunit with one predicted transmembrane segment only. Thus, this new member of the NSS transporter family adds a novel feature to this class of carriers, namely, the functional dependence on an additional small subunit.

  15. The lipid habitats of neurotransmitter receptors in brain.

    PubMed

    Borroni, María Virginia; Vallés, Ana Sofía; Barrantes, Francisco J

    2016-11-01

    Neurotransmitter receptors, the macromolecules specialized in decoding the chemical signals encrypted in the chemical signaling mechanism in the nervous system, occur either at the somatic cell surface of chemically excitable cells or at specialized subcellular structures, the synapses. Synapses have lipid compositions distinct from the rest of the cell membrane, suggesting that neurotransmitter receptors and their scaffolding and adaptor protein partners require specific lipid habitats for optimal operation. In this review we discuss some paradigmatic cases of neurotransmitter receptor-lipid interactions, highlighting the chemical nature of the intervening lipid species and providing examples of the receptor mechanisms affected by interaction with lipids. The focus is on the effects of cholesterol, glycerophospholipids and covalent fatty acid acylation on neurotransmitter receptors. We also briefly discuss the role of lipid phase states involving lateral heterogeneities of the host membrane known to modulate membrane transport, protein sorting and signaling. Modulation of neurotransmitter receptors by lipids occurs at multiple levels, affecting a wide span of activities including their trafficking, sorting, stability, residence lifetime at the cell surface, endocytosis, and recycling, among other important functional properties at the synapse. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Development of a novel high-throughput assay for the investigation of GlyT-1b neurotransmitter transporter function.

    PubMed

    Allan, Lynda; Leith, J Lianne; Papakosta, Marianthi; Morrow, John A; Irving, Nicholas G; McFerran, Brian W; Clark, Alan G

    2006-01-01

    The glycine transporter (GlyT-1b) is a Na(+)/Cl(-)-dependent electrogenic transporter which mediates the rapid re-uptake of glycine from the synaptic cleft. Based on its tissue distribution, GlyT-1 has been suggested to co-localise with the NMDA receptor where it may modulate the concentration of glycine at its co-agonist binding site. This data has led to GlyT-1 inhibitors being proposed as targets for disorders such as schizophrenia and cognitive dysfunction. Radiolabelled uptake assays (e.g. [(3)H]glycine) have been traditionally used in compound screening to identify glycine transporter inhibitors. While such an assay format is useful for testing limited numbers of compounds, the identification of novel glycine uptake inhibitors requires a functional assay compatible with high-throughput screening (HTS) of large compound libraries. Here, the authors present the development of a novel homogenous cell-based assay using the FLIPR membrane potential blue dye (Molecular Devices) and FLEXstation. Pharmacological data for the GlyT-1 inhibitors Org 24598 and ALX 5407 obtained using this novel electrogenic assay correlated well with the conventional [(3)H]-glycine uptake assay format. Furthermore, the assay has been successfully miniaturised using FLIPR(3) and therefore has the potential to be used for high-throughput screening.

  17. Is Aspartate an Excitatory Neurotransmitter?

    PubMed Central

    Herring, Bruce E.; Silm, Katlin

    2015-01-01

    Recent evidence has resurrected the idea that the amino acid aspartate, a selective NMDA receptor agonist, is a neurotransmitter. Using a mouse that lacks the glutamate-selective vesicular transporter VGLUT1, we find that glutamate alone fully accounts for the activation of NMDA receptors at excitatory synapses in the hippocampus. This excludes a role for aspartate and, by extension, a recently proposed role for the sialic acid transporter sialin in excitatory transmission. SIGNIFICANCE STATEMENT It has been proposed that the amino acid aspartate serves as a neurotransmitter. Although aspartate is a selective agonist for NMDA receptors, we find that glutamate alone fully accounts for neurotransmission at excitatory synapses in the hippocampus, excluding a role for aspartate. PMID:26180193

  18. How did the neurotransmitter cross the bilayer? A closer view.

    PubMed

    Sonders, Mark S; Quick, Matthias; Javitch, Jonathan A

    2005-06-01

    Plasma membrane neurotransmitter transporters for monoamines, GABA, glycine and excitatory amino acids are homologous to two sizable families of bacterial amino acid transporters. Recently, a high resolution structure was determined for a thermophilic glutamate transporter. Also, a bacterial tryptophan transporter related to the family of biogenic amine neurotransmitter transporters was functionally expressed. Structural insights from these and other bacterial transporters will help to rationalize the mechanisms for the increasingly complex functions that have been described for mammalian transporters, in addition to their modes of regulation. We touch on recent insights into the functions of neurotransmitter transporters in their physiological contexts.

  19. Turning off neurotransmitters.

    PubMed

    Snyder, Solomon H

    2006-04-07

    The historic discovery that the catecholamine neurotransmitters of the sympathetic nervous system, norepinephrine and epinephrine, are inactivated through their reuptake by presynaptic nerve terminals provided new insights into neurotransmitter action and paved the way for the development of modern antidepressant drugs.

  20. Effect of prenatal and early life paracetamol exposure on the level of neurotransmitters in rats--Focus on the spinal cord.

    PubMed

    Blecharz-Klin, Kamilla; Joniec-Maciejak, Ilona; Jawna, Katarzyna; Pyrzanowska, Justyna; Piechal, Agnieszka; Wawer, Adriana; Widy-Tyszkiewicz, Ewa

    2015-12-01

    The present study has examined the influence of the prenatal and early life administration of paracetamol on the level of neurotransmitters in the spinal cord of rat pups. The effect of the drug was evaluated in 2-month old Wistar male rats exposed to paracetamol in doses of 5 (P5, n=9) or 15 mg/kg (P15, n=9) p.o. during the prenatal period and after birth until the completion of the second month of life. A parallel control group received tap water (Con, n=9). In this study we have determined the level of monoamines, their metabolites and amino acids in the spinal cord of rats using high performance liquid chromatography (HPLC) in the second month of life. The present experiment demonstrates the action of paracetamol at the molecular level associated with significant modulation of neurotransmission in the spinal cord related to dopaminergic and noradrenergic systems. Simultaneously, paracetamol administration increases the content of an aspartic and glutamic acids in the spinal cord at a critical time during development. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Transverse centroid oscillations in solenoidially focused beam transport lattices

    SciTech Connect

    Lund, Steven M.; Wootton, Christopher J.; Lee, Edward P.

    2008-08-01

    Linear equations of motion are derived that describe small-amplitude centroid oscillations induced by displacement and rotational misalignments of the focusing solenoids in the transport lattice, dipole steering elements, and initial centroid offset errors. These equations are analyzed in a local rotating Larmor frame to derive complex-variable"alignment functions" and"bending functions" that efficiently describe the characteristics of the centroid oscillations induced by mechanical misalignments of the solenoids and dipole steering elements. The alignment and bending functions depend only on properties of the ideal lattice in the absence of errors and steering and have associated expansion amplitudes set by the misalignments and steering fields. Applications of this formulation are presented for statistical analysis of centroid deviations, calculation of actual lattice misalignments from centroid measurements, and optimal beam steering.

  2. Transverse Centroid Oscillations in Solenoidially Focused Beam Transport Lattices

    SciTech Connect

    Lund, S M; Wootton, C J; Lee, E P

    2008-08-01

    Linear equations of motion are derived that describe small-amplitude centroid oscillations induced by displacement and rotational misalignments of the focusing solenoids in the transport lattice, dipole steering elements, and initial centroid offset errors. These equations are analyzed in a local rotating Larmor frame to derive complex-variable 'alignment functions' and 'bending functions' that efficiently describe the characteristics of the centroid oscillations induced by mechanical misalignments of the solenoids and dipole steering elements. The alignment and bending functions depend only on properties of the ideal lattice in the absence of errors and steering and have associated expansion amplitudes set by the misalignments and steering fields. Applications of this formulation are presented for statistical analysis of centroid deviations, calculation of actual lattice misalignments from centroid measurements, and optimal beam steering.

  3. Electrochemical Analysis of Neurotransmitters.

    PubMed

    Bucher, Elizabeth S; Wightman, R Mark

    2015-01-01

    Chemical signaling through the release of neurotransmitters into the extracellular space is the primary means of communication between neurons. More than four decades ago, Ralph Adams and his colleagues realized the utility of electrochemical methods for the study of easily oxidizable neurotransmitters, such as dopamine, norepinephrine, and serotonin and their metabolites. Today, electrochemical techniques are frequently coupled to microelectrodes to enable spatially resolved recordings of rapid neurotransmitter dynamics in a variety of biological preparations spanning from single cells to the intact brain of behaving animals. In this review, we provide a basic overview of the principles underlying constant-potential amperometry and fast-scan cyclic voltammetry, the most commonly employed electrochemical techniques, and the general application of these methods to the study of neurotransmission. We thereafter discuss several recent developments in sensor design and experimental methodology that are challenging the current limitations defining the application of electrochemical methods to neurotransmitter measurements.

  4. Electrochemical Analysis of Neurotransmitters

    PubMed Central

    Bucher, Elizabeth S.; Wightman, R. Mark

    2016-01-01

    Chemical signaling through the release of neurotransmitters into the extracellular space is the primary means of communication between neurons. More than four decades ago, Ralph Adams and his colleagues realized the utility of electrochemical methods for the study of easily oxidizable neurotransmitters, such as dopamine, norepinephrine, and serotonin and their metabolites. Today, electrochemical techniques are frequently coupled to microelectrodes to enable spatially resolved recordings of rapid neurotransmitter dynamics in a variety of biological preparations spanning from single cells to the intact brain of behaving animals. In this review, we provide a basic overview of the principles underlying constant-potential amperometry and fast-scan cyclic voltammetry, the most commonly employed electrochemical techniques, and the general application of these methods to the study of neurotransmission. We thereafter discuss several recent developments in sensor design and experimental methodology that are challenging the current limitations defining the application of electrochemical methods to neurotransmitter measurements. PMID:25939038

  5. Electrochemical Analysis of Neurotransmitters

    NASA Astrophysics Data System (ADS)

    Bucher, Elizabeth S.; Wightman, R. Mark

    2015-07-01

    Chemical signaling through the release of neurotransmitters into the extracellular space is the primary means of communication between neurons. More than four decades ago, Ralph Adams and his colleagues realized the utility of electrochemical methods for the study of easily oxidizable neurotransmitters, such as dopamine, norepinephrine, and serotonin and their metabolites. Today, electrochemical techniques are frequently coupled to microelectrodes to enable spatially resolved recordings of rapid neurotransmitter dynamics in a variety of biological preparations spanning from single cells to the intact brain of behaving animals. In this review, we provide a basic overview of the principles underlying constant-potential amperometry and fast-scan cyclic voltammetry, the most commonly employed electrochemical techniques, and the general application of these methods to the study of neurotransmission. We thereafter discuss several recent developments in sensor design and experimental methodology that are challenging the current limitations defining the application of electrochemical methods to neurotransmitter measurements.

  6. Neurotransmitter transporter family including SLC6A6 and SLC6A13 contributes to the 5-aminolevulinic acid (ALA)-induced accumulation of protoporphyrin IX and photodamage, through uptake of ALA by cancerous cells.

    PubMed

    Tran, Tai Tien; Mu, Anfeng; Adachi, Yuka; Adachi, Yasushi; Taketani, Shigeru

    2014-01-01

    δ-Aminolevulinic acid (ALA)-induced protoporphyrin accumulation is widely used in the treatment of cancer, as photodynamic therapy (PDT). To clarify the mechanisms of ALA uptake by tumor cells, we have examined the ALA-induced accumulation of protoporphyrin by the treatment of colon cancer DLD-1 and epithelial cancer HeLa cells with γ-aminobutyric acid (GABA)-related compounds. When the cells were treated with GABA, taurine and β-alanine, the level of protoporphyrin was decreased, suggesting that plasma membrane transporters involved in the transport of neurotransmitters contribute to the uptake of ALA. By transfection with neurotransmitter transporters SLC6A6, SLC6A8 and SLC6A13 cDNA, the ALA- and ALA methylester-dependent accumulation of protoporphyrin markedly increased in HEK293T cells, dependent on an increase in the uptake of ALA. When ALA-treated cells were exposed to white light, the extent of photodamage increased in SLC6A6- and SLC6A13-expressing cells. Conversely, knockdown of SLC6A6 or SLC6A13 with siRNAs in DLD-1 and HeLa cells decreased the ALA-induced accumulation. The expression of SLC6A6 and SLC6A13 was found in some cancer cell lines. Immunohistochemical studies revealed that the presence of these transporters was elevated in colon cancerous cells. These results indicated that neurotransmitter transporters including SLC6A6 and SLC6A13 mediate the uptake of ALA and can play roles in the enhancement of ALA-induced accumulation of protoporphyrin in cancerous cells.

  7. Plasma Pinch for HIF Final Focus and Transport

    NASA Astrophysics Data System (ADS)

    Vella, M.; Fessenden, T.; Leemans, W.; Ponce, D.; Yu, S.

    1997-11-01

    A laser initiated, double pulse technique is used to create straight, stable Z-pinch channels with electronic timing reproducibility (10 nsec). A KrF laser designates the channel path. After a 20 μsec laser-resistor phase in the 7 T fill gas, a prepulse channel forms by avalanche breakdown. The prepulse channel heats a low density gas region that provides a preferred breakdown path for the high current discharge Z-pinch. After a delay to absorb the timing uncertainty of the prepulse channel, a stable high current Z-pinch is triggered. Earlier experiments(Ref. 1. Tauschwitz, S.S. Yu, S. Eylon, R.O. Bangerter, W. Leemans, C. Peters, J.O. Rasmussen, L. Teginato, J.J. Barnard and W.M. Sharp. Fusion Eng. and Design 32-33 (1996) 493-502.) at LBNL demonstrated narrow, stable 50 kA channels, which is more than enough for Heavy Ion Fusion (HIF) final focus and transport. We present interferometer and Schlieren studies of pinch density and small scale stability. Stable return current paths at 90^o to the high current channel are documented, and the implication for an HIF reactor scenario mentioned.

  8. Solenoidal Fields for Ion Beam Transport and Focusing

    SciTech Connect

    Lee, Edward P.; Leitner, Matthaeus

    2007-11-01

    In this report we calculate time-independent fields of solenoidal magnets that are suitable for ion beam transport and focusing. There are many excellent Electricity and Magnetism textbooks that present the formalism for magnetic field calculations and apply it to simple geometries [1-1], but they do not include enough relevant detail to be used for designing a charged particle transport system. This requires accurate estimates of fringe field aberrations, misaligned and tilted fields, peak fields in wire coils and iron, external fields, and more. Specialized books on magnet design, technology, and numerical computations [1-2] provide such information, and some of that is presented here. The AIP Conference Proceedings of the US Particle Accelerator Schools [1-3] contain extensive discussions of design and technology of magnets for ion beams - except for solenoids. This lack may be due to the fact that solenoids have been used primarily to transport and focus particles of relatively low momenta, e.g. electrons of less than 50 MeV and protons or H- of less than 1.0 MeV, although this situation may be changing with the commercial availability of superconducting solenoids with up to 20T bore field [1-4]. Internal reports from federal laboratories and industry treat solenoid design in detail for specific applications. The present report is intended to be a resource for the design of ion beam drivers for Inertial Fusion Energy [1-5] and Warm Dense Matter experiments [1-6], although it should also be useful for a broader range of applications. The field produced by specified currents and material magnetization can always be evaluated by solving Maxwell's equations numerically, but it is also desirable to have reasonably accurate, simple formulas for conceptual system design and fast-running beam dynamics codes, as well as for general understanding. Most of this report is devoted to such formulas, but an introduction to the Tosca{copyright} code [1-7] and some numerical

  9. Hybrid dopamine uptake blocker-serotonin releaser ligands: a new twist on transporter-focused therapeutics.

    PubMed

    Blough, Bruce E; Landavazo, Antonio; Partilla, John S; Baumann, Michael H; Decker, Ann M; Page, Kevin M; Rothman, Richard B

    2014-06-12

    As part of our program to study neurotransmitter releasers, we report herein a class of hybrid dopamine reuptake inhibitors that display serotonin releasing activity. Hybrid compounds are interesting since they increase the design potential of transporter related compounds and hence represent a novel and unexplored strategy for therapeutic drug discovery. A series of N-alkylpropiophenones was synthesized and assessed for uptake inhibition and release activity using rat brain synaptosomes. Substitution on the aromatic ring yielded compounds that maintained hybrid activity, with the two disubstituted analogues (PAL-787 and PAL-820) having the most potent hybrid activity.

  10. Hybrid Dopamine Uptake Blocker–Serotonin Releaser Ligands: A New Twist on Transporter-Focused Therapeutics

    PubMed Central

    2014-01-01

    As part of our program to study neurotransmitter releasers, we report herein a class of hybrid dopamine reuptake inhibitors that display serotonin releasing activity. Hybrid compounds are interesting since they increase the design potential of transporter related compounds and hence represent a novel and unexplored strategy for therapeutic drug discovery. A series of N-alkylpropiophenones was synthesized and assessed for uptake inhibition and release activity using rat brain synaptosomes. Substitution on the aromatic ring yielded compounds that maintained hybrid activity, with the two disubstituted analogues (PAL-787 and PAL-820) having the most potent hybrid activity. PMID:24944732

  11. Transportation training: Focusing on movement of hazardous substances and wastes

    SciTech Connect

    Jones, E.; Moreland, W.M.

    1988-01-01

    Over the past 25 years extensive federal legislation involving the handling and transport of hazardous materials/waste has been passed that has resulted in numerous overlapping regulations administered and enforced by different federal agencies. The handling and transport of hazardous materials/waste involves a significant number of workers who are subject to a varying degree of risk should an accident occur during handling or transport. Effective transportation training can help workers address these risks and mitigate them, and at the same time enable ORNL to comply with the federal regulations concerning the transport of hazardous materials/waste. This presentation will outline how the Environmental and Health Protection Division's Technical Resources and Training Program at the Oak Ridge National Laboratory, working with transportation and waste disposal personnel, are developing and implementing a comprehensive transportation safety training program to meet the needs of our workers while satisfying appropriate federal regulations. 8 refs., 5 figs., 3 tabs.

  12. Phosphate Import in Plants: Focus on the PHT1 Transporters

    PubMed Central

    Nussaume, Laurent; Kanno, Satomi; Javot, Hélène; Marin, Elena; Pochon, Nathalie; Ayadi, Amal; Nakanishi, Tomoko M.; Thibaud, Marie-Christine

    2011-01-01

    The main source of phosphorus for plants is inorganic phosphate (Pi), which is characterized by its poor availability and low mobility. Uptake of this element from the soil relies heavily upon the PHT1 transporters, a specific family of plant plasma membrane proteins that were identified by homology with the yeast PHO84 Pi transporter. Since the discovery of PHT1 transporters in 1996, various studies have revealed that their function is controlled by a highly complex network of regulation. This review will summarize the current state of research on plant PHT1 multigenic families, including physiological, biochemical, molecular, cellular, and genetics studies. PMID:22645553

  13. Phosphate Import in Plants: Focus on the PHT1 Transporters.

    PubMed

    Nussaume, Laurent; Kanno, Satomi; Javot, Hélène; Marin, Elena; Pochon, Nathalie; Ayadi, Amal; Nakanishi, Tomoko M; Thibaud, Marie-Christine

    2011-01-01

    The main source of phosphorus for plants is inorganic phosphate (Pi), which is characterized by its poor availability and low mobility. Uptake of this element from the soil relies heavily upon the PHT1 transporters, a specific family of plant plasma membrane proteins that were identified by homology with the yeast PHO84 Pi transporter. Since the discovery of PHT1 transporters in 1996, various studies have revealed that their function is controlled by a highly complex network of regulation. This review will summarize the current state of research on plant PHT1 multigenic families, including physiological, biochemical, molecular, cellular, and genetics studies.

  14. Microsphere-chain waveguides: Focusing and transport properties

    SciTech Connect

    Allen, Kenneth W. Astratov, Vasily N.; Darafsheh, Arash; Abolmaali, Farzaneh; Mojaverian, Neda; Limberopoulos, Nicholaos I.; Lupu, Anatole

    2014-07-14

    It is shown that the focusing properties of polystyrene microsphere-chain waveguides (MCWs) formed by sufficiently large spheres (D ≥ 20λ, where D is the sphere diameter and λ is the wavelength of light) scale with the sphere diameter as predicted by geometrical optics. However, this scaling behavior does not hold for mesoscale MCWs with D ≤ 10λ resulting in a periodical focusing with gradually reducing beam waists and in extremely small propagation losses. The observed effects are related to properties of nanojet-induced and periodically focused modes in such structures. The results can be used for developing focusing microprobes, laser scalpels, and polarization filters.

  15. Stereoselectivity of chiral drug transport: a focus on enantiomer-transporter interaction.

    PubMed

    Zhou, Quan; Yu, Lu-Shan; Zeng, Su

    2014-08-01

    Drug transporters and drug metabolism enzymes govern drug absorption, distribution, metabolism and elimination. Many literature works presenting important aspects related to stereochemistry of drug metabolism are available. However, there is very little literature on stereoselectivity of chiral drug transport and enantiomer-transporter interaction. In recent years, the experimental research within this field showed good momentum. Herein, an up-to-date review on this topic was presented. Breast Cancer Resistance Protein (BCRP), Multidrug Resistance Proteins (MRP), P-glycoprotein (P-gp), Organic Anion Transporters (OATs), Organic Anion Transporting Polypeptides (OATPs), Organic Cation Transporters (OCTs), Peptide Transport Proteins (PepTs), Human Proton-Coupled Folate Transporter (PCFT) and Multidrug and Toxic Extrusion Proteins (MATEs), have been reported to exhibit either positive or negative enantio-selective substrate recognition. The approaches utilized to study chirality in enantiomer-transporter interaction include inhibition experiments of specific transporters in cell models (e.g. Caco-2 cells), transport study using drug resistance cell lines or transgenic cell lines expressing transporters in wild type or variant, the use of transporter knockout mice, pharmacokinetics association of single nucleotide polymorphism in transporters, pharmacokinetic interaction study of racemate in the presence of specific transporter inhibitor or inducer, molecule cellular membrane affinity chromatography and pharmacophore modeling. Enantiomer-enantiomer interactions exist in chiral transport. The strength and/or enantiomeric preference of stereoselectivity may be species or tissue-specific, concentration-dependent and transporter family member-dependent. Modulation of specific drug transporter by pure enantiomers might exhibit opposite stereoselectivity. Further studies with integrated approaches will open up new horizons in stereochemistry of pharmacokinetics.

  16. Injury and fatality risks in aeromedical transport: focus on prevention.

    PubMed

    Hon, Heidi H; Wojda, Thomas R; Barry, Noran; MacBean, Ulunna; Anagnostakos, John P; Evans, David C; Thomas, Peter G; Stawicki, Stanislaw P

    2016-08-01

    Aeromedical transport (AMT) is a reliable and well-established life-saving option for rapid patient transfers to health care delivery hubs. However, owing to the very nature of AMT, fatal and nonfatal events may occur. This study reviews aeromedical incidents reported since the publication of the last definitive review in 2003, aiming to provide additional insight into a wide range of factors potentially associated with fatal and nonfatal AMT incidents (AMTIs). We hypothesized that weather and/or visual conditions, postcrash fire, aircraft make and/or type, and time of day all correlate with the risk of AMTI with injury or fatality. Specialty databases were queried for AMTI between January 1, 2003 and July 31, 2015. Additional Internet-based resources were also used to find any additional AMTI (including non-US occurrences) to augment the event sample size available for analysis. Univariate analyses of the collected sample were then performed for association between "fatal crash or injury" (FCOI) and weather/visual conditions, aircraft type and/or make, pilot error, equipment failure, post-incident fire, time of day (6 am-7 pm versus 7 pm-6 am), weekend (Friday-Sunday) versus weekday (Monday-Thursday), season of the year, and presence of patient on board. Variables reaching significance level of P < 0.20 were included in multivariate analysis. A total of 59 AMTIs were identified. Helicopters were involved in 52 of 59 AMTIs, with 7 of 59 fixed-wing incidents. Comparing pre-2003 data with post-2003 data, we noted a significant decrease in AMTIs per month (0.70 versus 0.39, respectively, P = 0.048), whereas the number of fatalities per year increased slightly (7.20 versus 8.26, p = n/s). In univariate analyses, abnormal weather conditions, impaired visibility, time of incident (7 pm-6 am), aircraft model/make, and post-incident fire all reached statistical significance sufficient for inclusion in multivariate analysis (P < 0.20). Factors independently

  17. Stable two-plane focusing for emittance-dominated sheet-beam transport

    NASA Astrophysics Data System (ADS)

    Carlsten, B. E.; Earley, L. M.; Krawczyk, F. L.; Russell, S. J.; Potter, J. M.; Ferguson, P.; Humphries, S.

    2005-06-01

    Two-plane focusing of sheet electron beams will be an essential technology for an emerging class of high-power, 100 to 300 GHz rf sources [Carlsten et al., IEEE Trans. Plasma Sci. 33, 85 (2005), ITPSBD, 0093-3813, 10.1109/TPS.2004.841172]. In these devices, the beam has a unique asymmetry in which the transport is emittance dominated in the sheet’s thin dimension and space-charge dominated in the sheet’s wide dimension. Previous work has studied the stability of the transport of beams in the emittance-dominated regime for both wiggler and periodic permanent magnet (PPM) configurations with single-plane focusing, and has found that bigger envelope scalloping occurs for equilibrium transport, as compared to space-charge dominated beams [Carlsten et al., this issue, Phys. Rev. ST Accel. Beams 8, 062001 (2005), PRABFM, 1098-4402]. In this paper, we describe the differences in transport stability when two-plane focusing is included. Two-plane wiggler focusing degrades the transport stability slightly, whereas two-plane PPM focusing greatly compromises the transport. On the other hand, single-plane PPM focusing can be augmented with external quadrupole fields to provide weak focusing in the sheet’s wide dimension, which has stability comparable to two-plane wiggler transport.

  18. Neurotransmitters of the suprachiasmatic nuclei

    PubMed Central

    Reghunandanan, Vallath; Reghunandanan, Rajalaxmy

    2006-01-01

    There has been extensive research in the recent past looking into the molecular basis and mechanisms of the biological clock, situated in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. Neurotransmitters are a very important component of SCN function. Thorough knowledge of neurotransmitters is not only essential for the understanding of the clock but also for the successful manipulation of the clock with experimental chemicals and therapeutical drugs. This article reviews the current knowledge about neurotransmitters in the SCN, including neurotransmitters that have been identified only recently. An attempt was made to describe the neurotransmitters and hormonal/diffusible signals of the SCN efference, which are necessary for the master clock to exert its overt function. The expression of robust circadian rhythms depends on the integrity of the biological clock and on the integration of thousands of individual cellular clocks found in the clock. Neurotransmitters are required at all levels, at the input, in the clock itself, and in its efferent output for the normal function of the clock. The relationship between neurotransmitter function and gene expression is also discussed because clock gene transcription forms the molecular basis of the clock and its working. PMID:16480518

  19. Challenges and recent advances in mass spectrometric imaging of neurotransmitters

    PubMed Central

    Gemperline, Erin; Chen, Bingming; Li, Lingjun

    2014-01-01

    Mass spectrometric imaging (MSI) is a powerful tool that grants the ability to investigate a broad mass range of molecules, from small molecules to large proteins, by creating detailed distribution maps of selected compounds. To date, MSI has demonstrated its versatility in the study of neurotransmitters and neuropeptides of different classes toward investigation of neurobiological functions and diseases. These studies have provided significant insight in neurobiology over the years and current technical advances are facilitating further improvements in this field. neurotransmitters, focusing specifically on the challenges and recent Herein, we advances of MSI of neurotransmitters. PMID:24568355

  20. Increased oxidative metabolism and neurotransmitter cycling in the brain of mice lacking the thyroid hormone transporter SLC16A2 (MCT8).

    PubMed

    Rodrigues, Tiago B; Ceballos, Ainhoa; Grijota-Martínez, Carmen; Nuñez, Barbara; Refetoff, Samuel; Cerdán, Sebastian; Morte, Beatriz; Bernal, Juan

    2013-01-01

    Mutations of the monocarboxylate transporter 8 (MCT8) cause a severe X-linked intellectual deficit and neurological impairment. MCT8 is a specific thyroid hormone (T4 and T3) transporter and the patients also present unusual abnormalities in the serum profile of thyroid hormone concentrations due to altered secretion and metabolism of T4 and T3. Given the role of thyroid hormones in brain development, it is thought that the neurological impairment is due to restricted transport of thyroid hormones to the target neurons. In this work we have investigated cerebral metabolism in mice with Mct8 deficiency. Adult male mice were infused for 30 minutes with (1-(13)C) glucose and brain extracts prepared and analyzed by (13)C nuclear magnetic resonance spectroscopy. Genetic inactivation of Mct8 resulted in increased oxidative metabolism as reflected by increased glutamate C4 enrichment, and of glutamatergic and GABAergic neurotransmissions as observed by the increases in glutamine C4 and GABA C2 enrichments, respectively. These changes were distinct to those produced by hypothyroidism or hyperthyroidism. Similar increments in glutamate C4 enrichment and GABAergic neurotransmission were observed in the combined inactivation of Mct8 and D2, indicating that the increased neurotransmission and metabolic activity were not due to increased production of cerebral T3 by the D2-encoded type 2 deiodinase. In conclusion, Mct8 deficiency has important metabolic consequences in the brain that could not be correlated with deficiency or excess of thyroid hormone supply to the brain during adulthood.

  1. Mechanism of chloride interaction with neurotransmitter:sodium symporters.

    PubMed

    Zomot, Elia; Bendahan, Annie; Quick, Matthias; Zhao, Yongfang; Javitch, Jonathan A; Kanner, Baruch I

    2007-10-11

    Neurotransmitter:sodium symporters (NSS) have a critical role in regulating neurotransmission and are targets for psychostimulants, anti-depressants and other drugs. Whereas the non-homologous glutamate transporters mediate chloride conductance, in the eukaryotic NSS chloride is transported together with the neurotransmitter. In contrast, transport by the bacterial NSS family members LeuT, Tyt1 and TnaT is chloride independent. The crystal structure of LeuT reveals an occluded binding pocket containing leucine and two sodium ions, and is highly relevant for the neurotransmitter transporters. However, the precise role of chloride in neurotransmitter transport and the location of its binding site remain elusive. Here we show that introduction of a negatively charged amino acid at or near one of the two putative sodium-binding sites of the GABA (gamma-aminobutyric acid) transporter GAT-1 from rat brain (also called SLC6A1) renders both net flux and exchange of GABA largely chloride independent. In contrast to wild-type GAT-1, a marked stimulation of the rate of net flux, but not of exchange, was observed when the internal pH was lowered. Equivalent mutations introduced in the mouse GABA transporter GAT4 (SLC6A11) and the human dopamine transporter DAT (SLC6A3) also result in chloride-independent transport, whereas the reciprocal mutations in LeuT and Tyt1 render substrate binding and/or uptake by these bacterial NSS chloride dependent. Our data indicate that the negative charge, provided either by chloride or by the transporter itself, is required during binding and translocation of the neurotransmitter, probably to counterbalance the charge of the co-transported sodium ions.

  2. Increased Oxidative Metabolism and Neurotransmitter Cycling in the Brain of Mice Lacking the Thyroid Hormone Transporter Slc16a2 (Mct8)

    PubMed Central

    Rodrigues, Tiago B.; Ceballos, Ainhoa; Grijota-Martínez, Carmen; Nuñez, Barbara; Refetoff, Samuel; Cerdán, Sebastian; Morte, Beatriz; Bernal, Juan

    2013-01-01

    Mutations of the monocarboxylate transporter 8 (MCT8) cause a severe X-linked intellectual deficit and neurological impairment. MCT8 is a specific thyroid hormone (T4 and T3) transporter and the patients also present unusual abnormalities in the serum profile of thyroid hormone concentrations due to altered secretion and metabolism of T4 and T3. Given the role of thyroid hormones in brain development, it is thought that the neurological impairment is due to restricted transport of thyroid hormones to the target neurons. In this work we have investigated cerebral metabolism in mice with Mct8 deficiency. Adult male mice were infused for 30 minutes with (1-13C) glucose and brain extracts prepared and analyzed by 13C nuclear magnetic resonance spectroscopy. Genetic inactivation of Mct8 resulted in increased oxidative metabolism as reflected by increased glutamate C4 enrichment, and of glutamatergic and GABAergic neurotransmissions as observed by the increases in glutamine C4 and GABA C2 enrichments, respectively. These changes were distinct to those produced by hypothyroidism or hyperthyroidism. Similar increments in glutamate C4 enrichment and GABAergic neurotransmission were observed in the combined inactivation of Mct8 and D2, indicating that the increased neurotransmission and metabolic activity were not due to increased production of cerebral T3 by the D2-encoded type 2 deiodinase. In conclusion, Mct8 deficiency has important metabolic consequences in the brain that could not be correlated with deficiency or excess of thyroid hormone supply to the brain during adulthood. PMID:24098341

  3. Focused transport of energetic particles along magnetic field lines draped around a coronal mass ejection

    NASA Technical Reports Server (NTRS)

    Tan, L. C.; Mason, G. M.; Lee, M. A.; Klecker, B.; Ipavich, F. M.

    1992-01-01

    Evidence is presented for focused transport of energetic particles along magnetic field lines draped around a coronal mass ejection. This evidence was obtained with the University of Maryland/Max-Planck-Institute experiment on the ISEE-3 spacecraft during the decay phase of the June 6, 1979, solar particle event. During the early portion of the decay phase of this event, interplanetary magnetic field lines were apparently draped around a coronal mass ejection, leading to a small focusing length on the western flank where ISEE 3 was located. A period of very slow decrease of particle intensity was observed, along with large sunward anisotropy in the solar wind frame, which is inconsistent with predictions of the standard Fokker-Planck equation models for diffusive transport. It was found possible to fit the observations, assuming that focused transport dominates and that the particle pitch angle scattering is isotropic.

  4. Electrochemical nanoprobes for the chemical detection of neurotransmitters

    PubMed Central

    Colombo, Michelle L.

    2015-01-01

    Neurotransmitters, acting as chemical messengers, play an important role in neurotransmission, which governs many functional aspects of nervous system activity. Electrochemical probes have proven a very useful technique to study neurotransmission, especially to quantify and qualify neurotransmitters. With the emerging interests in probing neurotransmission at the level of single cells, single vesicles, as well as single synapses, probes that enable detection of neurotransmitters at the nanometer scale become vitally important. Electrochemical nanoprobes have been successfully employed in nanometer spatial resolution imaging of single nanopores of Si membrane and single Au nanoparticles, providing both topographical and chemical information, thus holding great promise for nanometer spatial study of neurotransmission. Here we present the current state of electrochemical nanoprobes for chemical detection of neurotransmitters, focusing on two types of nanoelectrodes, i.e. carbon nanoelectrode and nano-ITIES pipet electrode. PMID:26327927

  5. Heptanoate as a neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-deficient (G1D) brain

    PubMed Central

    Marin-Valencia, Isaac; Good, Levi B; Ma, Qian; Malloy, Craig R; Pascual, Juan M

    2013-01-01

    It has been postulated that triheptanoin can ameliorate seizures by supplying the tricarboxylic acid cycle with both acetyl-CoA for energy production and propionyl-CoA to replenish cycle intermediates. These potential effects may also be important in other disorders associated with impaired glucose metabolism because glucose supplies, in addition to acetyl-CoA, pyruvate, which fulfills biosynthetic demands via carboxylation. In patients with glucose transporter type I deficiency (G1D), ketogenic diet fat (a source only of acetyl-CoA) reduces seizures, but other symptoms persist, providing the motivation for studying heptanoate metabolism. In this work, metabolism of infused [5,6,7-13C3]heptanoate was examined in the normal mouse brain and in G1D by 13C-nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS). In both groups, plasma glucose was enriched in 13C, confirming gluconeogenesis from heptanoate. Acetyl-CoA and glutamine levels became significantly higher in the brain of G1D mice relative to normal mice. In addition, brain glutamine concentration and 13C enrichment were also greater when compared with glutamate in both animal groups, suggesting that heptanoate and/or C5 ketones are primarily metabolized by glia. These results enlighten the mechanism of heptanoate metabolism in the normal and glucose-deficient brain and encourage further studies to elucidate its potential antiepileptic effects in disorders of energy metabolism. PMID:23072752

  6. Role of perisynaptic parameters in neurotransmitter homeostasis--computational study of a general synapse.

    PubMed

    Pendyam, Sandeep; Mohan, Ashwin; Kalivas, Peter W; Nair, Satish S

    2012-07-01

    Extracellular neurotransmitter concentrations vary over a wide range depending on the type of neurotransmitter and location in the brain. Neurotransmitter homeostasis near a synapse is achieved by a balance of several mechanisms including vesicular release from the presynapse, diffusion, uptake by transporters, nonsynaptic production, and regulation of release by autoreceptors. These mechanisms are also affected by the glia surrounding the synapse. However, the role of these mechanisms in achieving neurotransmitter homeostasis is not well understood. A biophysical modeling framework was proposed, based on a cortico-accumbens synapse example case, to reverse engineer glial configurations and parameters related to homeostasis for synapses that support a range of neurotransmitter gradients. Model experiments reveal that synapses with extracellular neurotransmitter concentrations in the micromolar range require nonsynaptic neurotransmitter sources and tight synaptic isolation by extracellular glial formations. The model was used to identify the role of perisynaptic parameters on neurotransmitter homeostasis and to propose glial configurations that could support different levels of extracellular neurotransmitter concentrations. Ranking the parameters based on their effect on neurotransmitter homeostasis, nonsynaptic sources were found to be the most important followed by transporter concentration and diffusion coefficient. Copyright © 2012 Wiley Periodicals, Inc.

  7. Emittance growth of an nonequilibrium intense electron beam in a transport channel with discrete focusing

    SciTech Connect

    Carlsten, B.E.

    1997-02-01

    The author analyzes the emittance growth mechanisms for a continuous, intense electron beam in a focusing transport channel, over distances short enough that the beam does not reach equilibrium. The emittance grows from the effect of nonlinear forces arising from (1) current density nonuniformities, (2) energy variations leading to nonlinearities in the space-charge force even if the current density is uniform, (3) axial variations in the radial vector potential, (4) an axial velocity shear along the beam, and (5) an energy redistribution of the beam as the beam compresses or expands. The emittance growth is studied analytically and numerically for the cases of balanced flow, tight focusing, and slight beam scalloping, and is additionally studied numerically for an existing 6-MeV induction linear accelerator. Rules for minimizing the emittance along a beamline are established. Some emittance growth will always occur, both from current density nonuniformities that arise along the transport and from beam radius changes along the transport.

  8. Complications during intrahospital transport of critically ill patients: Focus on risk identification and prevention

    PubMed Central

    Knight, Patrick H; Maheshwari, Neelabh; Hussain, Jafar; Scholl, Michael; Hughes, Michael; Papadimos, Thomas J; Guo, Weidun Alan; Cipolla, James; Stawicki, Stanislaw P; Latchana, Nicholas

    2015-01-01

    Intrahospital transportation of critically ill patients is associated with significant complications. In order to reduce overall risk to the patient, such transports should well organized, efficient, and accompanied by the proper monitoring, equipment, and personnel. Protocols and guidelines for patient transfers should be utilized universally across all healthcare facilities. Care delivered during transport and at the site of diagnostic testing or procedure should be equivalent to the level of care provided in the originating environment. Here we review the most common problems encountered during transport in the hospital setting, including various associated adverse outcomes. Our objective is to make medical practitioners, nurses, and ancillary health care personnel more aware of the potential for various complications that may occur during patient movement from the intensive care unit to other locations within a healthcare facility, focusing on risk reduction and preventive strategies. PMID:26807395

  9. Electrokinetically-driven transport of DNA through focused ion beam milled nanofluidic channels.

    PubMed

    Menard, Laurent D; Ramsey, J Michael

    2013-01-15

    The electrophoretically driven transport of double-stranded λ-phage DNA through focused ion beam (FIB) milled nanochannels is described. Nanochannels were fabricated having critical dimensions (width and depth) corresponding to 0.5×, 1×, and 2× the DNA persistence length, or 25 nm, 50 nm, and 100 nm, respectively. The threshold field strength required to drive transport, the threading mobility, and the transport mobility were measured as a function of nanochannel size. As the nanochannel dimensions decreased, the entropic barrier to translocation increased and transport became more constrained. Equilibrium models of confinement provide a framework in which to understand the observed trends, although the dynamic nature of the experiments resulted in significant deviations from theory. It was also demonstrated that the use of dynamic wall coatings for the purpose of electroosmotic flow suppression can have a significant impact on transport dynamics that may obfuscate entropic contributions. The nonintermittent DNA transport through the FIB milled nanochannels demonstrates that they are well suited for use in nanofluidic devices. We expect that an understanding of the dynamic transport properties reported here will facilitate the incorporation of FIB-milled nanochannels in devices for single molecule and ensemble analyses.

  10. Neurotransmitters: The Critical Modulators Regulating Gut-Brain Axis.

    PubMed

    Mittal, Rahul; Debs, Luca H; Patel, Amit P; Nguyen, Desiree; Patel, Kunal; O'Connor, Gregory; Grati, M'hamed; Mittal, Jeenu; Yan, Denise; Eshraghi, Adrien A; Deo, Sapna K; Daunert, Sylvia; Liu, Xue Zhong

    2017-09-01

    Neurotransmitters, including catecholamines and serotonin, play a crucial role in maintaining homeostasis in the human body. Studies on these neurotransmitters mainly revolved around their role in the "fight or flight" response, transmitting signals across a chemical synapse and modulating blood flow throughout the body. However, recent research has demonstrated that neurotransmitters can play a significant role in the gastrointestinal (GI) physiology. Norepinephrine (NE), epinephrine (E), dopamine (DA), and serotonin have recently been a topic of interest because of their roles in the gut physiology and their potential roles in GI and central nervous system pathophysiology. These neurotransmitters are able to regulate and control not only blood flow, but also affect gut motility, nutrient absorption, GI innate immune system, and the microbiome. Furthermore, in pathological states, such as inflammatory bowel disease (IBD) and Parkinson's disease, the levels of these neurotransmitters are dysregulated, therefore causing a variety of GI symptoms. Research in this field has shown that exogenous manipulation of catecholamine serum concentrations can help in decreasing symptomology and/or disease progression. In this review article, we discuss the current state-of-the-art research and literature regarding the role of neurotransmitters in regulation of normal GI physiology, their impact on several disease processes, and novel work focused on the use of exogenous hormones and/or psychotropic medications to improve disease symptomology. J. Cell. Physiol. 232: 2359-2372, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. Dynamic neurotransmitter interactions measured with PET

    SciTech Connect

    Schiffer, W.K.; Dewey, S.L.

    2001-04-02

    Positron emission tomography (PET) has become a valuable interdisciplinary tool for understanding physiological, biochemical and pharmacological functions at a molecular level in living humans, whether in a healthy or diseased state. The utility of tracing chemical activity through the body transcends the fields of cardiology, oncology, neurology and psychiatry. In this, PET techniques span radiochemistry and radiopharmaceutical development to instrumentation, image analysis, anatomy and modeling. PET has made substantial contributions in each of these fields by providing a,venue for mapping dynamic functions of healthy and unhealthy human anatomy. As diverse as the disciplines it bridges, PET has provided insight into an equally significant variety of psychiatric disorders. Using the unique quantitative ability of PET, researchers are now better able to non-invasively characterize normally occurring neurotransmitter interactions in the brain. With the knowledge that these interactions provide the fundamental basis for brain response, many investigators have recently focused their efforts on an examination of the communication between these chemicals in both healthy volunteers and individuals suffering from diseases classically defined as neurotransmitter specific in nature. In addition, PET can measure the biochemical dynamics of acute and sustained drug abuse. Thus, PET studies of neurotransmitter interactions enable investigators to describe a multitude of specific functional interactions in the human brain. This information can then be applied to understanding side effects that occur in response to acute and chronic drug therapy, and to designing new drugs that target multiple systems as opposed to single receptor types. Knowledge derived from PET studies can be applied to drug discovery, research and development (for review, see (Fowler et al., 1999) and (Burns et al., 1999)). Here, we will cover the most substantial contributions of PET to understanding

  12. Making a semi-convex Focus area in a Focus+Glue+Context map, considering map visibility and transport access points

    NASA Astrophysics Data System (ADS)

    Hirako, Y.; Yamamoto, D.; Takahashi, N.

    2016-04-01

    We previously implemented the Focus+Glue+Context map system EMMA that provides local detailed data in Focus, global context data in Context, and connection data between both in the same view. Introducing the Glue area between Focus and Context makes it possible to provide uniform scaling for the two latter areas. This paper enhances EMMA through the implementation of a Focus creation function that considers transportation access points, such as stations and bus stops. The enhanced EMMA searches a route from the current location to the transportation access point, and allows users to identify the spatial relationship between the various locations in a small-scale Context, and view the route from the current location to the transportation access points in a large-scale Focus. However, if Focus is too large because of unnecessary areas used to identify the route, some parts of Context might be hidden by Focus. The proposed system solves this problem by implementing the following functions: (1) it searches stations that are adjacent to the current location and makes a semiconvex Focus that includes the current location and those stations in order for Focus to include really necessary areas. (2) It reduces Focus distortion by setting a fixed point as the center of the Focus area. (3) It smoothens the Focus shape in order to improve visibility in the Glue area. We developed a prototype of the proposed system that implements these functions.

  13. Nanojunctions in conducting polypyrrole single nanowire made by focused electron beam: Charge transport characteristics

    SciTech Connect

    Koo, Min Ho; Hong, Young Ki; Park, Dong Hyuk; Jo, Seong Gi; Joo, Jinsoo

    2011-07-15

    A focused electron (E)-beam with various doses was irradiated on the intended positions of conducting polypyrrole (PPy) single nanowire (NW) to fabricate nanojunctions. The current-voltage characteristics and their temperature dependence of the PPy single NW with nanojunctions were measured and analyzed. By increasing the E-beam dose and the number of nanojunctions, the current level of the single NW was dramatically decreased, and the conductance gap became more severe as the temperature decreased. The charge transport behavior varied from three-dimensional variable range hopping to fluctuation induced tunneling models, depending on the dose of focused E-beam. From micro-Raman spectra, the focused E-beam irradiation induced the de-doped states and conformational modification of polymer chains in the nanojunctions. The results suggest that the nanojunctions made by focused E-beam acted as a quasi-potential barrier for charge conduction in the conducting PPy single NW.

  14. Immunophilin regulation of neurotransmitter release.

    PubMed Central

    Steiner, J. P.; Dawson, T. M.; Fotuhi, M.; Snyder, S. H.

    1996-01-01

    BACKGROUND: The immunophilins are proteins that mediate actions of immunosuppressant drugs such as FK506 and cyclosporin A by binding to calcineurin, inhibiting its phosphatase activity, and increasing the phosphorylation level of transcription factors required for interleukin 2 formation. Though concentrations in the brain greatly exceed levels in immune tissues, no function has been previously established for nervous system immunophilins. Nitric oxide (NO) has been implicated in neurotransmitter release. FK506 appears to inhibit NO production by maintaining NO synthase in a highly phosphorylated and thereby inactivated state. Accordingly, we examined effects of FK506 and cyclosporin A on neurotransmitter release in PC12 cells treated with nerve growth factor (NGF) and in rat brain striatal synaptosomes. MATERIALS AND METHODS: We monitored effects of immunophilin ligands on [3H]-neurotransmitter release from PC12 cells differentiated with NGF. Rat brain striatal synaptosomes were loaded with radiolabeled transmitters and treated with FK506 or cyclosporin A prior to initiating neurotransmitter release with N-methyl-D-aspartate (NMDA) or potassium depolarization. Striatal synaptosomes were also loaded with 32P-orthophosphate and treated with FK506. 32P-labeled synaptic vesicle proteins were isolated from these synaptosomes in an attempt to relate specific FK506-dependent phosphorylation of vesicle proteins with the effects of FK506 on neurotransmitter release. Identification of proteins targetted by FK506 was made by immunoblot analysis and immunoprecipitation. RESULTS: Low nanomolar concentrations of the immunosuppressant drugs FK506 and cyclosporin A (CsA) inhibit transmitter release from PC-12 cells and from NMDA-stimulated brain synaptosomes. By contrast, the immunosuppressants augment depolarization-induced transmitter release from synaptosomes. Synapsin I, a synaptic vesicle phosphoprotein, displays enhanced phosphorylation in the presence of FK506

  15. Ion fluxes and neurotransmitters signaling in neural development.

    PubMed

    Andäng, Michael; Lendahl, Urban

    2008-06-01

    The brain develops and functions in a complex ionic milieu, which is a prerequisite for neurotransmitter function and neuronal signaling. Neurotransmitters and ion fluxes are, however, important not only in neuronal signaling, but also in the control of neural differentiation, and in this review, we highlight the recent advances in our understanding of how the gamma-amino butyric acid (GABA) neurotransmitter and ion fluxes are relevant for cell cycle control and neural differentiation. Conversely, proteins previously associated with ion transport across membranes have been endowed with novel ion-independent functions, and we discuss this in the context of gap junctions in cell adhesion and of the neuron-specific K(+)-Cl(-) cotransporter KCC2 in dendritic spine development. Collectively, these findings provide a richer and more complex picture of when ion fluxes are needed in neural development and when they are not.

  16. Time-coded neurotransmitter release at excitatory and inhibitory synapses

    PubMed Central

    Rodrigues, Serafim; Desroches, Mathieu; Krupa, Martin; Cortes, Jesus M.; Sejnowski, Terrence J.; Ali, Afia B.

    2016-01-01

    Communication between neurons at chemical synapses is regulated by hundreds of different proteins that control the release of neurotransmitter that is packaged in vesicles, transported to an active zone, and released when an input spike occurs. Neurotransmitter can also be released asynchronously, that is, after a delay following the spike, or spontaneously in the absence of a stimulus. The mechanisms underlying asynchronous and spontaneous neurotransmitter release remain elusive. Here, we describe a model of the exocytotic cycle of vesicles at excitatory and inhibitory synapses that accounts for all modes of vesicle release as well as short-term synaptic plasticity (STSP). For asynchronous release, the model predicts a delayed inertial protein unbinding associated with the SNARE complex assembly immediately after vesicle priming. Experiments are proposed to test the model’s molecular predictions for differential exocytosis. The simplicity of the model will also facilitate large-scale simulations of neural circuits. PMID:26858411

  17. Neurotransmitters in the vestibular system.

    PubMed

    Balaban, C D

    2016-01-01

    Neuronal networks that are linked to the peripheral vestibular system contribute to gravitoinertial sensation, balance control, eye movement control, and autonomic function. Ascending connections to the limbic system and cerebral cortex are also important for motion perception and threat recognition, and play a role in comorbid balance and anxiety disorders. The vestibular system also shows remarkable plasticity, termed vestibular compensation. Activity in these networks is regulated by an interaction between: (1) intrinsic neurotransmitters of the inner ear, vestibular nerve, and vestibular nuclei; (2) neurotransmitters associated with thalamocortical and limbic pathways that receive projections originating in the vestibular nuclei; and (3) locus coeruleus and raphe (serotonergic and nonserotonergic) projections that influence the latter components. Because the ascending vestibular interoceptive and thalamocortical pathways include networks that influence a broad range of stress responses (endocrine and autonomic), memory consolidation, and cognitive functions, common transmitter substrates provide a basis for understanding features of acute and chronic vestibular disorders.

  18. Energy transport in plasmas produced by a high brightness krypton fluoride laser focused to a line

    NASA Astrophysics Data System (ADS)

    Al-Hadithi, Y.; Tallents, G. J.; Zhang, J.; Key, M. H.; Norreys, P. A.; Kodama, R.

    1994-05-01

    A high brightness krypton fluoride Raman laser (wavelength 0.268 μm) generating 0.3 TW, 12 ps pulses with 20 μrad beam divergence and a prepulse of less than 10-10 has been focused to produce a 10 μm wide line focus (irradiances ˜0.8-4×1015 W cm-2) on plastic targets with a diagnostic sodium fluoride (NaF) layer buried within the target. Axial and lateral transport of energy has been measured by analysis of x-ray images of the line focus and from x-ray spectra emitted by the layer of NaF with varying overlay thicknesses. It is shown that the ratio of the distance between the critical density surface and the ablation surface to the laser focal width controls lateral transport in a similar manner as for previous spot focus experiments. The measured axial energy transport is compared to medusa [J. P. Christiansen, D. E. T. F. Ashby, and K. V. Roberts, Comput. Phys. Commun. 7, 271 (1974)] one-dimensional hydrodynamic code simulations with an average atom post-processor for predicting spectral line intensities. An energy absorption of ˜10% in the code gives agreement with the experimental axial penetration. Various measured line ratios of hydrogen- and helium-like Na and F are investigated as temperature diagnostics in the NaF layer using the ration [R. W. Lee, B. L. Whitten, and R. E. Strout, J. Quant. Spectrosc. Radiat. Transfer 32, 91 (1984)] code.

  19. Energy transport in plasmas produced by a high brightness krypton fluoride laser focused to a line

    SciTech Connect

    Al-Hadithi, Y.; Tallents, G.J. ); Zhang, J. ); Key, M.H.; Norreys, P.A.; Kodama, R. )

    1994-05-01

    A high brightness krypton fluoride Raman laser (wavelength 0.268 [mu]m) generating 0.3 TW, 12 ps pulses with 20 [mu]rad beam divergence and a prepulse of less than 10[sup [minus]10] has been focused to produce a 10 [mu]m wide line focus (irradiances [similar to]0.8--4[times]10[sup 15] W cm[sup [minus]2]) on plastic targets with a diagnostic sodium fluoride (NaF) layer buried within the target. Axial and lateral transport of energy has been measured by analysis of x-ray images of the line focus and from x-ray spectra emitted by the layer of NaF with varying overlay thicknesses. It is shown that the ratio of the distance between the critical density surface and the ablation surface to the laser focal width controls lateral transport in a similar manner as for previous spot focus experiments. The measured axial energy transport is compared to MEDUSA [J. P. Christiansen, D. E. T. F. Ashby, and K. V. Roberts, Comput. Phys. Commun. [bold 7], 271 (1974)] one-dimensional hydrodynamic code simulations with an average atom post-processor for predicting spectral line intensities. An energy absorption of [similar to]10% in the code gives agreement with the experimental axial penetration. Various measured line ratios of hydrogen- and helium-like Na and F are investigated as temperature diagnostics in the NaF layer using the RATION [R. W. Lee, B. L. Whitten, and R. E. Strout, J. Quant. Spectrosc. Radiat. Transfer [bold 32], 91 (1984)] code.

  20. Interactions between Transporters and Herbal Medicines/Drugs: A Focus on Hepatoprotective Compounds.

    PubMed

    Zhang, Aijie; Li, Quansheng; He, Xin; Si, Duanyun; Liu, Changxiao

    2015-01-01

    Many herbal medicines and drugs are available in the clinic as potent hepatoprotective agents for the treatment of commonly occurring liver diseases. Recently, herbal medicines such as silymarin and curcumin have gained more attention and popularity for the treatment of various liver diseases because of their safety and efficacy profiles. Some of them are related to transporters for drug disposition processes, therapeutic efficacy and/or adverse drug reactions. Currently, herbal medicines and diet supplements made from natural products are widely used in patients who are being treated with conventional prescription medicines, which are related to an increasing risk of herbal-drug interactions (HDIs) and/or drug-drug interactions (DDIs). The purpose of present review is to summarize the contemporary knowledge of transporter-mediated HDIs or DDIs for herbal medicines/drugs focusing on hepatoprotective compounds. Several herbal medicines/drugs are discussed in detail in this review.

  1. Heat guiding and focusing using ballistic phonon transport in phononic nanostructures

    PubMed Central

    Anufriev, Roman; Ramiere, Aymeric; Maire, Jeremie; Nomura, Masahiro

    2017-01-01

    Unlike classical heat diffusion at macroscale, nanoscale heat conduction can occur without energy dissipation because phonons can ballistically travel in straight lines for hundreds of nanometres. Nevertheless, despite recent experimental evidence of such ballistic phonon transport, control over its directionality, and thus its practical use, remains a challenge, as the directions of individual phonons are chaotic. Here, we show a method to control the directionality of ballistic phonon transport using silicon membranes with arrays of holes. First, we demonstrate that the arrays of holes form fluxes of phonons oriented in the same direction. Next, we use these nanostructures as directional sources of ballistic phonons and couple the emitted phonons into nanowires. Finally, we introduce thermal lens nanostructures, in which the emitted phonons converge at the focal point, thus focusing heat into a spot of a few hundred nanometres. These results motivate the concept of ray-like heat manipulations at the nanoscale. PMID:28516909

  2. Heat guiding and focusing using ballistic phonon transport in phononic nanostructures

    NASA Astrophysics Data System (ADS)

    Anufriev, Roman; Ramiere, Aymeric; Maire, Jeremie; Nomura, Masahiro

    2017-05-01

    Unlike classical heat diffusion at macroscale, nanoscale heat conduction can occur without energy dissipation because phonons can ballistically travel in straight lines for hundreds of nanometres. Nevertheless, despite recent experimental evidence of such ballistic phonon transport, control over its directionality, and thus its practical use, remains a challenge, as the directions of individual phonons are chaotic. Here, we show a method to control the directionality of ballistic phonon transport using silicon membranes with arrays of holes. First, we demonstrate that the arrays of holes form fluxes of phonons oriented in the same direction. Next, we use these nanostructures as directional sources of ballistic phonons and couple the emitted phonons into nanowires. Finally, we introduce thermal lens nanostructures, in which the emitted phonons converge at the focal point, thus focusing heat into a spot of a few hundred nanometres. These results motivate the concept of ray-like heat manipulations at the nanoscale.

  3. Heat guiding and focusing using ballistic phonon transport in phononic nanostructures.

    PubMed

    Anufriev, Roman; Ramiere, Aymeric; Maire, Jeremie; Nomura, Masahiro

    2017-05-18

    Unlike classical heat diffusion at macroscale, nanoscale heat conduction can occur without energy dissipation because phonons can ballistically travel in straight lines for hundreds of nanometres. Nevertheless, despite recent experimental evidence of such ballistic phonon transport, control over its directionality, and thus its practical use, remains a challenge, as the directions of individual phonons are chaotic. Here, we show a method to control the directionality of ballistic phonon transport using silicon membranes with arrays of holes. First, we demonstrate that the arrays of holes form fluxes of phonons oriented in the same direction. Next, we use these nanostructures as directional sources of ballistic phonons and couple the emitted phonons into nanowires. Finally, we introduce thermal lens nanostructures, in which the emitted phonons converge at the focal point, thus focusing heat into a spot of a few hundred nanometres. These results motivate the concept of ray-like heat manipulations at the nanoscale.

  4. Ferrographic tracking of bacterial transport in the field at the Narrow Channel focus area, Oyster, VA

    SciTech Connect

    Johnson, William P.; Zhang, Pengfei; Fuller, Mark E.; Scheibe, Timothy D. ); Mailloux, Brian J.; Onstott, Tullis C.; Deflaun, Mary F.; Hubbard, Susan; Radtke, Jon; Kovacic, William P.; Holben, William

    2001-01-01

    The first results from an innovative bacterial tracking technique, ferrographic capture, applied to bacterial transport in groundwater are reported in this paper. Ferrographic capture was used to analyze samples during an October 1999 bacterial injection experiment at the Narrow Channel Focus Area of the South Oyster Site, VA. Data obtained using this method showed that the timing of bacterial breakthrough was controlled by physical (hydraulic conductivity) heterogeneity in the vertical dimension, as opposed to variation in sediment surface or aqueous chemical properties. Ferrographic tracking yielded results that compared well with results from other tracking techniques over a concentration range of eight orders of magnitude, and provided a low detection limit relative to most other bacterial tracking techniques. The low detection limit of this method allowed observation of transport of an adhesion-deficient bacterium over distances greater than 20 m in the fine sand aquifer under lying this site.

  5. Dynamics of laser-driven proton beam focusing and transport into solid density matter

    NASA Astrophysics Data System (ADS)

    Kim, J.; McGuffey, C.; Beg, F.; Wei, M.; Mariscal, D.; Chen, S.; Fuchs, J.

    2016-10-01

    Isochoric heating and local energy deposition capabilities make intense proton beams appealing for studying high energy density physics and the Fast Ignition of inertial confinement fusion. To study proton beam focusing that results in high beam density, experiments have been conducted using different target geometries irradiated by a kilojoule, 10 ps pulse of the OMEGA EP laser. The beam focus was measured by imaging beam-induced Cu K-alpha emission on a Cu foil that was positioned at a fixed distance. Compared to a free target, structured targets having shapes of wedge and cone show a brighter and narrower K-alpha radiation emission spot on a Cu foil indicating higher beam focusability. Experimentally observed images with proton radiography demonstrate the existence of transverse fields on the structures. Full-scale simulations including the contribution of a long pulse duration of the laser confirm that such fields can be caused by hot electrons moving through the structures. The simulated fields are strong enough to reflect the diverging main proton beam and pinch a transverse probe beam. Detailed simulation results including the beam focusing and transport of the focused intense proton beam in Cu foil will be presented. This work was supported by the National Laser User Facility Program through Award DE-NA0002034.

  6. Acceleration of low-energy ions at parallel shocks with a focused transport model

    SciTech Connect

    Zuo, Pingbing; Zhang, Ming; Rassoul, Hamid K.

    2013-03-19

    Here we present a test particle simulation on the injection and acceleration of low-energy suprathermal particles by parallel shocks with a focused transport model. The focused transport equation contains all necessary physics of shock acceleration, but avoids the limitation of diffusive shock acceleration (DSA) that requires a small pitch angle anisotropy. This simulation verifies that the particles with speeds of a fraction of to a few times the shock speed can indeed be directly injected and accelerated into the DSA regime by parallel shocks. At higher energies starting from a few times the shock speed, the energy spectrum of accelerated particles is a power law with the same spectral index as the solution of standard DSA theory, although the particles are highly anisotropic in the upstream region. The intensity, however, is different from that predicted by DSA theory, indicating a different level of injection efficiency. It is found that the shock strength, the injection speed, and the intensity of an electric cross-shock potential (CSP) jump can affect the injection efficiency of the low-energy particles. A stronger shock has a higher injection efficiency. In addition, if the speed of injected particles is above a few times the shock speed, the produced power-law spectrum is consistent with the prediction of standard DSA theory in both its intensity and spectrum index with an injection efficiency of 1. CSP can increase the injection efficiency through direct particle reflection back upstream, but it has little effect on the energetic particle acceleration once the speed of injected particles is beyond a few times the shock speed. Finally, this test particle simulation proves that the focused transport theory is an extension of DSA theory with the capability of predicting the efficiency of particle injection.

  7. Acceleration of low-energy ions at parallel shocks with a focused transport model

    DOE PAGES

    Zuo, Pingbing; Zhang, Ming; Rassoul, Hamid K.

    2013-03-19

    Here we present a test particle simulation on the injection and acceleration of low-energy suprathermal particles by parallel shocks with a focused transport model. The focused transport equation contains all necessary physics of shock acceleration, but avoids the limitation of diffusive shock acceleration (DSA) that requires a small pitch angle anisotropy. This simulation verifies that the particles with speeds of a fraction of to a few times the shock speed can indeed be directly injected and accelerated into the DSA regime by parallel shocks. At higher energies starting from a few times the shock speed, the energy spectrum of acceleratedmore » particles is a power law with the same spectral index as the solution of standard DSA theory, although the particles are highly anisotropic in the upstream region. The intensity, however, is different from that predicted by DSA theory, indicating a different level of injection efficiency. It is found that the shock strength, the injection speed, and the intensity of an electric cross-shock potential (CSP) jump can affect the injection efficiency of the low-energy particles. A stronger shock has a higher injection efficiency. In addition, if the speed of injected particles is above a few times the shock speed, the produced power-law spectrum is consistent with the prediction of standard DSA theory in both its intensity and spectrum index with an injection efficiency of 1. CSP can increase the injection efficiency through direct particle reflection back upstream, but it has little effect on the energetic particle acceleration once the speed of injected particles is beyond a few times the shock speed. Finally, this test particle simulation proves that the focused transport theory is an extension of DSA theory with the capability of predicting the efficiency of particle injection.« less

  8. Vitamin transport and homeostasis in mammalian brain: focus on Vitamins B and E.

    PubMed

    Spector, Reynold; Johanson, Conrad E

    2007-10-01

    With the application of genetic and molecular biology techniques, there has been substantial progress in understanding how vitamins are transferred across the mammalian blood-brain barrier and choroid plexus into brain and CSF and how vitamin homeostasis in brain is achieved. In most cases (with the exception of the sodium-dependent multivitamin transporter for biotin, pantothenic acid, and lipoic acid), the vitamins are transported by separate carriers through the blood-brain barrier or choroid plexus. Then the vitamins are accumulated by brain cells by separate, specialized systems. This review focuses on six vitamins (B(1), B(3), B(6), pantothenic acid, biotin, and E) and the newer genetic information including relevant 'knockdown' or 'knockout' models in mice and humans. The overall objective is to integrate this newer information with previous physiological and biochemical observations to achieve a better understanding of vitamin transport and homeostasis in brain. This is especially important in view of the newly described non-cofactor vitamin roles in brain (e.g. of B(1), B(3), B(6), and E) and the potential roles of vitamins in the therapy of brain disorders.

  9. Absorption of vitamin A and carotenoids by the enterocyte: focus on transport proteins.

    PubMed

    Reboul, Emmanuelle

    2013-09-12

    Vitamin A deficiency is a public health problem in most developing countries, especially in children and pregnant women. It is thus a priority in health policy to improve preformed vitamin A and/or provitamin A carotenoid status in these individuals. A more accurate understanding of the molecular mechanisms of intestinal vitamin A absorption is a key step in this direction. It was long thought that β-carotene (the main provitamin A carotenoid in human diet), and thus all carotenoids, were absorbed by a passive diffusion process, and that preformed vitamin A (retinol) absorption occurred via an unidentified energy-dependent transporter. The discovery of proteins able to facilitate carotenoid uptake and secretion by the enterocyte during the past decade has challenged established assumptions, and the elucidation of the mechanisms of retinol intestinal absorption is in progress. After an overview of vitamin A and carotenoid fate during gastro-duodenal digestion, our focus will be directed to the putative or identified proteins participating in the intestinal membrane and cellular transport of vitamin A and carotenoids across the enterocyte (i.e., Scavenger Receptors or Cellular Retinol Binding Proteins, among others). Further progress in the identification of the proteins involved in intestinal transport of vitamin A and carotenoids across the enterocyte is of major importance for optimizing their bioavailability.

  10. Absorption of Vitamin A and Carotenoids by the Enterocyte: Focus on Transport Proteins

    PubMed Central

    Reboul, Emmanuelle

    2013-01-01

    Vitamin A deficiency is a public health problem in most developing countries, especially in children and pregnant women. It is thus a priority in health policy to improve preformed vitamin A and/or provitamin A carotenoid status in these individuals. A more accurate understanding of the molecular mechanisms of intestinal vitamin A absorption is a key step in this direction. It was long thought that β-carotene (the main provitamin A carotenoid in human diet), and thus all carotenoids, were absorbed by a passive diffusion process, and that preformed vitamin A (retinol) absorption occurred via an unidentified energy-dependent transporter. The discovery of proteins able to facilitate carotenoid uptake and secretion by the enterocyte during the past decade has challenged established assumptions, and the elucidation of the mechanisms of retinol intestinal absorption is in progress. After an overview of vitamin A and carotenoid fate during gastro-duodenal digestion, our focus will be directed to the putative or identified proteins participating in the intestinal membrane and cellular transport of vitamin A and carotenoids across the enterocyte (i.e., Scavenger Receptors or Cellular Retinol Binding Proteins, among others). Further progress in the identification of the proteins involved in intestinal transport of vitamin A and carotenoids across the enterocyte is of major importance for optimizing their bioavailability. PMID:24036530

  11. Issues connected with indirect cost quantification: a focus on the transportation system

    NASA Astrophysics Data System (ADS)

    Křivánková, Zuzana; Bíl, Michal; Kubeček, Jan; Vodák, Rostislav

    2017-04-01

    Transportation and communication networks in general are vital parts of modern society. The economy relies heavily on transportation system performance. A number of people commutes to work regularly. Stockpiles in many companies are being reduced as the just-in-time production process is able to supply resources via the transportation network on time. Natural hazards have the potential to disturb transportation systems. Earthquakes, flooding or landsliding are examples of high-energetic processes which are capable of causing direct losses (i.e. physical damage to the infrastructure). We have focused on quantification of the indirect cost of natural hazards which are not easy to estimate. Indirect losses can also emerge as a result of meteorological hazards with low energy which only seldom cause direct losses, e.g. glaze, snowfall. Whereas evidence of repair work and general direct costs usually exist or can be estimated, indirect costs are much more difficult to identify particularly when they are not covered by insurance agencies. Delimitations of alternative routes (detours) are the most frequent responses to blocked road links. Indirect costs can then be related to increased fuel consumption and additional operating costs. Detours usually result in prolonged travel times. Indirect costs quantification has to therefore cover the value of the time. The costs from the delay are a nonlinear function of travel time, however. The existence of an alternative transportation pattern may also result in an increased number of traffic crashes. This topic has not been studied in depth but an increase in traffic crashes has been reported when people suddenly changed their traffic modes, e.g. when air traffic was not possible. The lost user benefit from those trips that were cancelled or suppressed is also difficult to quantify. Several approaches, based on post-event questioner surveys, have been applied to communities and companies affected by transportation accessibility

  12. Design of a superconducting beam transport channel and beam dynamics for a strong-focusing cyclotron

    NASA Astrophysics Data System (ADS)

    Badgley, Karie Elizabeth

    There is an increasing interest in high power proton accelerators for use as neutron and muon sources, accelerator driven systems (ADS) for nuclear waste transmutation, high energy physics, medical physics, nuclear physics, and medical isotope production. Accelerating high current beams has a number of challenges; including avoiding harmful resonance crossing, space charge effects and, specific to cyclotrons, sufficient turn separation at injection and extraction. The Accelerator Research Laboratory at Texas A&M University is developing a high-power strong-focusing cyclotron with two main technologies to overcome these challenges. The first is a superconducting RF cavity to provide the energy gain required for fully separated turns. The second is the use of superconducting beam transport channels within the sectors of the cyclotron to provide strong-focusing with alternating focusing and defocusing quadrupoles. A method has been developed to find the equilibrium spiral orbit through the cyclotron which maintains isochronicity. The isochronous spiral orbit was then used to perform full linear optics calculations. The strengths of the quadrupoles were adjusted to hold the horizontal and vertical betatron tunes constant per turn to avoid resonance crossing. Particle tracking was performed with a modified MAD-X-PTC code and Synergia to provide a framework for future space charge studies. Magnetic modeling was performed on a 2D cross section of the beam transport channel. The wire locations were adjusted to reduce the higher order multipoles and a good field region was obtained at 70% of the beam pipe aperture with multipoles less than 10-4 . The 2D model was also used to determine the required current density needed to produce the quadrupole gradients. MgB2 superconducting wire was chosen as it meets all the field and current requirements and can operate at a reduced cryogenic cost. A winding mandrel was also designed and fabricated which minimized the bend radius for

  13. Neurotransmitters, psychotropic drugs and microglia: clinical implications for psychiatry.

    PubMed

    Kato, T A; Yamauchi, Y; Horikawa, H; Monji, A; Mizoguchi, Y; Seki, Y; Hayakawa, K; Utsumi, H; Kanba, S

    2013-01-01

    Psychiatric disorders have long and dominantly been regarded to be induced by disturbances of neuronal networks including synapses and neurotransmitters. Thus, the effects of psychotropic drugs such as antipsychotics and antidepressants have been understood to modulate synaptic regulation via receptors and transporters of neurotransmitters such as dopamine and serotonin. Recently, microglia, immunological/inflammatory cells in the brain, have been indicated to have positive links to psychiatric disorders. Positron emission tomography (PET) imaging and postmortem studies have revealed microglial activation in the brain of neuropsychiatric disorders such as schizophrenia, depression and autism. Animal models of neuropsychiatric disorders have revealed the underlying microglial pathologies. In addition, various psychotropic drugs have been suggested to have direct effects on microglia. Until now, the relationship between microglia, neurotransmitters and psychiatric disorders has not been well understood. Therefore, in this review, at first, we summarize recent findings of interaction between microglia and neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine and glutamate. Next, we introduce up-to-date knowledge of the effects of psychotropic drugs such as antipsychotics, antidepressants and antiepileptics on microglial modulation. Finally, we propose the possibility that modulating microglia may be a key target in the treatment of various psychiatric disorders. Further investigations and clinical trials should be conducted to clarify this perspective, using animal in vivo studies and imaging studies with human subjects.

  14. Synaptic Neurotransmitter-Gated Receptors

    PubMed Central

    Smart, Trevor G.; Paoletti, Pierre

    2012-01-01

    Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin, GABA, and glycine, followed later by similar determinations for the glutamate receptors, comprising non-NMDA and NMDA subtypes. The last decade has seen a rapid advance resulting in the first structures of Cys-loop receptors, related bacterial and molluscan homologs, and glutamate receptors, determined down to atomic resolution. This now provides a basis for determining not just the complete structures of these important receptor classes, but also for understanding how various domains and residues interact during agonist binding, receptor activation, and channel opening, including allosteric modulation. This article reviews our current understanding of these mechanisms for the Cys-loop and glutamate receptor families. PMID:22233560

  15. Why are neurotransmitters neurotoxic? An evolutionary perspective

    PubMed Central

    Harris, Keith D.; Weiss, Meital; Zahavi, Amotz

    2014-01-01

    In the CNS, minor changes in the concentration of neurotransmitters such as glutamate or dopamine can lead to neurodegenerative diseases. We present an evolutionary perspective on the function of neurotransmitter toxicity in the CNS. We hypothesize that neurotransmitters are selected because of their toxicity, which serves as a test of neuron quality and facilitates the selection of neuronal pathways. This perspective may offer additional explanations for the reduction of neurotransmitter concentration in the CNS with age, and suggest an additional role for the blood-brain barrier. It may also suggest a connection between the specific toxicity of the neurotransmitters released in a specific region of the CNS, and elucidate their role as chemicals that are optimal for testing the quality of cells in that region. PMID:25580225

  16. Volatiles beneath mid-ocean ridges: Deep melting, channelised transport, focusing, and metasomatism

    NASA Astrophysics Data System (ADS)

    Keller, Tobias; Katz, Richard F.; Hirschmann, Marc M.

    2017-04-01

    Deep-Earth volatile cycles couple the mantle with near-surface reservoirs. Volatiles are emitted by volcanism and, in particular, from mid-ocean ridges, which are the most prolific source of basaltic volcanism. Estimates of volatile extraction from the asthenosphere beneath ridges typically rely on measurements of undegassed lavas combined with simple petrogenetic models of the mean degree of melting. Estimated volatile fluxes have large uncertainties; this is partly due to a poor understanding of how volatiles are transported by magma in the asthenosphere. Here, we assess the fate of mantle volatiles through numerical simulations of melting and melt transport at mid-ocean ridges. Our simulations are based on two-phase, magma/mantle dynamics theory coupled to an idealised thermodynamic model of mantle melting in the presence of water and carbon dioxide. We combine simulation results with catalogued observations of all ridge segments to estimate a range of likely volatile output from the global mid-ocean ridge system. We thus predict global MOR crust production of 66-73 Gt/yr (22-24 km3/yr) and global volatile output of 52-110 Mt/yr, corresponding to mantle volatile contents of 100-200 ppm. We find that volatile extraction is limited: up to half of deep, volatile-rich melt is not focused to the axis but is rather deposited along the LAB. As these distal melts crystallise and fractionate, they metasomatise the base of the lithosphere, creating rheological heterogeneity that could contribute to the seismic signature of the LAB.

  17. Three-dimensional nanometry of vesicle transport in living cells using dual-focus imaging optics

    SciTech Connect

    Watanabe, Tomonobu M.; Sato, Takashi; Gonda, Kohsuke; Higuchi, Hideo . E-mail: higuchi@tubero.tohoku.ac.jp

    2007-07-20

    Dual-focus imaging optics for three-dimensional tracking of individual quantum dots has been developed to study the molecular mechanisms of motor proteins in cells. The new system has a high spatial and temporal precision, 2 nm in the x-y sample plane and 5 nm along the z-axis at a frame time of 2 ms. Three-dimensional positions of the vesicles labeled with quantum dots were detected in living cells. Vesicles were transported on the microtubules using 8-nm steps towards the nucleus. The steps had fluctuation of {approx}20 nm which were perpendicular to the axis of the microtubule but with the constant distance from the microtubule. The most of perpendicular movement was not synchronized with the 8-nm steps, indicating that dynein moved on microtubules without changing the protofilaments. When the vesicles changed their direction of movement toward the cell membrane, they moved perpendicular with the constant distance from the microtubule. The present method is powerful tool to investigate three dimensional movement of molecules in cells with nanometer and millisecond accuracy.

  18. Calcium Control of Neurotransmitter Release

    PubMed Central

    Südhof, Thomas C.

    2012-01-01

    Upon entering a presynaptic terminal, an action potential opens Ca2+ channels, and transiently increases the local Ca2+ concentration at the presynaptic active zone. Ca2+ then triggers neurotransmitter release within a few hundred microseconds by activating synaptotagmins Ca2+. Synaptotagmins bind Ca2+ via two C2-domains, and transduce the Ca2+ signal into a nanomechanical activation of the membrane fusion machinery; this activation is mediated by the Ca2+-dependent interaction of the synaptotagmin C2-domains with phospholipids and SNARE proteins. In triggering exocytosis, synaptotagmins do not act alone, but require an obligatory cofactor called complexin, a small protein that binds to SNARE complexes and simultaneously activates and clamps the SNARE complexes, thereby positioning the SNARE complexes for subsequent synaptotagmin action. The conserved function of synaptotagmins and complexins operates generally in most, if not all, Ca2+-regulated forms of exocytosis throughout the body in addition to synaptic vesicle exocytosis, including in the degranulation of mast cells, acrosome exocytosis in sperm cells, hormone secretion from endocrine cells, and neuropeptide release. PMID:22068972

  19. Quadrupole Strong Focusing for Transport of Space-Charge Dominated Electron Beams in Traveling-Wave Tubes

    NASA Astrophysics Data System (ADS)

    Nichols, Kimberley E. L.

    Analysis of quadrupole focusing lattices for high-frequency TWT's is presented. This work is motivated by recent work performed at the Naval Research Laboratory (NRL) which demonstrated an advantageous case for strong focusing employing a Halbach quadrupole lattice. Using realistic Permanent Magnet Quadruple (PMQ) field cancellation, the advantage of using PMQ to transport higher current densities than Permanent Periodic Magnet (PPM) lattices disappears, while other advantages for employing quadrupole focusing remain. This dissertation gives a comprehensive analysis of the applicability of PMQ focusing in vacuum electronic devices.

  20. Investigation of Generation, Acceleration, Transport and Final Focusing of High-Intensity Heavy Ion Beams from Sources to Targets

    SciTech Connect

    Chiping Chen

    2006-10-26

    Under the auspices of the research grant, the Intense Beam Theoretical Research Goup at Massachusetts Institute of Technology's Plasma Science and Fusion Center made significant contributions in a number of important areas in the HIF and HEDP research, including: (a) Derivation of rms envelope equations and study of rms envelope dynamics for high-intensity heavy ion beams in a small-aperture AG focusing transport systems; (b) Identification of a new mechanism for chaotic particle motion, halo formation, and beam loss in high-intensity heavy ion beams in a small-aperture AG focusing systems; Development of elliptic beam theory; (d) Study of Physics Issues in the Neutralization Transport Experiment (NTX).

  1. Amino acid neurotransmitters in the retina: a functional overview.

    PubMed

    Wu, S M; Maple, B R

    1998-05-01

    Physiological and pharmacological mechanisms of glutamatergic, GABAergic and glycinergic synapses in the tiger salamander retina were studied. We used immunocytochemical and autoradiographic methods to study localizations of these neurotransmitters and their uptake transporters; and electrophysiological methods (intracellular, extracellular and whole cell patch electrode recordings) to study the light responses, miniature postsynaptic currents and neurotransmitter-induced postsynaptic currents in various retinal neurons. Our results are consistent with the following scheme: Glutamate is used by the photoreceptor and bipolar cell output synapses and the release of glutamate is largely mediated by calcium-dependent vesicular processes. The postsynaptic glutamate receptors in DBCs are L-AP4 receptors, in HBCs, HCs and ganglion cells are the kainate/AMPA and NMDA receptors. Subpopulations of HCs make GABAergic synapses on cones and gate chloride condunctance through GABAA receptors. GABAergic HCs do not make feedforward synapses on bipolar cell dendrites and the neurotransmitter identity of the HCs making feedforward synapses is unknown. Subpopulations of amacrine cells make GABAergic synapses on bipolar cell synaptic terminals, other amacrine cells and ganglion cells and GABA gates chloride conductances in theses cells. Glycinergic amacrine cells make synapses on bipolar cell synaptic terminals, other amacrine cells and ganglion cells and glycine opens postsynaptic chloride channels. Glycinergic interplexiform cells make synapses on bipolar cells in the outer retina and glycine released from these cells open chloride channels in bipolar cell dendrites.

  2. Scaling approach to tight-binding transport in realistic graphene devices: The case of transverse magnetic focusing

    NASA Astrophysics Data System (ADS)

    Beconcini, M.; Valentini, S.; Kumar, R. Krishna; Auton, G. H.; Geim, A. K.; Ponomarenko, L. A.; Polini, M.; Taddei, F.

    2016-09-01

    Ultraclean graphene sheets encapsulated between hexagonal boron nitride crystals host two-dimensional electron systems in which low-temperature transport is solely limited by the sample size. We revisit the theoretical problem of carrying out microscopic calculations of nonlocal ballistic transport in such micron-scale devices. By employing the Landauer-Büttiker scattering theory, we propose a scaling approach to tight-binding nonlocal transport in realistic graphene devices. We test our numerical method against experimental data on transverse magnetic focusing (TMF), a textbook example of nonlocal ballistic transport in the presence of a transverse magnetic field. This comparison enables a clear physical interpretation of all the observed features of the TMF signal, including its oscillating sign.

  3. Microfabricated device and method for multiplexed electrokinetic focusing of fluid streams and a transport cytometry method using same

    DOEpatents

    Jacobson, Stephen C.; Ramsey, J. Michael

    2000-01-01

    A microfabricated device and method for electrokinetic transport of a liquid phase biological or chemical material is described. In accordance with one aspect of the present invention there is provided a microchip that is adapted for the simultaneous spatial confinement of electrokinetically driven fluidic material streams on a substrate. The apparatus includes a focusing chamber formed in a surface of the substrate and in fluid communication with two sample fluid channels and three focusing fluid channels. The device further includes electromotive means operatively connected to the sources of the sample fluid and the source of focusing fluid for electrokinetically driving the respective streams of the sample and focusing fluids through the respective channels into the focusing chamber such that the focusing fluid streams spatially confine the first and second sample fluid streams within the focusing chamber. In accordance with another aspect of this invention, there is provided a cytometry method for analyzing microscopic particles in a fluid medium on a microchip by utilizing the focusing function of the microchip. In the disclosed cytometry process the width of the fluid stream is narrowed in the focusing chamber. The microscopic particles in the focused sample fluid are then detected and/or measured using light scattering or other techniques.

  4. Focusing Resources, Economic Investment, and Guidance to Help Transportation Act of 2010

    THOMAS, 111th Congress

    Sen. Lautenberg, Frank R. [D-NJ

    2010-07-22

    Senate - 07/22/2010 Read twice and referred to the Committee on Commerce, Science, and Transportation. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

  5. Focusing Resources, Economic Investment, and Guidance to Help Transportation Act of 2011

    THOMAS, 112th Congress

    Sen. Lautenberg, Frank R. [D-NJ

    2011-02-16

    Senate - 02/16/2011 Read twice and referred to the Committee on Commerce, Science, and Transportation. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

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

    PubMed

    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

  7. Microtubule-stabilizing peptides and small molecules protecting axonal transport and brain function: focus on davunetide (NAP).

    PubMed

    Magen, Iddo; Gozes, Illana

    2013-12-01

    This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an eight amino acid snippet derived from activity-dependent neuroprotective protein (ADNP) which was discovered in our laboratory. We have recently described the effects of NAP in neurodegenerative disorders, and we now review the beneficial effects of NAP and other microtubule-stabilizing agents on impairments in axonal transport. Experiments in animal models of microtubule-deficiency including tauopathy (spanning from drosophila to mammals) showed protection of axonal transport by microtubule-stabilizers and NAP, which was coupled to motor and cognitive protection. Clinical trials with NAP (davunetide) are reviewed paving the path to future developments.

  8. EFFECTS OF NON-ISOTROPIC SCATTERING, MAGNETIC HELICITY, AND ADIABATIC FOCUSING ON DIFFUSIVE TRANSPORT OF SOLAR ENERGETIC PARTICLES

    SciTech Connect

    Litvinenko, Yuri E.

    2012-06-10

    Transport of solar energetic particles in interplanetary space is analyzed. A new systematic derivation of the diffusion approximation is given, which incorporates the effects of non-isotropic scattering, magnetic helicity, and adiabatic focusing in a non-uniform large-scale magnetic field. The derivation is based on a system of stochastic differential equations, equivalent to the Fokker-Planck equation, and the new method is a generalization of the Smoluchowski approximation in the theory of the Brownian motion. Simple, physically transparent expressions for the transport coefficients are derived. Different results of earlier treatments of the problem are related to the assumptions regarding the evolving particle distribution.

  9. LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake

    SciTech Connect

    Zhou,Z.; Zhen, J.; Karpowich, N.; Goetz, R.; Law, C.; Reith, M.; Wang, D.

    2007-01-01

    Tricyclic antidepressants exert their pharmacological effect -- inhibiting the reuptake of serotonin, norepinephrine, and dopamine -- by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.

  10. LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake.

    PubMed

    Zhou, Zheng; Zhen, Juan; Karpowich, Nathan K; Goetz, Regina M; Law, Christopher J; Reith, Maarten E A; Wang, Da-Neng

    2007-09-07

    Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.

  11. Neurotransmitter properties of the newborn human retina

    SciTech Connect

    Hollyfield, J.G.; Frederick, J.M.; Rayborn, M.E.

    1983-07-01

    Human retinal tissue from a newborn was examined autoradiographically for the presence of high-affinity uptake and localization of the following putative neurotransmitters: dopamine, glycine, GABA, aspartate, and glutamate. In addition, the dopamine content of this newborn retina was measured by high pressure liquid chromatography. Our study reveals that specific uptake mechanisms for /sup 3/H-glycine, /sup 3/H-dopamine, and /sup 3/H-GABA are present at birth. However, the number and distribution of cells labeled with each of these /sup 3/H-transmitters are not identical to those observed in adult human retinas. Furthermore, the amount of endogenous dopamine in the newborn retina is approximately 1/20 the adult level. Photoreceptor-specific uptake of /sup 3/H-glutamate and /sup 3/H-aspartate are not observed. These findings indicate that, while some neurotransmitter-specific properties are present at birth, significant maturation of neurotransmitter systems occurs postnatally.

  12. Regulation of neurotransmitter release kinetics by NSF.

    PubMed

    Schweizer, F E; Dresbach, T; DeBello, W M; O'Connor, V; Augustine, G J; Betz, H

    1998-02-20

    NSF (N-ethylmaleimide-sensitive factor) is an adenosine triphosphatase (ATPase) that contributes to a protein complex essential for membrane fusion. The synaptic function of this protein was investigated by injecting, into the giant presynaptic terminal of squid, peptides that inhibit the ATPase activity of NSF stimulated by the soluble NSF attachment protein (SNAP). These peptides reduced the amount and slowed the kinetics of neurotransmitter release as a result of actions that required vesicle turnover and occurred at a step subsequent to vesicle docking. These results define NSF as an essential participant in synaptic vesicle exocytosis that regulates the kinetics of neurotransmitter release and, thereby, the integrative properties of synapses.

  13. The role of cross-shock potential on pickup ion shock acceleration in the framework of focused transport theory

    SciTech Connect

    Zuo, Pingbing; Zhang, Ming; Rassoul, Hamid K.

    2013-10-03

    The focused transport theory is appropriate to describe the injection and acceleration of low-energy particles at shocks as an extension of diffusive shock acceleration (DSA). In this investigation, we aim to characterize the role of cross-shock potential (CSP) originated in the charge separation across the shock ramp on pickup ion (PUI) acceleration at various types of shocks with a focused transport model. The simulation results of energy spectrum and spatial density distribution for the cases with and without CSP added in the model are compared. With sufficient acceleration time, the focused transport acceleration finally falls into the DSA regime with the power-law spectral index equal to the solution of the DSA theory. The CSP can affect the shape of the spectrum segment at lower energies, but it does not change the spectral index of the final power-law spectrum at high energies. It is found that the CSP controls the injection efficiency which is the fraction of PUIs reaching the DSA regime. A stronger CSP jump results in a dramatically improved injection efficiency. Our simulation results also show that the injection efficiency of PUIs is mass-dependent, which is lower for species with a higher mass. Additionally, the CSP is able to enhance the particle reflection upstream to produce a stronger intensity spike at the shock front. Lastly, we conclude that the CSP is a non-negligible factor that affects the dynamics of PUIs at shocks.

  14. The role of cross-shock potential on pickup ion shock acceleration in the framework of focused transport theory

    DOE PAGES

    Zuo, Pingbing; Zhang, Ming; Rassoul, Hamid K.

    2013-10-03

    The focused transport theory is appropriate to describe the injection and acceleration of low-energy particles at shocks as an extension of diffusive shock acceleration (DSA). In this investigation, we aim to characterize the role of cross-shock potential (CSP) originated in the charge separation across the shock ramp on pickup ion (PUI) acceleration at various types of shocks with a focused transport model. The simulation results of energy spectrum and spatial density distribution for the cases with and without CSP added in the model are compared. With sufficient acceleration time, the focused transport acceleration finally falls into the DSA regime withmore » the power-law spectral index equal to the solution of the DSA theory. The CSP can affect the shape of the spectrum segment at lower energies, but it does not change the spectral index of the final power-law spectrum at high energies. It is found that the CSP controls the injection efficiency which is the fraction of PUIs reaching the DSA regime. A stronger CSP jump results in a dramatically improved injection efficiency. Our simulation results also show that the injection efficiency of PUIs is mass-dependent, which is lower for species with a higher mass. Additionally, the CSP is able to enhance the particle reflection upstream to produce a stronger intensity spike at the shock front. Lastly, we conclude that the CSP is a non-negligible factor that affects the dynamics of PUIs at shocks.« less

  15. Pharmacokinetic interactions between herbal medicines and prescribed drugs: focus on drug metabolic enzymes and transporters.

    PubMed

    Meng, Qiang; Liu, Kexin

    2014-01-01

    Herbal medicines have been widely used for thousands of years, and now are gaining continued popularity worldwide as a complementary or alternative treatment for a variety of diseases, rehabilitation and health care. Since herbal medicines contain more than one pharmacologically active ingredient and are commonly used with many prescribed drugs, there are potential herb-drug interactions. A variety of reported herb-drug interactions are of pharmacokinetic origin, arising from the effects of herbal medicines on metabolic enzymes and/or transporters. Such an alteration in metabolism or transport can result in changes in absorption, distribution, metabolism, and excretion (e.g., induction or inhibition of metabolic enzymes, and modulation of uptake and efflux transporters), leading to changed pharmacokinetics of the concomitantly prescribed drugs. Pharmacokinetic herb-drug interactions have more clinical significance as pharmacokinetic parameters such as the area under the plasma concentration-time curve (AUC), the maximum plasma concentration (Cmax) or the elimination half-life (t1/2) of the concomitant drug alter. This review summarizes the mechanism underlying herb-drug interactions and the approaches to identify the interactions, and discusses pharmacokinetic interactions of eight widely used herbal medicines (Ginkgo biloba, ginseng, garlic, black cohosh, Echinacea, milk thistle, kava, and St. John's wort) with conventional drugs, using various in vitro, animal in vivo, and clinical studies. The increasing understanding of pharmacokinetic herb-drug interactions will make health care professionals and patients pay more attention to the potential interactions.

  16. Contactless transport of matter in the first five resonance modes of a line-focused acoustic manipulator.

    PubMed

    Foresti, Daniele; Nabavi, Majid; Poulikakos, Dimos

    2012-02-01

    The first five resonance modes for transport of matter in a line-focused acoustic levitation system are investigated. Contactless transport was achieved by varying the height between the radiating plate and the reflector. Transport and levitation of droplets in particular involve two limits of the acoustic forces. The lower limit corresponds to the minimum force required to overcome the gravitational force. The upper limit corresponds to the maximum acoustic pressure beyond which atomization of the droplet occurs. As the droplet size increases, the lower limit increases and the upper limit decreases. Therefore to have large droplets levitated, relatively flat radiation pressure amplitude during the translation is needed. In this study, using a finite element model, the Gor'kov potential was calculated for different heights between the reflector and the radiating plate. The application of the Gor'kov potential was extended to study the range of droplet sizes for which the droplets can be levitated and transported without atomization. It was found that the third resonant mode (H(3)-mode) represents the best compromise between high levitation force and smooth pattern transition, and water droplets of millimeter radius can be levitated and transported. The H(3)-mode also allows for three translation lines in parallel. © 2012 Acoustical Society of America

  17. Out-of-focus effects on microscale schlieren measurements of mass transport in a microfluidic device

    NASA Astrophysics Data System (ADS)

    Chen, Shao-Tuan; Sun, Chen-li

    2016-08-01

    The microscale schlieren technique provides a means for a non-invasive, full-field measurement for mixing microfluidics with excellent sensitivity and resolution. Nevertheless, an out-of-focus effect due to microscopic optics may lead to undesirable errors in quantifying the gradient information at high degrees of magnification. If the channel in the microfluidic device under study is too deep, light deflection caused by inhomogeneity located far from the focal plane may contributes little to the intensity change on the image plane. To address this issue, we propose the use of a weighting function that approximates a Gaussian profile with an optical-system-dependable width. We assume that the resultant intensity change is proportional to a weighted sum of the gradient across the channel depth and acquire micro-schlieren images of fluid mixing in a T-junction microchannel at various positions along the optical axis. For each objective, the width of the weighting function is then determined iteratively by curve fitting the ratio of changes in grayscale readouts for out-of-focus and focus micro-schlieren images. The standard deviation in the Gaussian distribution facilitates the quantification of the out-of-focus effect. In addition, we measure the sensitivities of a microscale schlieren system equipped with different objectives and compare the values to the model. Despite its better resolution, we find that an objective with higher magnification suffers from a more severe out-of-focus effect and a loss of sensitivity. Equations are proposed for estimations of the standard deviation and the sensitivity of microscale schlieren measurements. The outcome will facilitate the selection of proper microchannel depths for various microscale schlieren systems or vice versa, thus improving the precision of micro-schlieren measurements in microfluidic devices.

  18. Chemical delivery array with millisecond neurotransmitter release

    PubMed Central

    Jonsson, Amanda; Sjöström, Theresia Arbring; Tybrandt, Klas; Berggren, Magnus; Simon, Daniel T.

    2016-01-01

    Technologies that restore or augment dysfunctional neural signaling represent a promising route to deeper understanding and new therapies for neurological disorders. Because of the chemical specificity and subsecond signaling of the nervous system, these technologies should be able to release specific neurotransmitters at specific locations with millisecond resolution. We have previously demonstrated an organic electronic lateral electrophoresis technology capable of precise delivery of charged compounds, such as neurotransmitters. However, this technology, the organic electronic ion pump, has been limited to a single delivery point, or several simultaneously addressed outlets, with switch-on speeds of seconds. We report on a vertical neurotransmitter delivery device, configured as an array with individually controlled delivery points and a temporal resolution of 50 ms. This is achieved by supplementing lateral electrophoresis with a control electrode and an ion diode at each delivery point to allow addressing and limit leakage. By delivering local pulses of neurotransmitters with spatiotemporal dynamics approaching synaptic function, the high-speed delivery array promises unprecedented access to neural signaling and a path toward biochemically regulated neural prostheses. PMID:27847873

  19. Detection and Quantification of Neurotransmitters in Dialysates

    PubMed Central

    Zapata, Agustin; Chefer, Vladimir I.; Shippenberg, Toni S.; Denoroy, Luc

    2010-01-01

    Sensitive analytical methods are needed for the separation and quantification of neurotransmitters obtained in microdialysate studies. This unit describes methods that permit quantification of nanomolar concentrations of monoamines and their metabolites (high-pressure liquid chromatography electrochemical detection), acetylcholine (HPLC-coupled to an enzyme reactor), and amino acids (HPLC-fluorescence detection; capillary electrophoresis with laser-induced fluorescence detection). PMID:19575473

  20. Mechanisms of glutamate transport.

    PubMed

    Vandenberg, Robert J; Ryan, Renae M

    2013-10-01

    L-Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system and plays important roles in a wide variety of brain functions, but it is also a key player in the pathogenesis of many neurological disorders. The control of glutamate concentrations is critical to the normal functioning of the central nervous system, and in this review we discuss how glutamate transporters regulate glutamate concentrations to maintain dynamic signaling mechanisms between neurons. In 2004, the crystal structure of a prokaryotic homolog of the mammalian glutamate transporter family of proteins was crystallized and its structure determined. This has paved the way for a better understanding of the structural basis for glutamate transporter function. In this review we provide a broad perspective of this field of research, but focus primarily on the more recent studies with a particular emphasis on how our understanding of the structure of glutamate transporters has generated new insights.

  1. COSMIC RAY TRANSPORT WITH MAGNETIC FOCUSING AND THE “TELEGRAPH” MODEL

    SciTech Connect

    Malkov, M. A.; Sagdeev, R. Z.

    2015-08-01

    Cosmic rays (CR), constrained by scattering on magnetic irregularities, are believed to propagate diffusively. However, a well-known defect of diffusive approximation, whereby some of the particles propagate unrealistically fast, has directed interest toward an alternative CR transport model based on the “telegraph” equation. Though, its derivations often lack rigor and transparency leading to inconsistent results. We apply the classic Chapman–Enskog method to the CR transport problem. We show that no “telegraph” (second order time derivative) term emerges in any order of a proper asymptotic expansion with systematically eliminated short timescales. Nevertheless, this term may formally be converted from the fourth order hyper-diffusive term of the expansion. However, both the telegraph and hyperdiffusive terms may only be important for a short relaxation period associated with either strong pitch-angle anisotropy or spatial inhomogeneity of the initial CR distribution. Beyond this period the system evolves diffusively in both cases. The term conversion, that makes the telegraph and Chapman–Enskog approaches reasonably equivalent, is possible only after this relaxation period. During this period, the telegraph solution is argued to be unphysical. Unlike the hyperdiffusion correction, it is not uniformly valid and introduces implausible singular components to the solution. These dominate the solution during the relaxation period. Because they are shown not to be inherent in the underlying scattering problem, we argue that the telegraph term is involuntarily acquired in an asymptotic reduction of the problem.

  2. The GABA synapse as a target for antiepileptic drugs: a historical overview focused on GABA transporters.

    PubMed

    Schousboe, Arne; Madsen, Karsten K; Barker-Haliski, Melissa L; White, H Steve

    2014-10-01

    It is clear that normal neuronal function relies on a tight balance between excitatory and inhibitory neurotransmission. Inhibitory signaling through the GABAergic system can be tightly regulated at the level of GABA uptake via GABA transporters (GAT). As such, selectively modulating the GABA uptake process through pharmacological agents has been an area of active investigation over several decades. These studies have demonstrated that inhibition of astroglial, but not neuronal, GATs may be preferred for anticonvulsant action. To date, four distinct GAT subtypes have been identified and efforts to selectively target these transporters have led to the proliferation of pharmacological agents aimed at augmenting extrasynaptic GABA levels. These pharmacological tools have provided novel and informative insight into the role of GABA and GABAergic signaling in the brain, but have also provided critical information concerning the regulation of CNS disorders associated with an imbalance in inhibitory tone, such as epilepsy. One such compound with notable inhibitory effects at GATs, tiagabine, has demonstrated clinical anticonvulsant efficacy, and is, to date, the only approved GAT inhibitor for clinical use. Thus, efforts to identify and develop GAT subtype-specific compounds continue to be an area of active investigation for the management of epilepsy and other CNS disorders. Herein, the historical efforts to elucidate the role of GABA in the synapse, as well as the role of GAT inhibitors as anticonvulsants, are described.

  3. Epigenetic regulation of ADME-related genes: focus on drug metabolism and transport.

    PubMed

    Zhong, Xiao-bo; Leeder, J Steven

    2013-10-01

    Epigenetic regulation of gene expression refers to heritable factors that are functionally relevant genomic modifications but that do not involve changes in DNA sequence. Examples of such modifications include DNA methylation, histone modifications, noncoding RNAs, and chromatin architecture. Epigenetic modifications are crucial for packaging and interpreting the genome, and they have fundamental functions in regulating gene expression and activity under the influence of physiologic and environmental factors. Recently, epigenetics has become one of the fastest-growing areas of science and has now become a central issue in biologic studies of development and disease pathogenesis. The interest in epigenetics is also true for studies of drug metabolism and transport. In this issue of Drug Metabolism and Disposition, a series of articles is presented to demonstrate the role of epigenetic factors in regulating the expression of genes involved in drug absorption, distribution, metabolism, and excretion in organ development, tissue-specific gene expression, sexual dimorphism, and in the adaptive response to xenobiotic exposure, both therapeutic and toxic. The articles also demonstrate that, in addition to genetic polymorphisms, epigenetics may also contribute to wide interindividual variations in drug metabolism and transport. Identification of functionally relevant epigenetic biomarkers in human specimens has the potential to improve prediction of drug responses based on patient's epigenetic profiles.

  4. Atypical Neurotransmitters and the Neurobiology of Depression.

    PubMed

    Joca, Samia Regiane; Moreira, Fabricio Araujo; Wegener, Gregers

    2015-01-01

    Since the first report that the mechanism of action of antidepressants involves the facilitation of monoaminergic neurotransmission in the brain in the 1960s, the leading hypothesis about the neurobiology of depression has been the so called "monoaminergic hypothesis". However, a growing body of evidence from the last two decades also supports important involvement of non-monoaminergic mechanisms in the neurobiology of depression and antidepressant action. The discovery of nitric oxide (NO) and endocannabinoid signaling in the brain during the 1990s challenged the wellestablished criteria of classical neurotransmission. These transmitters are synthesized and released on demand by the postsynaptic neurons, and may act as a retrograde messenger on the presynaptic terminal, modulating neurotransmitter release. These unconventional signaling mechanisms and the important role as neural messengers have classified NO and endocannabinoids as atypical neurotransmitters. They are able to modulate neural signaling mediated by the main conventional neurotransmitters systems in the brain, including the monoaminergic, glutamatergic and GABAergic signaling systems. This review aims at discussing the fundamental aspects of NO- and endocannabinoid-mediated signaling in the brain, and how they can be related to the neurobiology of depression. Both preclinical and clinical evidence supporting the involvement of these atypical neurotransmitters in the neurobiology of depression, and in the antidepressant effects are presented here. The evidence is discussed on basis of their ability to modulate different neurotransmitter systems in the brain, including monoaminergic and glutamatergic ones. A better comprehension of NO and endocannabinoid signaling mechanisms in the neurobiology depression could provide new avenues for the development of novel non-monoamine based antidepressants.

  5. Survey of Genes Involved in Biosynthesis, Transport, and Signaling of Phytohormones with Focus on Solanum lycopersicum

    PubMed Central

    Simm, Stefan; Scharf, Klaus-Dieter; Jegadeesan, Sridharan; Chiusano, Maria Luisa; Firon, Nurit; Schleiff, Enrico

    2016-01-01

    Phytohormones control the development and growth of plants, as well as their response to biotic and abiotic stress. The seven most well-studied phytohormone classes defined today are as follows: auxins, ethylene, cytokinin, abscisic acid, jasmonic acid, gibberellins, and brassinosteroids. The basic principle of hormone regulation is conserved in all plants, but recent results suggest adaptations of synthesis, transport, or signaling pathways to the architecture and growth environment of different plant species. Thus, we aimed to define the extent to which information from the model plant Arabidopsis thaliana is transferable to other plants such as Solanum lycopersicum. We extracted the co-orthologues of genes coding for major pathway enzymes in A. thaliana from the translated genomes of 12 species from the clade Viridiplantae. Based on predicted domain architecture and localization of the identified proteins from all 13 species, we inspected the conservation of phytohormone pathways. The comparison was complemented by expression analysis of (co-) orthologous genes in S. lycopersicum. Altogether, this information allowed the assignment of putative functional equivalents between A. thaliana and S. lycopersicum but also pointed to some variations between the pathways in eudicots, monocots, mosses, and green algae. These results provide first insights into the conservation of the various phytohormone pathways between the model system A. thaliana and crop plants such as tomato. We conclude that orthologue prediction in combination with analysis of functional domain architecture and intracellular localization and expression studies are sufficient tools to transfer information from model plants to other plant species. Our results support the notion that hormone synthesis, transport, and response for most part of the pathways are conserved, and species-specific variations can be found. PMID:27695302

  6. Intense electron-beam transport in the ion-focused regime through the collision-dominated regime

    SciTech Connect

    Sanford, T.W.L.; Poukey, J.W.; Welch, D.R.; Mock, R.C.

    1993-12-31

    This paper reviews the transport of the 19-MeV, 700-kA, 25-ns Hermes-III electron beam in long gas cells filled with N{sub 2} gas spanning six decades in pressure from 10{sup 3} to {approximately}10{sup 3} Torr. We show through measurements and theoretical analyses that the beam has two windows of stable transport: a low-pressure window (between {approximately}1 and {approximately}100 mTorr) that is dominated by propagation in the semi-collisionless IFR (ion-focused regime), and a high-pressure window (between {approximately}1 and {approximately}100 Torr) that is dominated by propagation in the resistive CDR (collision-dominated regime). In the CDR, 79{plus_minus}1.5% of the beam energy is transported over 11 m at 20 Torr. In the IFR, we show that intense radiation fields with controllable rise times and pulse widths can be generated on axis at a bremsstrahlung target. In summary, the measurements and analyses presented here provide a quantitative description of the Hermes-III beam transport over six decades in pressure.

  7. Simulation of Electron Beam Transport in Ion-Focused Regime Conditioning Cells

    DTIC Science & Technology

    1992-07-21

    leflhron Davis lgharay. Swft, I M. Arlington. VA 22Z02.4302. and to the office of Management and Budget. Paperwork Reduction Protect (07044 1in). Wahngon...nb(r, rz) and nh(r, rz) are the beam and ion densities, respectively, and vi is the gas ionization rate. In sir at pressure P, vi =P(torr) nsecŕ . In... Humphries and Ekdah156 and Fernsler, et al.57 FRIEZR employs a variation of Adler’s thin lens approximation to treat foil focusing. The impulse has the

  8. Modeling climate change impacts on maize growth with the focus on plant internal water transport

    NASA Astrophysics Data System (ADS)

    Heinlein, Florian; Biernath, Christian; Klein, Christian; Thieme, Christoph; Priesack, Eckart

    2015-04-01

    Based on climate change experiments in chambers and on field measurements, the scientific community expects regional and global changes of crop biomass production and yields. In central Europe one major aspect of climate change is the shift of precipitation towards winter months and the increase of extreme events, e.g. heat stress and heavy precipitation, during the main growing season in summer. To understand water uptake, water use, and transpiration rates by plants numerous crop models were developed. We tested the ability of two existing canopy models (CERES-Maize and SPASS) embedded in the model environment Expert-N5.0 to simulate the water balance, water use efficiency and crop growth. Additionally, sap flow was measured using heat-ratio measurement devices at the stem base of individual plants. The models were tested against data on soil water contents, as well as on evaporation and transpiration rates of Maize plants, which were grown on lysimeters at Helmholtz Zentrum München and in the field at the research station Scheyern, Germany, in summer 2013 and 2014. We present the simulation results and discuss observed shortcomings of the models. CERES-Maize and SPASS could simulate the measured dynamics of xylem sap flow. However, these models oversimplify plant water transport, and thus, cannot explain the underlying mechanisms. Therefore, to overcome these shortcomings, we additionally propose a new model, which is based on two coupled 1-D Richards equations, describing explicitly the plant and soil water transport. This model, which has previously successfully been applied to simulate water flux of 94 individual beech trees of an old-grown forest, will lead to a more mechanistic representation of the soil-plant-water-flow-continuum. This xylem water flux model was now implemented into the crop model SPASS and adjusted to simulate water flux of single maize plants. The modified version is presented and explained. Basic model input requirements are the plant

  9. The amyloid pathology progresses in a neurotransmitter-specific manner.

    PubMed

    Bell, Karen F S; Ducatenzeiler, Adriana; Ribeiro-da-Silva, Alfredo; Duff, Karen; Bennett, David A; Cuello, A Claudio

    2006-11-01

    Past studies using transgenic models of early-staged amyloid pathology, have suggested that the amyloid pathology progresses in a neurotransmitter-specific manner where cholinergic terminals appear most vulnerable, followed by glutamatergic terminals and finally by somewhat more resistant GABAergic terminals. To determine whether this neurotransmitter-specific progression persists at later pathological stages, presynaptic bouton densities, and the areas of occupation and localization of plaque adjacent dystrophic neurites were quantified in 18-month-old APP(K670N, M671L)+PS1(M146L) doubly transgenic mice. Quantification revealed that transgenic animals had significantly lower cholinergic, glutamatergic and GABAergic presynaptic bouton densities. Cholinergic and glutamatergic dystrophic neurites appear to be heavily influenced by fibrillar Abeta as both types displayed a decreasing area of occupation with respect to increasing plaque size. Furthermore, cholinergic dystrophic neurites reside in closer proximity to plaques than glutamatergic dystrophic neurites, while GABAergic dystrophic neurites were minimal regardless of plaque size. To investigate whether similarities exist in the human AD pathology, a monoclonal antibody (McKA1) against the human vesicular glutamate transporter 1 (VGluT1) was developed. Subsequent staining in AD brain tissue revealed the novel presence of glutamatergic dystrophic neurites, to our knowledge the first evidence of a structural glutamatergic deficit in the AD pathology.

  10. Mechanisms of material removal and mass transport in focused ion beam nanopore formation

    SciTech Connect

    Das, Kallol Johnson, Harley T.; Freund, Jonathan B.

    2015-02-28

    Despite the widespread use of focused ion beam (FIB) processing as a material removal method for applications ranging from electron microscope sample preparation to nanopore processing for DNA sequencing, the basic material removal mechanisms of FIB processing are not well understood. We present the first complete atomistic simulation of high-flux FIB using large-scale parallel molecular dynamics (MD) simulations of nanopore fabrication in freestanding thin films. We focus on the root mechanisms of material removal and rearrangement and describe the role of explosive boiling in forming nanopores. FIB nanopore fabrication is typically understood to occur via sputter erosion. This can be shown to be the case in low flux systems, where individual ion impacts are sufficiently separated in time that they may be considered as independent events. But our detailed MD simulations show that in high flux FIB processing, above a threshold level at which thermal effects become significant, the primary mechanism of material removal changes to a significantly accelerated, thermally dominated process. Under these conditions, the target is heated by the ion beam faster than heat is conducted away by the material, leading quickly to melting, and then continued heating to nearly the material critical temperature. This leads to explosive boiling of the target material with spontaneous bubble formation and coalescence. Mass is rapidly rearranged at the atomistic scale, and material removal occurs orders of magnitude faster than would occur by simple sputtering. While the phenomenology is demonstrated computationally in silicon, it can be expected to occur at lower beam fluxes in other cases where thermal conduction is suppressed due to material properties, geometry, or ambient thermal conditions.

  11. Temperature dependence of electrical properties of mixture of exogenous neurotransmitters dopamine and epinephrine

    NASA Astrophysics Data System (ADS)

    Patki, Mugdha; Patil, Vidya

    2016-05-01

    Neurotransmitters are chemical messengers that support the communication between the neurons. In vitro study of exogenous neurotransmitters Dopamine and Epinephrine and their mixture, carried out to learn about their electrical properties being dielectric constant and conductivity amongst others. Dielectric constant and conductivity of the selected neurotransmitters are found to increase with temperature. As a result, the time constant of the system increases with temperature. This change leads to increase in the time taken by the synapse to transport the action potential. The correlation between physical properties of exogenous neurotransmitters and psychological and physiological behaviour of human being may be understood with the help of current study. The response time of Epinephrine is in microseconds whereas response time of Dopamine is in milliseconds. The response time for both the neurotransmitters and their mixture is found to be increasing with temperature indicating the symptoms such as depression, apathy, chronic fatigue and low physical energy with no desire to exercise the body, which are observed during the fever.

  12. SIMULATION OF ENERGETIC PARTICLE TRANSPORT AND ACCELERATION AT SHOCK WAVES IN A FOCUSED TRANSPORT MODEL: IMPLICATIONS FOR MIXED SOLAR PARTICLE EVENTS

    SciTech Connect

    Kartavykh, Y. Y.; Dröge, W.; Gedalin, M.

    2016-03-20

    We use numerical solutions of the focused transport equation obtained by an implicit stochastic differential equation scheme to study the evolution of the pitch-angle dependent distribution function of protons in the vicinity of shock waves. For a planar stationary parallel shock, the effects of anisotropic distribution functions, pitch-angle dependent spatial diffusion, and first-order Fermi acceleration at the shock are examined, including the timescales on which the energy spectrum approaches the predictions of diffusive shock acceleration theory. We then consider the case that a flare-accelerated population of ions is released close to the Sun simultaneously with a traveling interplanetary shock for which we assume a simplified geometry. We investigate the consequences of adiabatic focusing in the diverging magnetic field on the particle transport at the shock, and of the competing effects of acceleration at the shock and adiabatic energy losses in the expanding solar wind. We analyze the resulting intensities, anisotropies, and energy spectra as a function of time and find that our simulations can naturally reproduce the morphologies of so-called mixed particle events in which sometimes the prompt and sometimes the shock component is more prominent, by assuming parameter values which are typically observed for scattering mean free paths of ions in the inner heliosphere and energy spectra of the flare particles which are injected simultaneously with the release of the shock.

  13. Magnetotransport along a boundary: from coherent electron focusing to edge channel transport

    NASA Astrophysics Data System (ADS)

    Stegmann, T.; Wolf, D. E.; Lorke, A.

    2013-11-01

    We study theoretically how electrons, coherently injected at one point on the boundary of a two-dimensional electron system, are focused by a perpendicular magnetic field B onto another point on the boundary. Using the non-equilibrium Green's function approach, we calculate the generalized four-point Hall resistance Rxy as a function of B. In weak fields, Rxy shows the characteristic equidistant peaks observed in the experiment and explained by classical cyclotron motion along the boundary. In strong fields, Rxy shows a single extended plateau reflecting the quantum Hall effect. In intermediate fields, we find superimposed upon the lower Hall plateaus anomalous oscillations, which are neither periodic in 1/B (quantum Hall effect) nor in B (classical cyclotron motion). The oscillations are explained by the interference between the occupied edge channels, which causes beatings in Rxy. In the case of two occupied edge channels, these beatings constitute a new commensurability between the magnetic flux enclosed within the edge channels and the flux quantum. Introducing decoherence and a partially specular boundary shows that this new effect is quite robust.

  14. [Neurotransmitters, calcium signalling and neuronal communication].

    PubMed

    Eguiagaray, J G; Egea, J; Bravo-Cordero, J J; García, A G

    2004-04-01

    In this article we show some recent findings that constitute a great progress in the molecular knowledge of synaptic dynamics. To communicate, neurons use a code that includes electrical (action potentials) and chemical signals (neurotransmitters, neuromodulators). At the moment a great variety of molecules are known, whose neurotransmitter function in brain and the peripheral nervous system are out of question. Monoamines like acetylcholine, dopamine, noradrenaline, adrenaline, histamine, serotonin, glutamate, aspartate, glycine, ATP and GABA are good examples. Opioid neuropeptides, vasoactive intestinal peptide (VIP), neurokinines (substance P), somatostatin, neurotensin, neuropeptide Y, cholecystokinine, vasopressin or oxitocin have been related to the control of the stress response, sexual behaviour, food intake, pain, learning and memory, qualities that are also related to nitric oxide (NO). A great part of the molecular structure of the secretory machinery is known to be responsible for fast neurotransmitter release at the synapse, in response to action potentials. Proteins like sinaptobrevin (located in the membrane of the synaptic vesicle), sintaxin and SNAP-25 (both located at the presynaptic plasma membrane) constitute a trimeric complex which is responsible of the vesicular docking at the active sites for exocytosis. From this strategic location, vesicles release their neurotransmitter within few milliseconds, when the action potential invades the nerve terminal and activates the opening of the different subtypes of voltage-dependent Ca2+ channels. The asymmetric geographical distribution of each type of channel, in different neurons, rose the hypothesis that Ca2+ that enters through each subtype of channel is compartmentalised, thus favouring the generation of Ca2+ microdomains, in the cytosol and the nucleus, involved in different cellular functions. This great biochemical synaptic heterogeneity is facilitating the selection of many biological targets

  15. Modelisation of transport in fractured media with a smeared fractures modeling approach: special focus on matrix diffusion process.

    NASA Astrophysics Data System (ADS)

    Fourno, A.; Grenier, C.; Benabderrahmane, H.

    2003-04-01

    the fractured network. For a long time scale, the diffusion process can't be neglected. It plays an important retention role for the transport of plume. This is why we focus here on the evaluation of the approach for matrix diffusion. In addition, this is, here, a key issue because one of the specificities of the smeared fractures method is that it can deal with the actual rock block volume. Nevertheless we only devote a limited number of meshes to rock matrix blocks so that the limits of the approach in terms of time and space discretization level as well as transport regimes have to be addressed. So, having implemented the developed smeared fracture approach in our code CAST3M, we study the diffusion process for different transport regimes from dominant fracture network transport to dominant matrix diffusion transport and we estimate the validity as well as the precision of the results for different mesh sizes. This is done by comparing the smeared fracture approach results to reference calculations obtained by explicitly meshing the fractured system. Results show that the smeared fracture approach fairly well captures the main features of transport and reduces the simulation costs. For the cases studied, we succeed in having a good precision with different discretization levels. This finally makes this approach an interesting compromise between precision and versatility associated to low computer costs in the perspective of Monte Carlo simulations. A more realistic application is provided based on data from the Äspö underground laboratory (Sweden) and discussed. Future steps include extension of the approach to 3D cases.

  16. Computational Studies of Glutamate Transporters

    PubMed Central

    Setiadi, Jeffry; Heinzelmann, Germano; Kuyucak, Serdar

    2015-01-01

    Glutamate is the major excitatory neurotransmitter in the human brain whose binding to receptors on neurons excites them while excess glutamate are removed from synapses via transporter proteins. Determination of the crystal structures of bacterial aspartate transporters has paved the way for computational investigation of their function and dynamics at the molecular level. Here, we review molecular dynamics and free energy calculation methods used in these computational studies and discuss the recent applications to glutamate transporters. The focus of the review is on the insights gained on the transport mechanism through computational methods, which otherwise is not directly accessible by experimental probes. Recent efforts to model the mammalian glutamate and other amino acid transporters, whose crystal structures have not been solved yet, are included in the review. PMID:26569328

  17. Molecular mechanisms driving homeostatic plasticity of neurotransmitter release

    PubMed Central

    Lazarevic, Vesna; Pothula, Santosh; Andres-Alonso, Maria; Fejtova, Anna

    2013-01-01

    Homeostatic plasticity is a process by which neurons adapt to the overall network activity to keep their firing rates in a reasonable range. At the cellular level this kind of plasticity comprises modulation of cellular excitability and tuning of synaptic strength. In this review we concentrate on presynaptic homeostatic plasticity controlling the efficacy of neurotransmitter release from presynaptic boutons. While morphological and electrophysiological approaches were successful to describe homeostatic plasticity-induced changes in the presynaptic architecture and function, cellular and molecular mechanisms underlying those modifications remained largely unknown for a long time. We summarize the latest progress made in the understanding of homeostasis-induced regulation of different steps of the synaptic vesicle cycle and the molecular machineries involved in this process. We particularly focus on the role of presynaptic scaffolding proteins, which functionally and spatially organize synaptic vesicle clusters, neurotransmitter release sites and the associated endocytic machinery. These proteins turned out to be major presynaptic substrates for remodeling during homeostatic plasticity. Finally, we discuss cellular processes and signaling pathways acting during homeostatic molecular remodeling and their potential involvement in the maladaptive plasticity occurring in multiple neuropathologic conditions such as neurodegeneration, epilepsy and neuropsychiatric disorders. PMID:24348337

  18. Microfluidic platform for neurotransmitter sensing based on cyclic voltammetry and dielectrophoresis for in vitro experiments.

    PubMed

    Mathault, Jessy; Zamprogno, Pauline; Greener, Jesse; Miled, Amine

    2015-08-01

    This paper presents a new microfluidic platform that can simultaneously measure and locally modulate neurotransmitter concentration in a neuron network. This work focuses on the development of a first prototype including a potentiostat and electrode functionalization to detect several neurotransmitter's simultaneously. We tested dopamine as proof of concept to validate functionality. The system is based on 320 bidirectional electrode array for dielectrophoretic manipulation and cyclic voltammetry. Each electrode is connected to a mechanical multiplexer in order to reduce noise interference and fully isolate the electrode. The multiplexing rate is 476 kHz and each electrode can drive a signal with an amplitude of 60 V pp for dielectrophoretic manipulation.

  19. Receptor desensitization by neurotransmitters in membranes: are neurotransmitters the endogenous anesthetics?

    PubMed

    Cantor, Robert S

    2003-10-21

    A mechanism of anesthesia is proposed that addresses one of the most troubling peculiarities of general anesthesia: the remarkably small variability of sensitivity within the human population and across a broad range of animal phyla. It is hypothesized that in addition to the rapid, saturable binding of a neurotransmitter to its receptor that results in activation, the neurotransmitter also acts indirectly on the receptor by diffusing into the postsynaptic membrane and changing its physical properties, causing a shift in receptor conformational equilibrium (desensitization). Unlike binding, this slower indirect mechanism is nonspecific: each neurotransmitter will, in principle, affect all receptors in the membrane. For proteins modeled as having only resting and active conformational states, time-dependent ion currents are predicted that exhibit many characteristics of desensitization for both inhibitory and excitatory channels. If receptors have been engineered to regulate the time course of ion currents by this mechanism, then (a) mutations that significantly alter receptor sensitivity to this effect would be lethal and (b) by design, excitatory receptors would be inhibited, but inhibitory receptors activated, so that their effects are not counterproductive. The wide range of exogenous molecules that affect the physical properties of membranes as do neurotransmitters, but that do not bind to receptors, would thus inhibit excitatory channels and activate inhibitory channels, i.e., they would act as anesthesics. The endogenous anesthetics would thus be the neurotransmitters, the survival advantage conferred by their proper membrane-mediated desensitization of receptors explaining the selection pressure for anesthesic sensitivity.

  20. Modulation of neurotransmitter receptors and synaptic differentiation by proteins containing complement-related domains.

    PubMed

    Nakayama, Minoru; Hama, Chihiro

    2011-02-01

    Neurotransmitter receptors play central roles in basic neurotransmission and synaptic plasticity. Recent studies have revealed that some transmembrane and extracellular proteins bind to neurotransmitter receptors, forming protein complexes that are required for proper synaptic localization or gating of core receptor molecules. Consequently, the components of these complexes contribute to long-term potentiation, a process that is critical for learning and memory. Here, we review factors that regulate neurotransmitter receptors, with a focus on proteins containing CUB (complement C1r/C1s, Uegf, Bmp1) or CCP (complement control protein) domains, which are frequently found in complement system proteins. Proteins that contain these domains are structurally distinct from TARPs (transmembrane AMPA receptor regulatory proteins), and may constitute new protein families that modulate either the localization or function of neurotransmitter receptors. In addition, other CCP domain-containing proteins participate in dendritic patterning and/or synaptic differentiation, although current evidence has not identified any direct activities on neurotransmitter receptors. Some of these proteins are involved in pathologic conditions such as epileptic seizure and mental retardation. Together, these lines of information have shown that CUB and CCP domain-containing proteins contribute to a wide variety of neuronal events that ultimately establish neural circuits.

  1. Neuronal release and successful astrocyte uptake of aminoacidergic neurotransmitters after spinal cord injury in lampreys.

    PubMed

    Fernández-López, Blanca; Valle-Maroto, Silvia María; Barreiro-Iglesias, Antón; Rodicio, María Celina

    2014-08-01

    In contrast to mammals, the spinal cord of lampreys spontaneously recovers from a complete spinal cord injury (SCI). Understanding the differences between lampreys and mammals in their response to SCI could provide valuable information to propose new therapies. Unique properties of the astrocytes of lampreys probably contribute to the success of spinal cord regeneration. The main aim of our study was to investigate, in the sea lamprey, the release of aminoacidergic neurotransmitters and the subsequent astrocyte uptake of these neurotransmitters during the first week following a complete SCI by detecting glutamate, GABA, glycine, Hu and cytokeratin immunoreactivities. This is the first time that aminoacidergic neurotransmitter release from neurons and the subsequent astrocytic response after SCI are analysed by immunocytochemistry in any vertebrate. Spinal injury caused the immediate loss of glutamate, GABA and glycine immunoreactivities in neurons close to the lesion site (except for the cerebrospinal fluid-contacting GABA cells). Only after SCI, astrocytes showed glutamate, GABA and glycine immunoreactivity. Treatment with an inhibitor of glutamate transporters (DL-TBOA) showed that neuronal glutamate was actively transported into astrocytes after SCI. Moreover, after SCI, a massive accumulation of inhibitory neurotransmitters around some reticulospinal axons was observed. Presence of GABA accumulation significantly correlated with a higher survival ability of these neurons. Our data show that, in contrast to mammals, astrocytes of lampreys have a high capacity to actively uptake glutamate after SCI. GABA may play a protective role that could explain the higher regenerative and survival ability of specific descending neurons of lampreys.

  2. The reverse operation of Na+/Cl−-coupled neurotransmitter transporters–why amphetamines take two to tango

    PubMed Central

    Sitte, Harald H.; Freissmuth, Michael

    2015-01-01

    Sodium-chloride coupled neurotransmitter transporters achieve reuptake of their physiological substrate by exploiting the pre-existing sodium-gradient across the cellular membrane. This terminates the action of previously released substrate in the synaptic cleft. However, a change of the transmembrane ionic gradients or specific binding of some psychostimulant drugs to these proteins, like amphetamine and its derivatives, induce reverse operation of neurotransmitter:sodium symporters. This effect eventually leads to an increase in the synaptic concentration of non-exocytotically released neurotransmitters [and – in the case of the norepinephrine transporters, underlies the well-known indirect sympathomimetic activity]. While this action has long been appreciated, the underlying mechanistic details have been surprisingly difficult to understand. Some aspects can be resolved by incorporating insights into the oligomeric nature of transporters, into the nature of the accompanying ion fluxes, and changes in protein kinase activities. PMID:19891736

  3. Fabrication and electrical transport properties of binary Co-Si nanostructures prepared by focused electron beam-induced deposition

    SciTech Connect

    Porrati, F.; Huth, M.; Kaempken, B.; Terfort, A.

    2013-02-07

    CoSi-C binary alloys have been fabricated by focused electron beam-induced deposition by the simultaneous use of dicobaltoctacarbonyl, Co{sub 2}(CO){sub 8}, and neopentasilane, Si{sub 5}H{sub 12}, as precursor gases. By varying the relative flux of the precursors, alloys with variable chemical composition are obtained, as shown by energy dispersive x-ray analysis. Room temperature electrical resistivity measurements strongly indicate the formation of cobalt silicide and cobalt disilicide nanoclusters embedded in a carbonaceous matrix. Temperature-dependent electrical conductivity measurements show that the transport properties are governed by electron tunneling between neighboring CoSi or CoSi{sub 2} nanoclusters. In particular, by varying the metal content of the alloy, the electrical conductivity can be finely tuned from the insulating regime into the quasi-metallic tunneling coupling regime.

  4. Fabrication and electrical transport properties of binary Co-Si nanostructures prepared by focused electron beam-induced deposition

    NASA Astrophysics Data System (ADS)

    Porrati, F.; Kämpken, B.; Terfort, A.; Huth, M.

    2013-02-01

    CoSi-C binary alloys have been fabricated by focused electron beam-induced deposition by the simultaneous use of dicobaltoctacarbonyl, Co2(CO)8, and neopentasilane, Si5H12, as precursor gases. By varying the relative flux of the precursors, alloys with variable chemical composition are obtained, as shown by energy dispersive x-ray analysis. Room temperature electrical resistivity measurements strongly indicate the formation of cobalt silicide and cobalt disilicide nanoclusters embedded in a carbonaceous matrix. Temperature-dependent electrical conductivity measurements show that the transport properties are governed by electron tunneling between neighboring CoSi or CoSi2 nanoclusters. In particular, by varying the metal content of the alloy, the electrical conductivity can be finely tuned from the insulating regime into the quasi-metallic tunneling coupling regime.

  5. Artificial domain structures realized by local gallium focused Ion-beam modification of Pt /Co/Pt trilayer transport structure

    NASA Astrophysics Data System (ADS)

    Aziz, A.; Bending, S. J.; Roberts, H.; Crampin, S.; Heard, P. J.; Marrows, C. H.

    2005-12-01

    We demonstrate that a high-resolution Ga focused ion beam can be used to introduce artificial domain structures in Pt(1.6nm )/Co(0.5nm)/Pt(3.5nm) trilayer transport structures. We have used thin SiO2 overlayers to control the effective energy and dose of Ga ions at the Pt /Co interface. The extraordinary Hall effect (EHE) was used to characterize the magnetic properties of the patterned films. Using 30keV Ga ions and SiO2 overlayer thicknesses in the range of 0-24nm, we achieve complete control of the coercive field of our Pt /Co/Pt trilayer structures. The magnetization reversal mechanism for an artificial domain of size of 3×0.5μm2 is investigated using EHE.

  6. Pharmacology of neurotransmitter release: measuring exocytosis.

    PubMed

    Khvotchev, Mikhail; Kavalali, Ege T

    2008-01-01

    Neurotransmission in the nervous system is initiated at presynaptic terminals by fusion of synaptic vesicles with the plasma membrane and subsequent exocytic release of chemical transmitters. Currently, there are multiple methods to detect neurotransmitter release from nerve terminals, each with their own particular advantages and disadvantages. For instance, most commonly employed methods monitor actions of released chemical substances on postsynaptic receptors or artificial substrates such as carbon fibers. These methods are closest to the physiological setting because they have a rapid time resolution and they measure the action of the endogenous neurotransmitters rather than the signals emitted by exogenous probes. However, postsynaptic receptors only indirectly report neurotransmitter release in a form modified by the properties of receptors themselves, which are often nonlinear detectors of released substances. Alternatively, released chemical substances can be detected biochemically, albeit on a time scale slower than electrophysiological methods. In addition, in certain preparations, where presynaptic terminals are accessible to whole cell recording electrodes, fusion of vesicles with the plasma membrane can be monitored using capacitance measurements. In the last decade, in addition to electrophysiological and biochemical methods, several fluorescence imaging modalities have been introduced which report synaptic vesicle fusion, endocytosis, and recycling. These methods either take advantage of styryl dyes that can be loaded into recycling vesicles or exogenous expression of synaptic vesicle proteins tagged with a pH-sensitive GFP variant at regions facing the vesicle lumen. In this chapter, we will provide an overview of these methods with particular emphasis on their relative strengths and weaknesses and discuss the types of information one can obtain from them.

  7. Characterizing Enzymatic Deposition for Microelectrode Neurotransmitter Detection

    SciTech Connect

    Hosein, W. K.; Yorita, A. M.; Tolosa, V. M.

    2016-08-12

    The enzyme immobilization process, one step in creating an enzymatic biosensor, was characterized and analyzed as a function of its physical properties. The neural glutamic biosensor is a flexible device, effectively minimizing trauma to the area of implantation. The Multielectrode Array (MEA) is composed primarily of a proprietary polymer which has been successfully implanted into human subjects in recent years. This polymer allows the device the pliability that other devices normally lack, though this poses some challenges to implantation. The electrodes are made of Platinum (Pt), and can range in number from eight to thirty two electrodes per device. These electrodes are electroplated with a semipermeable polymer layer to improve selectivity of the electrode to the neurotransmitter of interest, in this case glutamate. A signal is created from the interaction of glutamate in the brain with the glutamate oxidase (GluOx) which is immobilized on the surface of the electrode by using crosslinking chemistry in conjunction with glutaraldehyde and Bovine Serum Albumin (BSA). The glutamate is oxidized by glutamate oxidase, producing α-ketoglutarate and hydrogen peroxide (H2O2) as a by-product. The production of H2O2 is crucial for detection of the presence of the glutamate within the enzymatic coating, as it diffuses through the enzyme layer and oxidizes at the surface of the electrode. This oxidation is detectable by measurable change in the current using amperometry. Hence, the MEA allows for in vivo monitoring of neurotransmitter activity in real time. The sensitivity of the sensor to these neurotransmitters is dependent on the thickness of the layer, which is investigated in these experiments in order to optimize the efficacy of the device to detecting the substrate, once implanted.

  8. A FOCUSED TRANSPORT APPROACH TO THE TIME-DEPENDENT SHOCK ACCELERATION OF SOLAR ENERGETIC PARTICLES AT A FAST TRAVELING SHOCK

    SciTech Connect

    Le Roux, J. A.; Webb, G. M.

    2012-02-10

    Some of the most sophisticated models for solar energetic particle (SEP) acceleration at coronal mass ejection driven shocks are based on standard diffusive shock acceleration theory. However, this theory, which only applies when SEP pitch-angle anisotropies are small, might have difficulty in describing first-order Fermi acceleration or the shock pre-heating and injection of SEPs into first-order Fermi acceleration accurately at lower SEP speeds where SEP pitch-angle anisotropies upstream near the shock can be large. To avoid this problem, we use a time-dependent focused transport model to reinvestigate first-order Fermi acceleration at planar parallel and quasi-parallel spherical traveling shocks between the Sun and Earth with high shock speeds associated with rare extreme gradual SEP events. The focused transport model is also used to investigate and compare three different shock pre-heating mechanisms associated with different aspects of the nonuniform cross-shock solar wind flow, namely, the convergence of the flow (adiabatic compression), the shear tensor of the flow, and the acceleration of the flow, and a fourth shock pre-heating mechanism associated with the cross-shock electric field, to determine which pre-heating mechanism contributes the most to injecting shock pre-heated source particles into the first-order Fermi acceleration process. The effects of variations in traveling shock conditions, such as increasing shock obliquity and shock slowdown, and variations in the SEP source with increasing shock distance from the Sun on the coupled processes of shock pre-heating, injection, and first-order Fermi acceleration are analyzed. Besides the finding that the cross-shock acceleration of the solar wind flow yields the dominant shock pre-heating mechanism at high shock speeds, we find that first-order Fermi acceleration at fast traveling shocks differs in a number of respects from the predictions and assumptions of standard steady-state diffusive shock

  9. [Neurotransmitter mechanisms of context-dependent behavior].

    PubMed

    D'iakonova, V E

    2012-01-01

    The influence of context on behavioral choice is well known. Context can refer to behavioral state of an animal and to external factors such as season, presence of other individuals or food availability. How external and internal factors influencing decision-making are translated at the cellular level? I review the recent neuroethological data that strongly suggest that context reflects in content of neuroactive substances (neurotransmitters, modulators, hormones) that present in the extraneuronal milieu, while heterochemical neuronal microenvironment in its turn impacts motor program selection.

  10. PICKing on transporters.

    PubMed

    Deken, S L; Beckman, M L; Quick, M W

    2001-11-01

    Plasma membrane neurotransmitter transporters are regulators of extracellular transmitter levels in brain and are the primary sites of action for several drugs of abuse and therapy. Studies are beginning to reveal how neurons use synaptic machinery to modulate these regulators.

  11. The Role of Neurotrophins in Neurotransmitter Release

    PubMed Central

    Tyler, William J.; Perrett, Stephen P.; Pozzo-Miller, Lucas D.

    2009-01-01

    The neurotrophins (NTs) have recently been shown to elicit pronounced effects on quantal neurotransmitter release at both central and peripheral nervous system synapses. Due to their activity-dependent release, as well as the subcellular localization of both protein and receptor, NTs are ideally suited to modify the strength of neuronal connections by “fine-tuning” synaptic activity through direct actions at presynaptic terminals. Here, using BDNF as a prototypical example, the authors provide an update of recent evidence demonstrating that NTs enhance quantal neurotransmitter release at synapses through presynaptic mechanisms. The authors further propose that a potential target for NT actions at presynaptic terminals is the mechanism by which terminals retrieve synaptic vesicles after exocytosis. Depending on the temporal demands placed on synapses during high-frequency synaptic transmission, synapses may use two alternative modes of synaptic vesicle retrieval, the conventional slow endosomal recycling or a faster rapid retrieval at the active zone, referred to as “kiss-and-run.” By modulating Ca2+ microdomains associated with voltage-gated Ca2+ channels at active zones, NTs may elicit a switch from the slow to the fast mode of endocytosis of vesicles at presynaptic terminals during high-frequency synaptic transmission, allowing more reliable information transfer and neuronal signaling in the central nervous system. PMID:12467374

  12. Chloride binding site of neurotransmitter sodium symporters

    PubMed Central

    Kantcheva, Adriana K.; Quick, Matthias; Shi, Lei; Winther, Anne-Marie Lund; Stolzenberg, Sebastian; Weinstein, Harel; Javitch, Jonathan A.; Nissen, Poul

    2013-01-01

    Neurotransmitter:sodium symporters (NSSs) play a critical role in signaling by reuptake of neurotransmitters. Eukaryotic NSSs are chloride-dependent, whereas prokaryotic NSS homologs like LeuT are chloride-independent but contain an acidic residue (Glu290 in LeuT) at a site where eukaryotic NSSs have a serine. The LeuT-E290S mutant displays chloride-dependent activity. We show that, in LeuT-E290S cocrystallized with bromide or chloride, the anion is coordinated by side chain hydroxyls from Tyr47, Ser290, and Thr254 and the side chain amide of Gln250. The bound anion and the nearby sodium ion in the Na1 site organize a connection between their coordinating residues and the extracellular gate of LeuT through a continuous H-bond network. The specific insights from the structures, combined with results from substrate binding studies and molecular dynamics simulations, reveal an anion-dependent occlusion mechanism for NSS and shed light on the functional role of chloride binding. PMID:23641004

  13. Neurotransmitter signaling in the pathophysiology of microglia

    PubMed Central

    Domercq, María; Vázquez-Villoldo, Nuria; Matute, Carlos

    2013-01-01

    Microglial cells are the resident immune cells of the central nervous system. In the resting state, microglia are highly dynamic and control the environment by rapidly extending and retracting motile processes. Microglia are closely associated with astrocytes and neurons, particularly at the synapses, and more recent data indicate that neurotransmission plays a role in regulating the morphology and function of surveying/resting microglia, as they are endowed with receptors for most known neurotransmitters. In particular, microglia express receptors for ATP and glutamate, which regulate microglial motility. After local damage, the release of ATP induces microgliosis and activated microglial cells migrate to the site of injury, proliferate, and phagocytose cells, and cellular compartments. However, excessive activation of microglia could contribute to the progression of chronic neurodegenerative diseases, though the underlying mechanisms are still unclear. Microglia have the capacity to release a large number of substances that can be detrimental to the surrounding neurons, including glutamate, ATP, and reactive oxygen species. However, how altered neurotransmission following acute insults or chronic neurodegenerative conditions modulates microglial functions is still poorly understood. This review summarizes the relevant data regarding the role of neurotransmitter receptors in microglial physiology and pathology. PMID:23626522

  14. Chloride binding site of neurotransmitter sodium symporters.

    PubMed

    Kantcheva, Adriana K; Quick, Matthias; Shi, Lei; Winther, Anne-Marie Lund; Stolzenberg, Sebastian; Weinstein, Harel; Javitch, Jonathan A; Nissen, Poul

    2013-05-21

    Neurotransmitter:sodium symporters (NSSs) play a critical role in signaling by reuptake of neurotransmitters. Eukaryotic NSSs are chloride-dependent, whereas prokaryotic NSS homologs like LeuT are chloride-independent but contain an acidic residue (Glu290 in LeuT) at a site where eukaryotic NSSs have a serine. The LeuT-E290S mutant displays chloride-dependent activity. We show that, in LeuT-E290S cocrystallized with bromide or chloride, the anion is coordinated by side chain hydroxyls from Tyr47, Ser290, and Thr254 and the side chain amide of Gln250. The bound anion and the nearby sodium ion in the Na1 site organize a connection between their coordinating residues and the extracellular gate of LeuT through a continuous H-bond network. The specific insights from the structures, combined with results from substrate binding studies and molecular dynamics simulations, reveal an anion-dependent occlusion mechanism for NSS and shed light on the functional role of chloride binding.

  15. Imaging neurotransmitter release kinetics in living cells

    SciTech Connect

    Tan, Weihong; Yeung, E.S.; Haydon, P.G.

    1996-12-31

    A new UV-laser based optical microscope and CCD detection system has been developed to image neurotransmitter in living biological cells. We demonstrate the detection of serotonin that has been taken up into and released from individual living glial cells (astrocytes) based on its native fluorescence. The detection methodology has high sensitivity, low limit of detection and does not require coupling to fluorescence dyes. We have studied serotonin uptake kinetics and its release dynamics in single glial cells. Different regions of a glial cell have taken up different amounts of serotonin with a variety of kinetics. Similarly, different serotonin release mechanisms have been observed in different astrocyte cell regions. The temporal resolution of this detection system is as fast as 50 ms, and the spatial resolution is diffraction limited. We will also report on single enzyme molecule reaction studies and single metal ion detection based on CCD imaging of pL reaction vials formed by micromachining on fused silica.

  16. Marine Toxins Potently Affecting Neurotransmitter Release

    NASA Astrophysics Data System (ADS)

    Meunier, Frédéric A.; Mattei, César; Molgó, Jordi

    Synapses are specialised structures where interneuronal communication takes place. Not only brain function is absolutely dependent on synaptic activity, but also most of our organs are intimately controlled by synaptic activity. Synapses re therefore an ideal target to act upon and poisonous species have evolved fascinating neurotoxins capable of shutting down neuronal communication by blocking or activating essential components of the synapse. By hijacking key proteins of the communication machinery, neurotoxins are therefore extremely valuable tools that have, in turn, greatly helped our understanding of synaptic biology. Moreover, analysis and understanding of the molecular strategy used by certain neurotoxins has allowed the design of entirely new classes of drugs acting on specific targets with high selectivity and efficacy. This chapter will discuss the different classes of marine neurotoxins, their effects on neurotransmitter release and how they act to incapacitate key steps in the process leading to synaptic vesicle fusion.

  17. 13C MRS studies of neuroenergetics and neurotransmitter cycling in humans.

    PubMed

    Rothman, Douglas L; De Feyter, Henk M; de Graaf, Robin A; Mason, Graeme F; Behar, Kevin L

    2011-10-01

    In the last 25 years, (13)C MRS has been established as the only noninvasive method for the measurement of glutamate neurotransmission and cell-specific neuroenergetics. Although technically and experimentally challenging, (13)C MRS has already provided important new information on the relationship between neuroenergetics and neuronal function, the energy cost of brain function, the high neuronal activity in the resting brain state and how neuroenergetics and neurotransmitter cycling are altered in neurological and psychiatric disease. In this article, the current state of (13)C MRS as it is applied to the study of neuroenergetics and neurotransmitter cycling in humans is reviewed. The focus is predominantly on recent findings in humans regarding metabolic pathways, applications to clinical research and the technical status of the method. Results from in vivo (13)C MRS studies in animals are discussed from the standpoint of the validation of MRS measurements of neuroenergetics and neurotransmitter cycling, and where they have helped to identify key questions to address in human research. Controversies concerning the relationship between neuroenergetics and neurotransmitter cycling and factors having an impact on the accurate determination of fluxes through mathematical modeling are addressed. We further touch upon different (13)C-labeled substrates used to study brain metabolism, before reviewing a number of human brain diseases investigated using (13)C MRS. Future technological developments are discussed that will help to overcome the limitations of (13)C MRS, with special attention given to recent developments in hyperpolarized (13)C MRS.

  18. Secondary Abnormalities of Neurotransmitters in Infants with Neurological Disorders

    ERIC Educational Resources Information Center

    Garcia-Cazorla, A.; Serrano, M.; Perez-Duenas, B.; Gonzalez, V.; Ormazabal, A.; Pineda, M.; Fernandez-Alvarez, E.; Campistol, J. M. D.; Artuch, R. M. D.

    2007-01-01

    Neurotransmitters are essential in young children for differentiation and neuronal growth of the developing nervous system. We aimed to identify possible factors related to secondary neurotransmitter abnormalities in pediatric patients with neurological disorders. We analyzed cerebrospinal fluid (CSF) and biogenic amine metabolites in 56 infants…

  19. Secondary Abnormalities of Neurotransmitters in Infants with Neurological Disorders

    ERIC Educational Resources Information Center

    Garcia-Cazorla, A.; Serrano, M.; Perez-Duenas, B.; Gonzalez, V.; Ormazabal, A.; Pineda, M.; Fernandez-Alvarez, E.; Campistol, J. M. D.; Artuch, R. M. D.

    2007-01-01

    Neurotransmitters are essential in young children for differentiation and neuronal growth of the developing nervous system. We aimed to identify possible factors related to secondary neurotransmitter abnormalities in pediatric patients with neurological disorders. We analyzed cerebrospinal fluid (CSF) and biogenic amine metabolites in 56 infants…

  20. Chronic paroxetine treatment: effects on other non-serotonergic neurotransmitter systems.

    PubMed

    Ballesteros-Zebadua, Paola; Manjarrez-Marmolejo, Joaquin; Franco-Perez, Javier

    2013-12-01

    Due to its efficacy and acceptability, paroxetine is situated in the top ten of drugs prescribed for the treatment of major depression and essentially all anxiety disorders. Adults under paroxetine treatment report relief after 4-6 weeks of administration; furthermore, this drug can be prescribed for periods lasting longer than one year. Therefore, paroxetine treatment has a pattern of ingestion that is mainly chronic rather than acute. There is a considerable number of reviews in the literature concerning the effects of paroxetine on the serotonergic system; however, the alterations caused by chronic ingestion of this drug in other neurotransmitter systems have received little attention. For this reason, we consider very important to review the experimental studies concerning the effects of chronic paroxetine intake on neurotransmitter levels, neuronal firing rate and the expression of receptors and transporters in different neurotransmitter systems in the brain. According to the experimental data analyzed in this work, we can establish that long-term paroxetine intake has the ability to increase GABA, glutamate, dopamine and noradrenaline levels in the brain. Furthermore, high levels of AMPA, orexine-1,2 and histamine-1 receptors have been reported in different brain regions after treatment with paroxetine over several weeks. In addition, paroxetine has differential effects on neuropeptide systems, such as galanine, opioid receptors and substance P. Available data lead us to establish that chronic ingestion of paroxetine induces changes in several neurotransmitters and neuropeptides, thus illuminating how each one may contribute to the antidepressant and anxiolytic response elicited by this drug. We consider that all reported changes in the neurotransmitter systems should be further considered to individualize clinical treatment and, in the case of patients taking a drug "cocktail", to gain better control over drug interactions and adverse effects.

  1. A 109 neutrons/pulse transportable pulsed D-D neutron source based on flexible head plasma focus unit

    NASA Astrophysics Data System (ADS)

    Niranjan, Ram; Rout, R. K.; Srivastava, R.; Kaushik, T. C.; Gupta, Satish C.

    2016-03-01

    A 17 kJ transportable plasma focus (PF) device with flexible transmission lines is developed and is characterized. Six custom made capacitors are used for the capacitor bank (CB). The common high voltage plate of the CB is fixed to a centrally triggered spark gap switch. The output of the switch is coupled to the PF head through forty-eight 5 m long RG213 cables. The CB has a quarter time-period of 4 μs and an estimated current of 506 kA is delivered to the PF device at 17 kJ (60 μF, 24 kV) energy. The average neutron yield measured using silver activation detector in the radial direction is (7.1 ± 1.4) × 108 neutrons/shot over 4π sr at 5 mbar optimum D2 pressure. The average neutron yield is more in the axial direction with an anisotropy factor of 1.33 ± 0.18. The average neutron energies estimated in the axial as well as in the radial directions are (2.90 ± 0.20) MeV and (2.58 ± 0.20) MeV, respectively. The flexibility of the PF head makes it useful for many applications where the source orientation and the location are important factors. The influence of electromagnetic interferences from the CB as well as from the spark gap on applications area can be avoided by putting a suitable barrier between the bank and the PF head.

  2. Effects on the diet on brain neurotransmitters.

    PubMed

    Fernstrom, J D

    1977-02-01

    The synthesis of neurotransmitters in mammalian brain responds rapidly to changes in precursor availability. Serotonin synthesis depends largely on the brain concentrations of L-tryptophan, its precursor amino aicd. This relationship appears to be physiologic: when brain tryptophan levels vary because of insulin secretion or meal ingestion, corresponding alterations occur in the rate of serotonin formation. The ability of any food to modify brain tryptophan (and serotonin) depends on how its ingestion changes the serum concentration of not only tryptophan, but also several other large neutral amino acids that compete with tryptophan for uptake into the brain. Such precursor-induced changes in brain serotonin appear to be functionally important: animals having a reduced level of brain serotonin (caused by the chronic ingestion of a naturally tryptophan-poor diet, such as corn) demonstrate a heightened sensitivity to painful stimuli; this pain sensitivity can be acutely restored to normal values by a single injection of L-tryptophan, which rapidly elevates brain serotonin. The synthesis of catecholamines (e.g., dopamine, norepinephrine) in the brain also varies with the availability of the precursor amino acid L-tyrosine. Single injections of this amino acid increase brain tyrosine levels and accelerate brain catechol synthesis, while injections of a competing neutral amino acid (e.g., leucine, tryptophan) reduce brain tyrosine and its rate of conversion to dopa. The rate of catecholamine synthesis, however, appears to be influenced less by precursor levels than is serotonin formation: tyrosine hydroxylase, whcih catalyzes the rate-limiting step in catecholamine synthesis, responds strongly to end-product inhibition and to other controls that reflect variations in neuronal activity. The synthesis of acetylcholine in brain responds to substrate (choline) availability much like serotonin synthesis. Short-term alterations in brain choline levels are mirrored by similar

  3. Glycine Transporters and Their Inhibitors

    NASA Astrophysics Data System (ADS)

    Gilfillan, Robert; Kerr, Jennifer; Walker, Glenn; Wishart, Grant

    Glycine plays a ubiquitous role in many biological processes. In the central nervous system it serves as an important neurotransmitter acting as an agonist at strychnine-sensitive glycine receptors and as an essential co-agonist with glutamate at the NMDA receptor complex. Control of glycine concentrations in the vicinity of these receptors is mediated by the specific glycine transporters, GlyT1 and GlyT2. Inhibition of these transporters has been postulated to be of potential benefit in several therapeutic indications including schizophrenia and pain. In this review we discuss our current knowledge of glycine transporters and focus on recent advances in the medicinal chemistry of GlyT1 and GlyT2 inhibitors.

  4. The Utility of CSF for the Diagnosis of Primary and Secondary Monoamine Neurotransmitter Deficiencies

    PubMed Central

    Celato, A.; Polo, G.; Edini, C.; Burlina, A.P.

    2017-01-01

    Biogenic amine defects constitute a complex and expanding group of neurotransmitter disorders affecting cognitive, motor and autonomic system development, mostly in the pediatric age. In recent years different enzymatic defects have been identified impairing the tetrahydrobiopterin cofactor pathway and/or biogenic amine synthesis, catabolism and transport, with subsequent new disease entities described. The lumbar puncture, with subsequent withdrawal of cerebrospinal fluid (CSF), remains a key step in the diagnostic procedure. Due to the specific nature of CSF, timing of analysis, sample collection and storage, technical issues of the analytic process are still crucial for the diagnosis and follow-up of patients. A progressive approach to the diagnosis of biogenic amine defects is presented, pointing out criticalities and difficulties concerning sample collection and results interpretation, especially due to the increasing reports of secondary neurotransmitter alterations that, at present, constitute a challenge. PMID:28439219

  5. Dirty electricity, chronic stress, neurotransmitters and disease.

    PubMed

    Milham, Samuel; Stetzer, David

    2013-12-01

    Dirty electricity, also called electrical pollution, is high-frequency voltage transients riding along the 50 or 60 Hz electricity provided by the electric utilities. It is generated by arcing, by sparking and by any device that interrupts current flow, especially switching power supplies. It has been associated with cancer, diabetes and attention deficit hyperactivity disorder in humans. Epidemiological evidence also links dirty electricity to most of the diseases of civilization including cancer, cardiovascular disease, diabetes and suicide, beginning at the turn of the twentieth century. The dirty electricity level in a public library was reduced from over 10 000 Graham/Stetzer (G/S) units to below 50 G/S units by installing plug-in capacitive filters. Before cleanup, the urinary dopamine level of only one of seven volunteers was within normal levels, while four of seven phenylethylamine levels were normal. After an initial decline, over the next 18 weeks the dopamine levels gradually increased to an average of over 215 μg/g creatinine, which is well above 170 μg/g creatinine, the high normal level for the lab. Average phenylethylamine levels also rose gradually to slightly above 70 μg/g creatinine, the high normal level for the lab. Neurotransmitters may be biomarkers for dirty electricity and other electromagnetic field exposures. We believe that dirty electricity is a chronic stressor of electrified populations and is responsible for many of their disease patterns.

  6. Effect of Dimerization on the Dynamics of Neurotransmitter:Sodium Symporters.

    PubMed

    Gur, Mert; Cheng, Mary Hongying; Zomot, Elia; Bahar, Ivet

    2017-02-07

    Dimerization is a common feature among the members of the neurotransmitter:sodium symporter (NSS) family of membrane proteins. Yet, the effect of dimerization on the mechanism of action of NSS members is not fully understood. In this study, we examined the collective dynamics of two members of the family, leucine transporter (LeuT) and dopamine transporter (DAT), to assess the significance of dimerization in modulating the functional motions of the monomers. We used to this aim the anisotropic network model (ANM), an efficient and robust method for modeling the intrinsic motions of proteins and their complexes. Transporters belonging to the NSS family are known to alternate between outward-facing (OF) and inward-facing (IF) states, which enables the uptake and release of their substrate (neurotransmitter) respectively, as the substrate is transported from the exterior to the interior of the cell. In both LeuT and DAT, dimerization is found to alter the collective motions intrinsically accessible to the individual monomers in favor of the functional transitions (OF ↔ IF), suggesting that dimerization may play a role in facilitating transport.

  7. Design and development of a MgB{sub 2}-based sector dipole and beam transport channel for a strong-focusing cyclotron

    SciTech Connect

    Melconian, K.; Damborsky, K.; Glasser, N.; Holik, E.; Kellams, J.; McIntyre, P.; Pogue, N.; Sattarov, A.

    2014-01-29

    A superconducting strong focusing cyclotron is being developed for high current applications. The ∼1 T sector dipoles incorporate superconducting main windings, and alternating-gradient focusing is provided by ∼6 Tm{sup –1} superconducting beam transport channels along the arced beam trajectory of each orbit of the cyclotron. All windings utilize MgB{sub 2} superconductor operating in the temperature window 15–20K. The main dipole windings are fabricated using the react-and-wind method; the beam transport channel windings are fabricated using the wind-and-react method. Previous reports have indicated that even wind and react MgB{sub 2} conductors can be irreversibly damaged by bending strain in the unreacted state. To determine the feasibility of MgB{sub 2} conductors for the beam transport channel windings, the dependence of critical current on bending radius of commercial wires was measured.

  8. Neurotransmitter receptors as targets for pesticides.

    PubMed

    Eldefrawi, M E; Eldefrawi, A T

    1983-01-01

    Nicotinic and muscarinic acetylcholine (ACh) receptors have been identified biochemically by means of their specific binding of [3H] alpha-bungarotoxin ([3H]alpha-BGT) and [3H]quinuclidinyl benzilate, respectively. There are some differences in the drug specificities, and sensitivities to active group reagents, of these receptors in insects when compared to those in vertebrates. Also, insect brain contains more nicotinic than muscarinic receptors, while the reverse is found in mammalian brain. Insect brain contains a third kind of putative ACh-receptor that is relatively soluble and is both nicotinic and muscarinic in its pharmacology but does not bind alpha-BGT. Toxic nicotine and analogs bind to it with high affinities. Several organophosphorus and carbamate insecticides and nereistoxin bind with high affinities to the nicotinic ACh-receptor of the electric organ of Torpedo. A few chlorinated hydrocarbon insecticides and derivatives interact with Torpedo nicotinic ACh-receptors, not at their 'receptor' sites but at their allosteric or 'channel' sites (which are identified by their specific binding of [3H]perhydrohistrionicotoxin). A few also bind to mammalian brain muscarinic receptors. The most potent on both receptors is the acaricide chlorobenzilate. Pyrethrins and synthetic pyrethroids also bind with high affinities to the channel sites of the Torpedo nicotinic ACh-receptor, though not to its receptor sites. Another group that binds to ACh-receptors is the organic and inorganic mercury compounds, which interact with both the Torpedo nicotinic and rat brain muscarinic receptors. Thus, neurotransmitter receptors act as molecular targets, primary or secondary for different pesticides.

  9. Four-dimensional multi-site photolysis of caged neurotransmitters

    PubMed Central

    Go, Mary Ann; To, Minh-Son; Stricker, Christian; Redman, Stephen; Bachor, Hans-A.; Stuart, Greg J.; Daria, Vincent R.

    2013-01-01

    Neurons receive thousands of synaptic inputs that are distributed in space and time. The systematic study of how neurons process these inputs requires a technique to stimulate multiple yet highly targeted points of interest along the neuron's dendritic tree. Three-dimensional multi-focal patterns produced via holographic projection combined with two-photon photolysis of caged compounds can provide for highly localized release of neurotransmitters within each diffraction-limited focus, and in this way emulate simultaneous synaptic inputs to the neuron. However, this technique so far cannot achieve time-dependent stimulation patterns due to fundamental limitations of the hologram-encoding device and other factors that affect the consistency of controlled synaptic stimulation. Here, we report an advanced technique that enables the design and application of arbitrary spatio-temporal photostimulation patterns that resemble physiological synaptic inputs. By combining holographic projection with a programmable high-speed light-switching array, we have overcome temporal limitations with holographic projection, allowing us to mimic distributed activation of synaptic inputs leading to action potential generation. Our experiments uniquely demonstrate multi-site two-photon glutamate uncaging in three dimensions with submillisecond temporal resolution. Implementing this approach opens up new prospects for studying neuronal synaptic integration in four dimensions. PMID:24348330

  10. Glucagon-related peptide 1 (GLP-1): hormone and neurotransmitter.

    PubMed

    Larsen, Philip J; Holst, Jens Juul

    2005-06-15

    The interest in glucagon-like petide-1 (GLP-1) and other pre-proglucagon derived peptides has risen almost exponentially since seminal papers in the early 1990s proposed to use GLP-1 agonists as therapeutic agents for treatment of type 2 diabetes. A wealth of interesting studies covering both normal and pathophysiological role of GLP-1 have been published over the last two decades and our understanding of GLP-1 action has widened considerably. In the present review, we have tried to cover our current understanding of GLP-1 actions both as a peripheral hormone and as a central neurotransmitter. From an initial focus on glycaemic control, GLP-1 research has been diverted to study its role in energy homeostasis, neurodegeneration, cognitive functions, anxiety and many more functions. With the upcoming introduction of GLP-1 agonists on the pharmaceutical venue, we have witnessed an outstanding example of how initial ideas from basic science laboratories have paved their way to become a novel therapeutic strategy to fight diabetes.

  11. Biophysical Approaches to the Study of LeuT, a Prokaryotic Homolog of Neurotransmitter Sodium Symporters.

    PubMed

    Singh, Satinder K; Pal, Aritra

    2015-01-01

    Ion-coupled secondary transport is utilized by multiple integral membrane proteins as a means of achieving the thermodynamically unfavorable translocation of solute molecules across the lipid bilayer. The chemical nature of these molecules is diverse and includes sugars, amino acids, neurotransmitters, and other ions. LeuT is a sodium-coupled, nonpolar amino acid symporter and eubacterial member of the solute carrier 6 (SLC6) family of Na(+)/Cl(-)-dependent neurotransmitter transporters. Eukaryotic counterparts encompass the clinically and pharmacologically significant transporters for γ-aminobutyric acid (GABA), glycine, serotonin (5-hydroxytryptamine, 5-HT), dopamine (DA), and norepinephrine (NE). Since the crystal structure of LeuT was first solved in 2005, subsequent crystallographic, binding, flux, and spectroscopic studies, complemented with homology modeling and molecular dynamic simulations, have allowed this protein to emerge as a remarkable mechanistic paradigm for both the SLC6 class as well as several other sequence-unrelated SLCs whose members possess astonishingly similar architectures. Despite yielding groundbreaking conceptual advances, this vast treasure trove of data has also been the source of contentious hypotheses. This chapter will present a historical scientific overview of SLC6s; recount how the initial and subsequent LeuT structures were solved, describing the insights they each provided; detail the accompanying functional techniques, emphasizing how they either supported or refuted the static crystallographic data; and assemble these individual findings into a mechanism of transport and inhibition. © 2015 Elsevier Inc. All rights reserved.

  12. Biophysical Approaches to the Study of LeuT, a Prokaryotic Homolog of Neurotransmitter Sodium Symporters

    PubMed Central

    Singh, Satinder K.; Pal, Aritra

    2016-01-01

    Ion-coupled secondary transport is utilized by multiple integral membrane proteins as a means of achieving the thermodynamically unfavorable translocation of solute molecules across the lipid bilayer. The chemical nature of these molecules is diverse and includes sugars, amino acids, neurotransmitters, and other ions. LeuT is a sodium-coupled, nonpolar amino acid symporter and eubacterial member of the solute carrier 6 (SLC6) family of Na+/Cl−-dependent neurotransmitter transporters. Eukaryotic counterparts encompass the clinically and pharmacologically significant transporters for γ-aminobutyric acid (GABA), glycine, serotonin (5-hydroxytryptamine, 5-HT), dopamine (DA), and norepinephrine (NE). Since the crystal structure of LeuT was first solved in 2005, subsequent crystallographic, binding, flux, and spectroscopic studies, complemented with homology modeling and molecular dynamic simulations, have allowed this protein to emerge as a remarkable mechanistic paradigm for both the SLC6 class as well as several other sequence-unrelated SLCs whose members possess astonishingly similar architectures. Despite yielding groundbreaking conceptual advances, this vast treasure trove of data has also been the source of contentious hypotheses. This chapter will present a historical scientific overview of SLC6s; recount how the initial and subsequent LeuT structures were solved, describing the insights they each provided; detail the accompanying functional techniques, emphasizing how they either supported or refuted the static crystallographic data; and assemble these individual findings into a mechanism of transport and inhibition. PMID:25950965

  13. Transition metal ion FRET uncovers K+ regulation of a neurotransmitter/sodium symporter

    PubMed Central

    Billesbølle, Christian B.; Mortensen, Jonas S.; Sohail, Azmat; Schmidt, Solveig G.; Shi, Lei; Sitte, Harald H.; Gether, Ulrik; Loland, Claus J.

    2016-01-01

    Neurotransmitter/sodium symporters (NSSs) are responsible for Na+-dependent reuptake of neurotransmitters and represent key targets for antidepressants and psychostimulants. LeuT, a prokaryotic NSS protein, constitutes a primary structural model for these transporters. Here we show that K+ inhibits Na+-dependent binding of substrate to LeuT, promotes an outward-closed/inward-facing conformation of the transporter and increases uptake. To assess K+-induced conformational dynamics we measured fluorescence resonance energy transfer (FRET) between fluorescein site-specifically attached to inserted cysteines and Ni2+ bound to engineered di-histidine motifs (transition metal ion FRET). The measurements supported K+-induced closure of the transporter to the outside, which was counteracted by Na+ and substrate. Promoting an outward-open conformation of LeuT by mutation abolished the K+-effect. The K+-effect depended on an intact Na1 site and mutating the Na2 site potentiated K+ binding by facilitating transition to the inward-facing state. The data reveal an unrecognized ability of K+ to regulate the LeuT transport cycle. PMID:27678200

  14. Transition metal ion FRET uncovers K(+) regulation of a neurotransmitter/sodium symporter.

    PubMed

    Billesbølle, Christian B; Mortensen, Jonas S; Sohail, Azmat; Schmidt, Solveig G; Shi, Lei; Sitte, Harald H; Gether, Ulrik; Loland, Claus J

    2016-09-28

    Neurotransmitter/sodium symporters (NSSs) are responsible for Na(+)-dependent reuptake of neurotransmitters and represent key targets for antidepressants and psychostimulants. LeuT, a prokaryotic NSS protein, constitutes a primary structural model for these transporters. Here we show that K(+) inhibits Na(+)-dependent binding of substrate to LeuT, promotes an outward-closed/inward-facing conformation of the transporter and increases uptake. To assess K(+)-induced conformational dynamics we measured fluorescence resonance energy transfer (FRET) between fluorescein site-specifically attached to inserted cysteines and Ni(2+) bound to engineered di-histidine motifs (transition metal ion FRET). The measurements supported K(+)-induced closure of the transporter to the outside, which was counteracted by Na(+) and substrate. Promoting an outward-open conformation of LeuT by mutation abolished the K(+)-effect. The K(+)-effect depended on an intact Na1 site and mutating the Na2 site potentiated K(+) binding by facilitating transition to the inward-facing state. The data reveal an unrecognized ability of K(+) to regulate the LeuT transport cycle.

  15. Amino Acid Neurotransmitters; Mechanisms of Their Uptake into Synaptic Vesicles

    DTIC Science & Technology

    1991-08-01

    uptake of the inhibitory neurotransmitters GABA and glycine and the excitatory neurotransmitter glutamate is essential for the understanding of the...1987)i Biochemistry, anatomy, and pharmacology of GABA neurons, In- Meltzer H Y (ed) Psycopharmacology : The third generation of progress, Raven Press...calculated with a linear GABA uptake experiments, regression program (Chou and Chou, 1985). Assay for GABA uptake GABA uptake was determined essentially as

  16. TRANSPORT

    EPA Science Inventory

    Presentation outline: transport principles, effective solubility; gasoline composition; and field examples (plume diving).
    Presentation conclusions: MTBE transport follows from - phyiscal and chemical properties and hydrology. Field examples show: MTBE plumes > benzene plu...

  17. Glycine receptors support excitatory neurotransmitter release in developing mouse visual cortex

    PubMed Central

    Kunz, Portia A; Burette, Alain C; Weinberg, Richard J; Philpot, Benjamin D

    2012-01-01

    Glycine receptors (GlyRs) are found in most areas of the brain, and their dysfunction can cause severe neurological disorders. While traditionally thought of as inhibitory receptors, presynaptic-acting GlyRs (preGlyRs) can also facilitate glutamate release under certain circumstances, although the underlying molecular mechanisms are unknown. In the current study, we sought to better understand the role of GlyRs in the facilitation of excitatory neurotransmitter release in mouse visual cortex. Using whole-cell recordings, we found that preGlyRs facilitate glutamate release in developing, but not adult, visual cortex. The glycinergic enhancement of neurotransmitter release in early development depends on the high intracellular to extracellular Cl− gradient maintained by the Na+–K+–2Cl− cotransporter and requires Ca2+ entry through voltage-gated Ca2+ channels. The glycine transporter 1, localized to glial cells, regulates extracellular glycine concentration and the activation of these preGlyRs. Our findings demonstrate a developmentally regulated mechanism for controlling excitatory neurotransmitter release in the neocortex. PMID:22988142

  18. Biochemical and Neurotransmitters Changes Associated with Tramadol in Streptozotocin-Induced Diabetes in Rats

    PubMed Central

    Ezzeldin, Essam; Souror, Wafaa A. H.; El-Nahhas, Toqa; Soudi, Abdel Nasser M. M.; Shahat, Abdelaaty A.

    2014-01-01

    The incidence of diabetes is increasing worldwide. Chronic neuropathic pain occurs in approximately 25% of diabetic patients. Tramadol, an atypical analgesic with a unique dual mechanism of action, is used in the management of painful diabetic neuropathy. It acts on monoamine transporters to inhibit the reuptake of norepinephrine (NE), serotonin (5-HT), and dopamine (DA). The purpose of this study was to evaluate the effects of diabetes on the brain neurotransmitter alterations induced by tramadol in rats, and to study the hepatic and renal toxicities of the drug. Eighty Sprague-Dawley rats were divided randomly into two sets: the normal set and the diabetic set. Diabetes was induced in rats. Tramadol was administered orally once daily for 28 days. The levels of DA, NE, and 5-HT in cerebral cortex, thalamus/hypothalamus, midbrain, and brainstem were evaluated in rats. In addition, the renal toxicity and histopathological effects of the drug were assessed. The induction of diabetes altered neurotransmitter levels. Oral administration of tramadol significantly decreased the neurotransmitter levels. Diabetes significantly altered the effects of tramadol in all brain regions. Tramadol affected function and histology of the liver and kidney. The clinical effects of tramadol in diabetic patients should be stressed. PMID:24971322

  19. Focus on Energy: A School Transportation Handbook. Proceedings of the Midwest School Transportation Fleet Management Seminar (Lansing, Michigan, November 28-29, 1979).

    ERIC Educational Resources Information Center

    Michigan State Dept. of Commerce, Lansing.

    Presented are proceedings and supplementary reports of the Midwest School Transportation Fleet Management Seminar, which was held in Lansing, Michigan, November 28-29, 1979. Among the school bus energy management topics discussed are energy feasibility studies, the use of programmed information systems, energy conservation strategies, and…

  20. Selected hormonal and neurotransmitter mechanisms regulating feed intake in sheep.

    PubMed

    Sartin, J L; Daniel, J A; Whitlock, B K; Wilborn, R R

    2010-11-01

    Appetite control is a major issue in normal growth and in suboptimal growth performance settings. A number of hormones, in particular leptin, activate or inhibit orexigenic or anorexigenic neurotransmitters within the arcuate nucleus of the hypothalamus, where feed intake regulation is integrated. Examples of appetite regulatory neurotransmitters are the stimulatory neurotransmitters neuropeptide Y (NPY), agouti-related protein (AgRP), orexin and melanin-concentrating hormone and the inhibitory neurotransmitter, melanocyte-stimulating hormone (MSH). Examination of messenger RNA (using in situ hybridization and real-time PCR) and proteins (using immunohistochemistry) for these neurotransmitters in ruminants has indicated that physiological regulation occurs in response to fasting for several of these critical genes and proteins, especially AgRP and NPY. Moreover, intracerebroventricular injection of each of the four stimulatory neurotransmitters can increase feed intake in sheep and may also regulate either growth hormone, luteinizing hormone, cortisol or other hormones. In contrast, both leptin and MSH are inhibitory to feed intake in ruminants. Interestingly, the natural melanocortin-4 receptor (MC4R) antagonist, AgRP, as well as NPY can prevent the inhibition of feed intake after injection of endotoxin (to model disease suppression of appetite). Thus, knowledge of the mechanisms regulating feed intake in the hypothalamus may lead to mechanisms to increase feed intake in normal growing animals and prevent the wasting effects of severe disease in animals.

  1. Radiotracers for PET and SPECT studies of neurotransmitter systems

    SciTech Connect

    Fowler, J.S.

    1991-01-01

    The study of neurotransmitter systems is one of the major thrusts in emission tomography today. The current generation of Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) radiotracers examines neurotransmitter properties from a number of different perspectives including their pre and post synaptic sites and the activity of the enzymes which regulate their concentration. Although the dopamine system has been the most extensively investigated, other neurotransmitter systems including the acetylcholine muscarine, serotonin, benzodiazepine, opiate, NMDA and others are also under intensive development. Enzymes involved in the synthesis and regulation of neurotransmitter concentration, for example monoamine oxidase and amino acid decarboxylase has also been probed in vivo. Medical applications range from the study of normal function and the characterization of neurotransmitter activity in neurological and psychiatric diseases and in heart disease and cancer to the study of the binding of therapeutic drugs and substances of abuse. This chapter will provide an overview of the current generation of radiotracers for PET and SPECT studies of neurotransmitter systems including radiotracer design, synthesis localization mechanisms and applications in emission tomography. 60 refs., 1 tab.

  2. IL-4 Inhibits IL-1β-Induced Depressive-Like Behavior and Central Neurotransmitter Alterations.

    PubMed

    Park, Hyun-Jung; Shim, Hyun-Soo; An, Kyungeh; Starkweather, Angela; Kim, Kyung Soo; Shim, Insop

    2015-01-01

    It has been known that activation of the central innate immune system or exposure to stress can disrupt balance of anti-/proinflammatory cytokines. The aim of the present study was to investigate the role of pro- and anti-inflammatory cytokines in the modulation of depressive-like behaviors, the hormonal and neurotransmitter systems in rats. We investigated whether centrally administered IL-1β is associated with activation of CNS inflammatory pathways and behavioral changes and whether treatment with IL-4 could modulate IL-1β-induced depressive-like behaviors and central neurotransmitter systems. Infusion of IL-4 significantly decreased IL-1β-induced anhedonic responses and increased social exploration and total activity. Treatment with IL-4 markedly blocked IL-1β-induced increase in PGE2 and CORT levels. Also, IL-4 reduced IL-1β-induced 5-HT levels by inhibiting tryptophan hydroxylase (TPH) mRNA and activating serotonin transporter (SERT) in the hippocampus, and levels of NE were increased by activating tyrosine hydroxylase (TH) mRNA expression. These results demonstrate that IL-4 may locally contribute to the regulation of noradrenergic and serotonergic neurotransmission and may inhibit IL-1β-induced behavioral and immunological changes. The present results suggest that IL-4 modulates IL-1β-induced depressive behavior by inhibiting IL-1β-induced central glial activation and neurotransmitter alterations. IL-4 reduced central and systemic mediatory inflammatory activation, as well as reversing the IL-1β-induced alterations in neurotransmitter levels. The present findings contribute a biochemical pathway regulated by IL-4 that may have therapeutic utility for treatment of IL-1β-induced depressive behavior and neuroinflammation which warrants further study.

  3. IL-4 Inhibits IL-1β-Induced Depressive-Like Behavior and Central Neurotransmitter Alterations

    PubMed Central

    Park, Hyun-Jung; Shim, Hyun-Soo; An, Kyungeh; Starkweather, Angela; Kim, Kyung Soo; Shim, Insop

    2015-01-01

    It has been known that activation of the central innate immune system or exposure to stress can disrupt balance of anti-/proinflammatory cytokines. The aim of the present study was to investigate the role of pro- and anti-inflammatory cytokines in the modulation of depressive-like behaviors, the hormonal and neurotransmitter systems in rats. We investigated whether centrally administered IL-1β is associated with activation of CNS inflammatory pathways and behavioral changes and whether treatment with IL-4 could modulate IL-1β-induced depressive-like behaviors and central neurotransmitter systems. Infusion of IL-4 significantly decreased IL-1β-induced anhedonic responses and increased social exploration and total activity. Treatment with IL-4 markedly blocked IL-1β-induced increase in PGE2 and CORT levels. Also, IL-4 reduced IL-1β-induced 5-HT levels by inhibiting tryptophan hydroxylase (TPH) mRNA and activating serotonin transporter (SERT) in the hippocampus, and levels of NE were increased by activating tyrosine hydroxylase (TH) mRNA expression. These results demonstrate that IL-4 may locally contribute to the regulation of noradrenergic and serotonergic neurotransmission and may inhibit IL-1β-induced behavioral and immunological changes. The present results suggest that IL-4 modulates IL-1β-induced depressive behavior by inhibiting IL-1β-induced central glial activation and neurotransmitter alterations. IL-4 reduced central and systemic mediatory inflammatory activation, as well as reversing the IL-1β-induced alterations in neurotransmitter levels. The present findings contribute a biochemical pathway regulated by IL-4 that may have therapeutic utility for treatment of IL-1β-induced depressive behavior and neuroinflammation which warrants further study. PMID:26417153

  4. Overview of transport and MHD stability study: focusing on the impact of magnetic field topology in the Large Helical Device

    NASA Astrophysics Data System (ADS)

    Ida, K.; Nagaoka, K.; Inagaki, S.; Kasahara, H.; Evans, T.; Yoshinuma, M.; Kamiya, K.; Ohdach, S.; Osakabe, M.; Kobayashi, M.; Sudo, S.; Itoh, K.; Akiyama, T.; Emoto, M.; Dinklage, A.; Du, X.; Fujii, K.; Goto, M.; Goto, T.; Hasuo, M.; Hidalgo, C.; Ichiguchi, K.; Ishizawa, A.; Jakubowski, M.; Kawamura, G.; Kato, D.; Morita, S.; Mukai, K.; Murakami, I.; Murakami, S.; Narushima, Y.; Nunami, M.; Ohno, N.; Pablant, N.; Sakakibara, S.; Seki, T.; Shimozuma, T.; Shoji, M.; Tanaka, K.; Tokuzawa, T.; Todo, Y.; Wang, H.; Yokoyama, M.; Yamada, H.; Takeiri, Y.; Mutoh, T.; Imagawa, S.; Mito, T.; Nagayama, Y.; Watanabe, K. Y.; Ashikawa, N.; Chikaraishi, H.; Ejiri, A.; Furukawa, M.; Fujita, T.; Hamaguchi, S.; Igami, H.; Isobe, M.; Masuzaki, S.; Morisaki, T.; Motojima, G.; Nagasaki, K.; Nakano, H.; Oya, Y.; Suzuki, C.; Suzuki, Y.; Sakamoto, R.; Sakamoto, M.; Sanpei, A.; Takahashi, H.; Tsuchiya, H.; Tokitani, M.; Ueda, Y.; Yoshimura, Y.; Yamamoto, S.; Nishimura, K.; Sugama, H.; Yamamoto, T.; Idei, H.; Isayama, A.; Kitajima, S.; Masamune, S.; Shinohara, K.; Bawankar, P. S.; Bernard, E.; von Berkel, M.; Funaba, H.; Huang, X. L.; T., Ii; Ido, T.; Ikeda, K.; Kamio, S.; Kumazawa, R.; Kobayashi, T.; Moon, C.; Muto, S.; Miyazawa, J.; Ming, T.; Nakamura, Y.; Nishimura, S.; Ogawa, K.; Ozaki, T.; Oishi, T.; Ohno, M.; Pandya, S.; Shimizu, A.; Seki, R.; Sano, R.; Saito, K.; Sakaue, H.; Takemura, Y.; Tsumori, K.; Tamura, N.; Tanaka, H.; Toi, K.; Wieland, B.; Yamada, I.; Yasuhara, R.; Zhang, H.; Kaneko, O.; Komori, A.; Collaborators

    2015-10-01

    The progress in the understanding of the physics and the concurrent parameter extension in the large helical device since the last IAEA-FEC, in 2012 (Kaneko O et al 2013 Nucl. Fusion 53 095024), is reviewed. Plasma with high ion and electron temperatures (Ti(0) ˜ Te(0) ˜ 6 keV) with simultaneous ion and electron internal transport barriers is obtained by controlling recycling and heating deposition. A sign flip of the nondiffusive term of impurity/momentum transport (residual stress and convection flow) is observed, which is associated with the formation of a transport barrier. The impact of the topology of three-dimensional magnetic fields (stochastic magnetic fields and magnetic islands) on heat momentum, particle/impurity transport and magnetohydrodynamic stability is also discussed. In the steady state operation, a 48 min discharge with a line-averaged electron density of 1 × 1019 m-3 and with high electron and ion temperatures (Ti(0) ˜ Te(0) ˜ 2 keV), resulting in 3.36 GJ of input energy, is achieved.

  5. Guiding, Focusing, and Collimated Transport of Hot Electrons in a Canal in the Extended Tip of Cone Targets

    NASA Astrophysics Data System (ADS)

    Renard-Le Galloudec, N.; D'Humières, E.; Cho, B. I.; Osterholz, J.; Sentoku, Y.; Ditmire, T.

    2009-05-01

    Hot electrons are produced, guided into a beam, and transported over 60μm in a small canal to the outside tip of a structured cone target. The diameter of the electron beam is defined by the inside tip diameter. This carries the potential to create electron beams of specific diameters propagating over specific distances of interest for several applications.

  6. Neurotransmitter/sodium symporter orthologue LeuT has a single high-affinity substrate site.

    PubMed

    Piscitelli, Chayne L; Krishnamurthy, Harini; Gouaux, Eric

    2010-12-23

    Neurotransmitter/sodium symporters (NSSs) couple the uptake of neurotransmitter with one or more sodium ions, removing neurotransmitter from the synaptic cleft. NSSs are essential to the function of chemical synapses, are associated with multiple neurological diseases and disorders, and are the targets of therapeutic and illicit drugs. LeuT, a prokaryotic orthologue of the NSS family, is a model transporter for understanding the relationships between molecular mechanism and atomic structure in a broad range of sodium-dependent and sodium-independent secondary transporters. At present there is a controversy over whether there are one or two high-affinity substrate binding sites in LeuT. The first-reported crystal structure of LeuT, together with subsequent functional and structural studies, provided direct evidence for a single, high-affinity, centrally located substrate-binding site, defined as the S1 site. Recent binding, flux and molecular simulation studies, however, have been interpreted in terms of a model where there are two high-affinity binding sites: the central, S1, site and a second, the S2 site, located within the extracellular vestibule. Furthermore, it was proposed that the S1 and S2 sites are allosterically coupled such that occupancy of the S2 site is required for the cytoplasmic release of substrate from the S1 site. Here we address this controversy by performing direct measurement of substrate binding to wild-type LeuT and to S2 site mutants using isothermal titration calorimetry, equilibrium dialysis and scintillation proximity assays. In addition, we perform uptake experiments to determine whether the proposed allosteric coupling between the putative S2 site and the S1 site manifests itself in the kinetics of substrate flux. We conclude that LeuT harbours a single, centrally located, high-affinity substrate-binding site and that transport is well described by a simple, single-substrate kinetic mechanism.

  7. Three perspectives on bedload transport at a sandy gravel beach (Advocate Harbour, Nova Scotia) with focus on sediment properties

    NASA Astrophysics Data System (ADS)

    Stark, N.; Hay, A. E.; Guest, T.; Hatcher, M. G.; Cheel, R. A.; Barclay, D. J.; Zedel, L. J.; Lake, C. B.

    2012-12-01

    Bedload transport is the major transport mode for coarse sediment in coastal zones. Understanding its mechanisms requires knowledge of the driving force (hydrodynamics), the stabilizing force (sediment properties), and the bed characteristics (bed roughness, bed slope, bedforms). During a 3-week-long field experiment at Advocate Beach, Nova Scotia, bedload transport was targeted from three perspectives: (i) The water column: using a new acoustic Doppler profiler (MFDop), 3D flow velocities were monitored to assess bed shear stress over a range of conditions. Additionally, sediment concentrations close to the bed (~10 cm) were determined by water sampling under calm conditions (0.15-0.6 g/l) and within the shorebreak (1-50 g/l). (ii) The bed: rotary sonars were used to observe the development of ripples and bed elevation change as a measure of ongoing sediment transport. Also, the net displacement of 20 marked cobbles on the seabed surface was measured, revealing significant changes in transport direction and distance (ranging from 0 to 50 m). (iii) The sediment properties: grain size ranged from medium sand to small cobbles. The finer-grained particles were rounded, but showed an elliptic to plate-like shape. Grain size distributions varied significantly across the shoreface as well as under different hydrodynamic conditions. Observed beach cusps were strongly sorted (coarse pebbles at the horns, coarse sand in the bays). Direct shear tests were carried out to determine peak shear strengths of the sediment and friction angles. Peak shear strengths under low normal stress (0.47 kPa) can be compared best to surficial sediment conditions, and did not exceed 9 kPa in the case of the sands. The sediment showed a surprisingly strong dilative behavior during shearing and high friction angles considering the grain size, the low load and low density conditions during the tests. Thus, grain shape and the particle re-organization under shearing played important roles. Finally

  8. Tuning Selectivity of Fluorescent Carbon Nanotube-Based Neurotransmitter Sensors.

    PubMed

    Mann, Florian A; Herrmann, Niklas; Meyer, Daniel; Kruss, Sebastian

    2017-06-28

    Detection of neurotransmitters is an analytical challenge and essential to understand neuronal networks in the brain and associated diseases. However, most methods do not provide sufficient spatial, temporal, or chemical resolution. Near-infrared (NIR) fluorescent single-walled carbon nanotubes (SWCNTs) have been used as building blocks for sensors/probes that detect catecholamine neurotransmitters, including dopamine. This approach provides a high spatial and temporal resolution, but it is not understood if these sensors are able to distinguish dopamine from similar catecholamine neurotransmitters, such as epinephrine or norepinephrine. In this work, the organic phase (DNA sequence) around SWCNTs was varied to create sensors with different selectivity and sensitivity for catecholamine neurotransmitters. Most DNA-functionalized SWCNTs responded to catecholamine neurotransmitters, but both dissociation constants (Kd) and limits of detection were highly dependent on functionalization (sequence). Kd values span a range of 2.3 nM (SWCNT-(GC)15 + norepinephrine) to 9.4 μM (SWCNT-(AT)15 + dopamine) and limits of detection are mostly in the single-digit nM regime. Additionally, sensors of different SWCNT chirality show different fluorescence increases. Moreover, certain sensors (e.g., SWCNT-(GT)10) distinguish between different catecholamines, such as dopamine and norepinephrine at low concentrations (50 nM). These results show that SWCNTs functionalized with certain DNA sequences are able to discriminate between catecholamine neurotransmitters or to detect them in the presence of interfering substances of similar structure. Such sensors will be useful to measure and study neurotransmitter signaling in complex biological settings.

  9. Altered Expression of Genes Encoding Neurotransmitter Receptors in GnRH Neurons of Proestrous Mice

    PubMed Central

    Vastagh, Csaba; Rodolosse, Annie; Solymosi, Norbert; Liposits, Zsolt

    2016-01-01

    Gonadotropin-releasing hormone (GnRH) neurons play a key role in the central regulation of reproduction. In proestrous female mice, estradiol triggers the pre-ovulatory GnRH surge, however, its impact on the expression of neurotransmitter receptor genes in GnRH neurons has not been explored yet. We hypothesized that proestrus is accompanied by substantial changes in the expression profile of genes coding for neurotransmitter receptors in GnRH neurons. We compared the transcriptome of GnRH neurons obtained from intact, proestrous, and metestrous female GnRH-GFP transgenic mice, respectively. About 1500 individual GnRH neurons were sampled from both groups and their transcriptome was analyzed using microarray hybridization and real-time PCR. In this study, changes in mRNA expression of genes involved in neurotransmitter signaling were investigated. Differential gene expression was most apparent in GABA-ergic (Gabbr1, Gabra3, Gabrb3, Gabrb2, Gabrg2), glutamatergic (Gria1, Gria2, Grin1, Grin3a, Grm1, Slc17a6), cholinergic (Chrnb2, Chrm4) and dopaminergic (Drd3, Drd4), adrenergic (Adra1b, Adra2a, Adra2c), adenosinergic (Adora2a, Adora2b), glycinergic (Glra), purinergic (P2rx7), and serotonergic (Htr1b) receptors. In concert with these events, expression of genes in the signaling pathways downstream to the receptors, i.e., G-proteins (Gnai1, Gnai2, Gnas), adenylate-cyclases (Adcy3, Adcy5), protein kinase A (Prkaca, Prkacb) protein kinase C (Prkca) and certain transporters (Slc1a4, Slc17a6, Slc6a17) were also changed. The marked differences found in the expression of genes involved in neurotransmitter signaling of GnRH neurons at pro- and metestrous stages of the ovarian cycle indicate the differential contribution of these neurotransmitter systems to the induction of the pre-ovulatory GnRH surge, the known prerequisite of the subsequent hormonal cascade inducing ovulation. PMID:27774052

  10. Leukemia inhibitory factor induces neurotransmitter switching in transgenic mice.

    PubMed Central

    Bamber, B A; Masters, B A; Hoyle, G W; Brinster, R L; Palmiter, R D

    1994-01-01

    Leukemia inhibitory factor (LIF) is a cytokine growth factor that induces rat sympathetic neurons to switch their neurotransmitter phenotype from noradrenergic to cholinergic in vitro. To test whether LIF can influence neuronal differentiation in vivo, we generated transgenic mice that expressed LIF in pancreatic islets under the control of the insulin promoter and evaluated the neurotransmitter phenotype of the pancreatic sympathetic innervation. We also used the insulin promoter to coexpress nerve growth factor in the islets, which greatly increased the density of sympathetic innervation and facilitated analysis of the effects of LIF. Our data demonstrate that tyrosine hydroxylase and catecholamines declined and choline acetyltransferase increased in response to LIF. We conclude that LIF can induce neurotransmitter switching of sympathetic neurons in vivo. Images PMID:7914698

  11. Infrared photodissociation spectroscopy of protonated neurotransmitters in the gas phase

    NASA Astrophysics Data System (ADS)

    MacLeod, N. A.; Simons, J. P.

    2007-03-01

    Protonated neurotransmitters have been produced in the gas phase via a novel photochemical scheme: complexes of the species of interest, 1-phenylethylamine, 2-amino-1-phenylethanol and the diastereo-isomers, ephedrine and pseudoephedrine, with a suitable proton donor, phenol (or indole), are produced in a supersonic expansion and ionized by resonant two photon ionization of the donor. Efficient proton transfer generates the protonated neurotransmitters, complexed to a phenoxy radical. Absorption of infrared radiation, and subsequent evaporation of the phenoxy tag, coupled with time of flight mass spectrometry, provides vibrational spectra of the protonated (and also hydrated) complexes for comparison with the results of quantum chemical computation. Comparison with the conformational structures of the neutral neurotransmitters (established previously) reveals the effect of protonation on their structure. The photochemical proton transfer strategy allows spectra to be recorded from individual laser shots and their quality compares favourably with that obtained using electro-spray or matrix assisted laser desorption ion sources.

  12. THE PURINERGIC NEUROTRANSMITTER REVISITED: A SINGLE SUBSTANCE OR MULTIPLE PLAYERS?

    PubMed Central

    Mutafova-Yambolieva, Violeta N.; Durnin, Leonie

    2014-01-01

    The past half century has witnessed tremendous advances in our understanding of extracellular purinergic signaling pathways. Purinergic neurotransmission, in particular, has emerged as a key contributor in the efficient control mechanisms in the nervous system. The identity of the purine neurotransmitter, however, remains controversial. Identifying it is difficult because purines are present in all cell types, have a large variety of cell sources, and are released via numerous pathways. Moreover, studies on purinergic neurotransmission have relied heavily on indirect measurements of integrated postjunctional responses that do not provide direct information for neurotransmitter identity. This paper discusses experimental support for adenosine 5′-triphosphate (ATP) as a neurotransmitter and recent evidence for possible contribution of other purines, in addition to or instead of ATP, in chemical neurotransmission in the peripheral, enteric and central nervous systems. Sites of release and action of purines in model systems such as vas deferens, blood vessels, urinary bladder and chromaffin cells are discussed. This is preceded by a brief discussion of studies demonstrating storage of purines in synaptic vesicles. We examine recent evidence for cell type targets (e.g., smooth muscle cells, interstitial cells, neurons and glia) for purine neurotransmitters in different systems. This is followed by brief discussion of mechanisms of terminating the action of purine neurotransmitters, including extracellular nucleotide hydrolysis and possible salvage and reuptake in the cell. The significance of direct neurotransmitter release measurements is highlighted. Possibilities for involvement of multiple purines (e.g., ATP, ADP, NAD+, ADP-ribose, adenosine, and diadenosine polyphosphates) in neurotransmission are considered throughout. PMID:24887688

  13. Focused helium-ion beam irradiation effects on electrical transport properties of few-layer WSe2: Enabling nanoscale direct write homo-junctions

    DOE PAGES

    Stanford, Michael; Noh, Joo Hyon; Koehler, Michael R.; ...

    2016-06-06

    Atomically thin transition metal dichalcogenides (TMDs) are currently receiving significant attention due to their promising opto-electronic properties. Tuning optical and electrical properties of mono and few-layer TMDs, such as tungsten diselenide (WSe2), by controlling the defects, is an intriguing opportunity to synthesize next generation two dimensional material opto-electronic devices. Here, we report the effects of focused helium ion beam irradiation on the structural, optical and electrical properties of few-layer WSe2, via high resolution scanning transmission electron microscopy, Raman spectroscopy, and electrical transport measurements. By controlling the ion irradiation dose, we selectively introduce precise defects in few-layer WSe2 thereby locally tuningmore » the resistivity and transport properties of the material. Hole transport in the few layer WSe2 is degraded more severely relative to electron transport after helium ion irradiation. Moreover, by selectively exposing material with the ion beam, we demonstrate a simple yet highly tunable method to create lateral homo-junctions in few layer WSe2 flakes, which constitutes an important advance towards two dimensional opto-electronic devices.« less

  14. Focused helium-ion beam irradiation effects on electrical transport properties of few-layer WSe2: Enabling nanoscale direct write homo-junctions

    SciTech Connect

    Stanford, Michael; Noh, Joo Hyon; Koehler, Michael R.; Mandrus, David G.; Duscher, Gerd; Rondinone, Adam Justin; Ivanov, Ilia N.; Ward, Thomas Zac; Rack, Philip D.; Pudasaini, Pushpa Raj; Belianinov, Alex; Cross, Nicholas

    2016-06-06

    Atomically thin transition metal dichalcogenides (TMDs) are currently receiving significant attention due to their promising opto-electronic properties. Tuning optical and electrical properties of mono and few-layer TMDs, such as tungsten diselenide (WSe2), by controlling the defects, is an intriguing opportunity to synthesize next generation two dimensional material opto-electronic devices. Here, we report the effects of focused helium ion beam irradiation on the structural, optical and electrical properties of few-layer WSe2, via high resolution scanning transmission electron microscopy, Raman spectroscopy, and electrical transport measurements. By controlling the ion irradiation dose, we selectively introduce precise defects in few-layer WSe2 thereby locally tuning the resistivity and transport properties of the material. Hole transport in the few layer WSe2 is degraded more severely relative to electron transport after helium ion irradiation. Moreover, by selectively exposing material with the ion beam, we demonstrate a simple yet highly tunable method to create lateral homo-junctions in few layer WSe2 flakes, which constitutes an important advance towards two dimensional opto-electronic devices.

  15. Focused helium-ion beam irradiation effects on electrical transport properties of few-layer WSe2: enabling nanoscale direct write homo-junctions

    NASA Astrophysics Data System (ADS)

    Stanford, Michael G.; Pudasaini, Pushpa Raj; Belianinov, Alex; Cross, Nicholas; Noh, Joo Hyon; Koehler, Michael R.; Mandrus, David G.; Duscher, Gerd; Rondinone, Adam J.; Ivanov, Ilia N.; Ward, T. Zac; Rack, Philip D.

    2016-06-01

    Atomically thin transition metal dichalcogenides (TMDs) are currently receiving significant attention due to their promising opto-electronic properties. Tuning optical and electrical properties of mono and few-layer TMDs, such as tungsten diselenide (WSe2), by controlling the defects, is an intriguing opportunity to synthesize next generation two dimensional material opto-electronic devices. Here, we report the effects of focused helium ion beam irradiation on the structural, optical and electrical properties of few-layer WSe2, via high resolution scanning transmission electron microscopy, Raman spectroscopy, and electrical transport measurements. By controlling the ion irradiation dose, we selectively introduce precise defects in few-layer WSe2 thereby locally tuning the resistivity and transport properties of the material. Hole transport in the few layer WSe2 is degraded more severely relative to electron transport after helium ion irradiation. Furthermore, by selectively exposing material with the ion beam, we demonstrate a simple yet highly tunable method to create lateral homo-junctions in few layer WSe2 flakes, which constitutes an important advance towards two dimensional opto-electronic devices.

  16. Focused helium-ion beam irradiation effects on electrical transport properties of few-layer WSe2: enabling nanoscale direct write homo-junctions.

    PubMed

    Stanford, Michael G; Pudasaini, Pushpa Raj; Belianinov, Alex; Cross, Nicholas; Noh, Joo Hyon; Koehler, Michael R; Mandrus, David G; Duscher, Gerd; Rondinone, Adam J; Ivanov, Ilia N; Ward, T Zac; Rack, Philip D

    2016-06-06

    Atomically thin transition metal dichalcogenides (TMDs) are currently receiving significant attention due to their promising opto-electronic properties. Tuning optical and electrical properties of mono and few-layer TMDs, such as tungsten diselenide (WSe2), by controlling the defects, is an intriguing opportunity to synthesize next generation two dimensional material opto-electronic devices. Here, we report the effects of focused helium ion beam irradiation on the structural, optical and electrical properties of few-layer WSe2, via high resolution scanning transmission electron microscopy, Raman spectroscopy, and electrical transport measurements. By controlling the ion irradiation dose, we selectively introduce precise defects in few-layer WSe2 thereby locally tuning the resistivity and transport properties of the material. Hole transport in the few layer WSe2 is degraded more severely relative to electron transport after helium ion irradiation. Furthermore, by selectively exposing material with the ion beam, we demonstrate a simple yet highly tunable method to create lateral homo-junctions in few layer WSe2 flakes, which constitutes an important advance towards two dimensional opto-electronic devices.

  17. Benzodiazepine receptor and neurotransmitter studies in the brain of suicides

    SciTech Connect

    Manchon, M.; Kopp, N.; Rouzioux, J.J.; Lecestre, D.; Deluermoz, S.; Miachon, S.

    1987-12-14

    The characteristics of benzodiazepine binding sites were studied on frozen sections of hippocampus of 7 suicides and 5 controls subjects, using biochemical and autoradiographic techniques. /sup 3/H flunitrazepam was used as ligand, clonazepam and CL 218,872 as displacing agents. Some neurotransmitters or their derivatives were evaluated quantitatively in parallel in the hippocampal tissue by liquid chromatography. The authors observed mainly an increase in the Ki of CL 218,872 subtype I binding sites in suicides, and an increase in % of type I binding sites. Among neurotransmitters, only norepinephrine differed significantly between controls and suicides. 36 references, 3 figures, 1 table.

  18. A Mechanism for Intracellular Release of Na+ by Neurotransmitter: Sodium Symporters

    PubMed Central

    Malinauskaite, Lina; Reinhard, Linda; Lyons, Joseph A.; Yano, Hideaki; Javitch, Jonathan A.

    2015-01-01

    Neurotransmitter:sodium symporters (NSS) terminate synaptic signal transmission by Na+-dependent reuptake of released neurotransmitters, with key conformational states reported for a bacterial homolog LeuT and an inhibitor-bound Drosophila dopamine transporter. However, a coherent mechanism of Na+-driven transport has not been described. Here, we present two crystal structures of MhsT, a NSS member from Bacillus halodurans, in occluded inward-facing states with bound Na+ ions and L-Trp that provide insight into the cytoplasmic release of Na+. The switch from outward- to inward-oriented states is centered on the partial unwinding of transmembrane helix 5, which is facilitated by a conserved GlyX9Pro motif that opens an intracellular pathway for water to access the Na2 site. Based on our structural and functional findings we propose a mechanism according to which solvation through the TM5 pathway facilitates Na+ release from Na2 and the transition to an inward-open state. PMID:25282149

  19. Changes in cerebral neurotransmitters and metabolites induced by acute donepezil and memantine administrations: a microdialysis study.

    PubMed

    Shearman, E; Rossi, S; Szasz, B; Juranyi, Z; Fallon, S; Pomara, N; Sershen, H; Lajtha, A

    2006-03-31

    Cholinesterase inhibitors including donepezil, rivastigmine, and galantamine and the N-methyl-D-aspartate (NMDA) antagonist, memantine are the medications currently approved for the treatment of Alzheimer's disease (AD). In addition to their beneficial effects on cognitive and functional domains typically disrupted in AD, these agents have also been shown to slow down the emergence of behavioral and psychotic symptoms associated with this disease. However, the underlying mechanisms for these therapeutic effects remain poorly understood and could involve effects of these medications on non-cholinergic or non-glutamatergic neurotransmitter systems respectively. These considerations prompted us to initiate a series of investigations to examine the acute and chronic effects of donepezil (Aricept (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-1 hydrochloride and memantine (1-amino-3,5-dimethyladamantane hydrochloride C12H21N.HCl)). The present study focuses on the acute effects of donepezil and memantine on brain extracellular levels of acetylcholine, dopamine, serotonin, norepinephrine and their metabolites. We assayed changes in the ventral and dorsal hippocampus and the prefrontal and medial temporal cortex by microdialysis. Memantine resulted in significant increases in extracellular dopamine (DA), norepinephrine (NE), and their metabolites, in the cortical regions, and in a reduction of DA in the hippocampus. Donepezil produced an increase in extracellular DA in the cortex and in the dorsal hippocampus. Norepinephrine increased in the cortex; with donepezil it increased in the dorsal hippocampus and the medial temporal cortex, and decreased in the ventral hippocampus. Interestingly both compounds decreased extracellular serotonin (5HT) levels. The metabolites of the neurotransmitters were increased in most areas. We also found an increase in extracellular acetylcholine (ACh) by memantine in the nucleus accumbens and the

  20. Regulation of cognition and symptoms of psychosis: focus on GABA(A) receptors and glycine transporter 1.

    PubMed

    Möhler, Hanns; Rudolph, Uwe; Boison, Detlev; Singer, Philipp; Feldon, Joram; Yee, Benjamin K

    2008-07-01

    Adaptive purposeful behaviour depends on appropriate modifications of synaptic connectivity that incorporate an organism's past experience. At least some forms of such synaptic plasticity are believed to be mediated by NMDA receptors (NMDARs). Complementary interaction with inhibitory neurotransmission mediated by GABA(A) receptors, and upstream control of the excitability of NMDARs by glycine availability can greatly influence the efficacy of NMDAR mediated neuroplasticity, and thereby exert significant effects on cognition. Memory, selective attention or sensorimotor gating functions can be modified in mice with a reduction of alpha(5)GABA(A) receptors in the hippocampus or a selective deletion of glycine transporter 1 (GlyT1) in the forebrain. Both genetic manipulations altered the formation or persistence of associative links leading to distinct phenotypes on trace conditioning, extinction learning, latent inhibition, working memory, and object recognition. Behavioural assays of latent inhibition, prepulse inhibition, working memory, and sensitivity to psychostimulants in particular suggest that alpha(3) and alpha(5) subunit-containing GABA(A) receptors as well as GlyT1 are potential sites for ameliorating psychotic-like behaviour. Taken together, these results qualify distinct GABA-A receptor subtypes and GlyT1 as molecular targets for the development of a new pharmacology in the treatment of cognitive decline and psychotic symptoms.

  1. Ricardo Miledi and the calcium hypothesis of neurotransmitter release.

    PubMed

    Jeng, Jade-Ming

    2002-01-01

    Ricardo Miledi has made significant contributions to our basic understanding of how synapses work. Here I discuss aspects of Miledi's research that helped to establish the requirement of presynaptic calcium for neurotransmitter release, from his earliest scientific studies to his classic experiments in the squid giant synapse.

  2. Transportation

    NASA Technical Reports Server (NTRS)

    Vontiesenhausen, G.

    1986-01-01

    A summary of tether transportation is given. Four steps were used over a period of time. First, theoretical engineering feasibility and technology requirements were determined. Then the survivors of that effort went into step two in the analysis of promising candidates. Those survivors went into the third phase which is engineering design and cost benefits. Survivors entered into the demonstration mission definition phase. Transportation studies have covered two kinds of deployments. First, steady state deployment was studied. Like the TSS, it's nearly vertical. It takes a long time to deploy and involves relatively high tether tension. Secondly, dynamic deployment was studied. Deployment started in an almost horizontal direction under a very shallow angle which allows a high deployment rate under very low tension. Momentum transfer here occurs by libration. Specific payloads were used to study tethered transportation benefits. Four transportation concepts were studied with regard to cost benefits. A tethered orbiter deboost from the space station, an OTV boost up from the Space Station, a science platform on a tether with a possible micro-g lab moving in between platform and station, and a tethered boost of payloads fromthe orbiter are the four concepts. These benefits are examined in detail.

  3. Construction of cell-based neurotransmitter fluorescently engineered reporters (CNiFERs) for optical detection of neurotransmitters in vivo

    PubMed Central

    Lacin, Emre; Muller, Arnaud; Fernando, Marian; Kleinfeld, David; Slesinger, Paul A

    2016-01-01

    Cell-based neurotransmitter fluorescent engineered reporters (CNiFERs) provide a new tool for neuroscientists to optically detect the release of neurotransmitters in the brain in vivo. A specific CNiFER is created from a human embryonic kidney cell that stably expresses a specific G protein-coupled receptor, which couples to Gq/11 G proteins, and a FRET-based Ca2+-detector, TN-XXL – activation of the receptor leads to an increase in the FRET signal. Because a CNiFER clone utilizes the native receptor for a particular neurotransmitter (e.g. D2R for dopamine), it has nanomolar sensitivity and a temporal response of seconds. CNiFERs are directly implanted into the brain, enabling them to sense neurotransmitter release with a spatial resolution of less than one hundred micrometers, making them ideal to measure volume transmission in vivo. CNiFERs can also be used to screen other drugs for potential cross-reactivity in vivo. We recently expanded the family of CNiFERs to include GPCRs that couple to Gi/o G proteins. CNiFERs are available for detecting acetylcholine (ACh), dopamine (DA) and norepinephrine (NE). Given that any GPCR can be used to create a novel CNiFER and that there are approximately 800 GPCRs in the human genome, we describe here the general procedure to design, realize, and test any type of CNiFER. PMID:27214050

  4. Construction of Cell-based Neurotransmitter Fluorescent Engineered Reporters (CNiFERs) for Optical Detection of Neurotransmitters In Vivo.

    PubMed

    Lacin, Emre; Muller, Arnaud; Fernando, Marian; Kleinfeld, David; Slesinger, Paul A

    2016-05-12

    Cell-based neurotransmitter fluorescent engineered reporters (CNiFERs) provide a new tool for neuroscientists to optically detect the release of neurotransmitters in the brain in vivo. A specific CNiFER is created from a human embryonic kidney cell that stably expresses a specific G protein-coupled receptor, which couples to Gq/11 G proteins, and a FRET-based Ca(2+)-detector, TN-XXL. Activation of the receptor leads to an increase in the FRET signal. CNiFERs have nM sensitivity and a temporal response of seconds because a CNiFER clone utilizes the native receptor for a particular neurotransmitter, e.g., D2R for dopamine. CNiFERs are directly implanted into the brain, enabling them to sense neurotransmitter release with a spatial resolution of less than one hundred µm, making them ideal to measure volume transmission in vivo. CNiFERs can also be used to screen other drugs for potential cross-reactivity in vivo. We recently expanded the family of CNiFERs to include GPCRs that couple to Gi/o G proteins. CNiFERs are available for detecting acetylcholine (ACh), dopamine (DA) and norepinephrine (NE). Given that any GPCR can be used to create a novel CNiFER and that there are approximately 800 GPCRs in the human genome, we describe here the general procedure to design, realize, and test any type of CNiFER.

  5. Transportability

    DTIC Science & Technology

    2013-04-25

    psi). (g) Maximum axle load (pneumatic tires) - 2,268 kg (5,000 lb). (h) Maximum wheel load (pneumatic tires) - 1,134 kg (2,500 lb). (i...survivability following the shock or vibration environment induced. Vehicles not typically transported with payload such as wreckers, truck tractors ...combination weight rating (GCWR) means the value specified by the manufacturer as the loaded weight of the combination vehicle. (d) Gross axle weight

  6. Transportation

    DTIC Science & Technology

    2007-01-01

    International (cont.) European Commission – Directorate General for Energy and Transport, Brussels, Belgium Headquarters Netherlands Customs ...100,000 by 2014. As a result of these challenges and due to the increase in intermodal freight traffic, a customer /client relationship has...increase by 50% domestically and 110% internationally by 2016 (CRS, 2007). United Parcel Service (UPS), FedEx, and DHL currently control the package

  7. Role of neurotransmitters in palate development and teratologic implications.

    PubMed

    Zimmerman, E F

    1985-01-01

    It is hypothesized that neuropharmacologic agents are more teratogenic to humans. Since many neuropharmacologic agents function through neurotransmitter mechanisms, then neurotransmitters should function to regulate embryonic development. Evidence has been obtained that neurotransmitters do indeed function as biological signals in palate development. It has been shown that palate reorientation is modulated by neurotransmitters with a wide range of diversity, similar to the CNS. Thus serotonin and acetylcholine stimulate and GABA inhibits the reorientation process. Spatial diversity is also observed: serotonin functions at the anterior and acetylcholine at the posterior end, and GABA functions more efficiently at either end in different inbred strains. Many criteria for functioning neurotransmitters have been obtained. Both serotonin and GABA have been measured in the palate and developmental changes observed. Physiologic responses to serotonin have been monitored. Serotonin has been shown to stimulate palate cell motility as well as protein carboxyl methylation and cyclic GMP. The serotonin effects on protein carboxyl methylation and cyclic GMP could function to stimulate palate reorientation by modulating cell contractility and protein secretion. Further support for the hypothesis that neuropharmacologic agents could be teratogenic by perturbation of neurotransmitter mechanisms comes from studying GABA and diazepam. Evidence has been obtained that diazepam induces cleft palate by mimicking GABA in a functional GABAergic system in palate development. A significant finding is that genetic differences in both diazepam teratogenesis and in a GABAergic system have been observed. Comparing the SWV and AJ strains, the SWV mouse showed (1) a greater sensitivity to diazepam-induced cleft palate, (2) a greater sensitivity to GABA and diazepam inhibition of palate reorientation in embryo culture, (3) a greater concentration of palatal GABA and (4) a more efficient GABA

  8. Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior

    PubMed Central

    Huang, Fei; Wang, Tingting; Lan, Yunyi; Yang, Li; Pan, Weihong; Zhu, Yonghui; Lv, Boyang; Wei, Yuting; Shi, Hailian; Wu, Hui; Zhang, Beibei; Wang, Jie; Duan, Xiaofeng; Hu, Zhibi; Wu, Xiaojun

    2015-01-01

    Farnesoid X receptor (FXR) is a nuclear hormone receptor involved in bile acid synthesis and homeostasis. Dysfunction of FXR is involved in cholestasis and atherosclerosis. FXR is prevalent in liver, gallbladder, and intestine, but it is not yet clear whether it modulates neurobehavior. In the current study, we tested the hypothesis that mouse FXR deficiency affects a specific subset of neurotransmitters and results in an unique behavioral phenotype. The FXR knockout mice showed less depressive-like and anxiety-related behavior, but increased motor activity. They had impaired memory and reduced motor coordination. There were changes of glutamatergic, GABAergic, serotoninergic, and norepinephrinergic neurotransmission in either hippocampus or cerebellum. FXR deletion decreased the amount of the GABA synthesis enzyme GAD65 in hippocampus but increased GABA transporter GAT1 in cerebral cortex. FXR deletion increased serum concentrations of many bile acids, including taurodehydrocholic acid, taurocholic acid, deoxycholic acid (DCA), glycocholic acid (GCA), tauro-α-muricholic acid, tauro-ω-muricholic acid, and hyodeoxycholic acid (HDCA). There were also changes in brain concentrations of taurocholic acid, taurodehydrocholic acid, tauro-ω-muricholic acid, tauro-β-muricholic acid, deoxycholic acid, and lithocholic acid (LCA). Taken together, the results from studies with FXR knockout mice suggest that FXR contributes to the homeostasis of multiple neurotransmitter systems in different brain regions and modulates neurobehavior. The effect appears to be at least partially mediated by bile acids that are known to cross the blood-brain barrier (BBB) inducing potential neurotoxicity. PMID:25870546

  9. Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior.

    PubMed

    Huang, Fei; Wang, Tingting; Lan, Yunyi; Yang, Li; Pan, Weihong; Zhu, Yonghui; Lv, Boyang; Wei, Yuting; Shi, Hailian; Wu, Hui; Zhang, Beibei; Wang, Jie; Duan, Xiaofeng; Hu, Zhibi; Wu, Xiaojun

    2015-01-01

    Farnesoid X receptor (FXR) is a nuclear hormone receptor involved in bile acid synthesis and homeostasis. Dysfunction of FXR is involved in cholestasis and atherosclerosis. FXR is prevalent in liver, gallbladder, and intestine, but it is not yet clear whether it modulates neurobehavior. In the current study, we tested the hypothesis that mouse FXR deficiency affects a specific subset of neurotransmitters and results in an unique behavioral phenotype. The FXR knockout mice showed less depressive-like and anxiety-related behavior, but increased motor activity. They had impaired memory and reduced motor coordination. There were changes of glutamatergic, GABAergic, serotoninergic, and norepinephrinergic neurotransmission in either hippocampus or cerebellum. FXR deletion decreased the amount of the GABA synthesis enzyme GAD65 in hippocampus but increased GABA transporter GAT1 in cerebral cortex. FXR deletion increased serum concentrations of many bile acids, including taurodehydrocholic acid, taurocholic acid, deoxycholic acid (DCA), glycocholic acid (GCA), tauro-α-muricholic acid, tauro-ω-muricholic acid, and hyodeoxycholic acid (HDCA). There were also changes in brain concentrations of taurocholic acid, taurodehydrocholic acid, tauro-ω-muricholic acid, tauro-β-muricholic acid, deoxycholic acid, and lithocholic acid (LCA). Taken together, the results from studies with FXR knockout mice suggest that FXR contributes to the homeostasis of multiple neurotransmitter systems in different brain regions and modulates neurobehavior. The effect appears to be at least partially mediated by bile acids that are known to cross the blood-brain barrier (BBB) inducing potential neurotoxicity.

  10. Conformational dynamics of a neurotransmitter:sodium symporter in a lipid bilayer.

    PubMed

    Adhikary, Suraj; Deredge, Daniel J; Nagarajan, Anu; Forrest, Lucy R; Wintrode, Patrick L; Singh, Satinder K

    2017-03-07

    Neurotransmitter:sodium symporters (NSSs) are integral membrane proteins responsible for the sodium-dependent reuptake of small-molecule neurotransmitters from the synaptic cleft. The symporters for the biogenic amines serotonin (SERT), dopamine (DAT), and norepinephrine (NET) are targets of multiple psychoactive agents, and their dysfunction has been implicated in numerous neuropsychiatric ailments. LeuT, a thermostable eubacterial NSS homolog, has been exploited as a model protein for NSS members to canvass the conformational mechanism of transport with a combination of X-ray crystallography, cysteine accessibility, and solution spectroscopy. Despite yielding remarkable insights, these studies have primarily been conducted with protein in the detergent-solubilized state rather than embedded in a membrane mimic. In addition, solution spectroscopy has required site-specific labeling of nonnative cysteines, a labor-intensive process occasionally resulting in diminished transport and/or binding activity. Here, we overcome these limitations by reconstituting unlabeled LeuT in phospholipid bilayer nanodiscs, subjecting them to hydrogen-deuterium exchange coupled with mass spectrometry (HDX-MS), and facilitating interpretation of the data with molecular dynamics simulations. The data point to changes of accessibility and dynamics of structural elements previously implicated in the transport mechanism, in particular transmembrane helices (TMs) 1a and 7 as well as extracellular loops (ELs) 2 and 4. The results therefore illuminate the value of this strategy for interrogating the conformational mechanism of the more clinically significant mammalian membrane proteins including SERT and DAT, neither of which tolerates complete removal of endogenous cysteines, and whose activity is heavily influenced by neighboring lipids.

  11. Environmental impacts of the expected increase in sea transportation, with a particular focus on oil and gas scenarios for Norway and northwest Russia

    NASA Astrophysics Data System (ADS)

    Dalsøren, Stig B.; Endresen, Øyvind; Isaksen, Ivar S. A.; Gravir, Gjermund; Sørgârd, Eirik

    2007-01-01

    We have complemented existing global sea transportation emission inventories with new regional emission data sets and scenarios for ship traffic and coastal activity in 2015. Emission inventories for 2000 and 2015 are used in a global Chemical Transport Model (CTM) to quantify environmental atmospheric impacts with particular focus on the Arctic region. Although we assume that ship emissions continue to increase from 2000 to 2015, reductions are assumed for some chemical components and regions because of implementation of new regulations. Current ship traffic (2000) is estimated to contribute significantly to coastal pollution. Norwegian coastal ship traffic is responsible for more than 1/3 and 1/6 of the Norwegian NOx and SO2 emissions, respectively. For these short-lived components the impact of Norwegian coastal emissions is regionally important. For most components the international ship transportation outside coastal waters dominates the effects. Ship emissions increase wet deposition in Scandinavia with 30-50% for nitrate and 10-25% for sulfate. In general, coastal regions with prevailing onshore winds show substantial increases in deposition of acid components. Maximum surface increase in ozone is in excess of 10 ppbv. Column ozone increases are also significant. Assuming no changes in nonshipping emissions, scenarios for shipping activities in 2015 lead to more than 20% increase in NO2 from 2000 to 2015 in some coastal areas. Ozone increases are in general small. Wet deposition of acidic species increases up to 10% in areas where current critical loads are exceeded. Regulations limiting the sulfur content in the fuel in the North Sea and English Channel will be an efficient measure to reduce sulfate deposition in nearby coastal regions. The expected oil and gas transport by ships from Norway and northwest Russia, sea transport along the Northern Sea Route and new Norwegian coastal gas power plants will have a significant regional effect by increases of acid

  12. Dynamic Control of Neurotransmitter Release by Presynaptic Potential

    PubMed Central

    Zbili, Mickael; Rama, Sylvain; Debanne, Dominique

    2016-01-01

    Action potentials (APs) in the mammalian brain are thought to represent the smallest unit of information transmitted by neurons to their postsynaptic targets. According to this view, neuronal signaling is all-or-none or digital. Increasing evidence suggests, however, that subthreshold changes in presynaptic membrane potential before triggering the spike also determines spike-evoked release of neurotransmitter. We discuss here how analog changes in presynaptic voltage may regulate spike-evoked release of neurotransmitter through the modulation of biophysical state of voltage-gated potassium, calcium and sodium channels in the presynaptic compartment. The contribution of this regulation has been greatly underestimated and we discuss the impact for information processing in neuronal circuits. PMID:27994539

  13. Imaging Mass Spectrometric Analysis of Neurotransmitters: A Review

    PubMed Central

    Romero-Perez, Gustavo A.; Takei, Shiro; Yao, Ikuko

    2014-01-01

    Imaging mass spectrometry (IMS) is a toolbox of versatile techniques that enable us to investigate analytes in samples at molecular level. In recent years, IMS, and especially matrix-assisted laser desorption/ionisation (MALDI), has been used to visualise a wide range of metabolites in biological samples. Simultaneous visualisation of the spatial distribution of metabolites in a single sample with little tissue disruption can be considered as one important advantage of MALDI over other techniques. However, several technical hurdles including low concentrations and rapid degradation rates of small molecule metabolites, matrix interference of signals and poor ionisation, need to be addressed before MALDI can be considered as a reliable tool for the analysis of metabolites such as neurotransmitters in brain tissues from different sources including humans. In the present review we will briefly describe current MALDI IMS techniques used to study neurotransmitters and discuss their current status, challenges, as well as future prospects. PMID:26819893

  14. Imaging Mass Spectrometric Analysis of Neurotransmitters: A Review.

    PubMed

    Romero-Perez, Gustavo A; Takei, Shiro; Yao, Ikuko

    2014-01-01

    Imaging mass spectrometry (IMS) is a toolbox of versatile techniques that enable us to investigate analytes in samples at molecular level. In recent years, IMS, and especially matrix-assisted laser desorption/ionisation (MALDI), has been used to visualise a wide range of metabolites in biological samples. Simultaneous visualisation of the spatial distribution of metabolites in a single sample with little tissue disruption can be considered as one important advantage of MALDI over other techniques. However, several technical hurdles including low concentrations and rapid degradation rates of small molecule metabolites, matrix interference of signals and poor ionisation, need to be addressed before MALDI can be considered as a reliable tool for the analysis of metabolites such as neurotransmitters in brain tissues from different sources including humans. In the present review we will briefly describe current MALDI IMS techniques used to study neurotransmitters and discuss their current status, challenges, as well as future prospects.

  15. The molecular machinery of neurotransmitter release (Nobel lecture).

    PubMed

    Südhof, Thomas C

    2014-11-17

    The most important property of synaptic transmission is its speed, which is crucial for the overall workings of the brain. In his Nobel Lecture, T. C. Südhof explains how the synaptic vesicle and the plasma membrane undergo rapid fusion during neurotransmitter release and how this process is spatially organized, such that opening of Ca(2+) -channels allows rapid translation of the entering Ca(2+) signal into a fusion event.

  16. Regulation of Neurotransmitter Responses in the Central Nervous System

    DTIC Science & Technology

    1990-02-05

    neurotransmitter systems was of general physiological relevance to mammalian central nervous system function and (2) that multiple CABA receptors may exist...pharmacologically distinct CABA receptors in mammalian tissues. Furthermore, the results predict it may be possible to develop more potent compounds which...present. Project co-ordination and scientific direction. E. Coupling Activities. S.J. Enna, Ph.D., invited speaker, First International CABA Receptor

  17. Alterations in Brain Monoamine Neurotransmitter Release at High Pressure

    DTIC Science & Technology

    1989-01-01

    exposure results from a general imbalance of encephalopathies. Parkinson’s Syndrome, MPTP the three monoamine neurotransmitter systems toxicity . or...the [3 H]monoamines by Dopamine release, on the other hand, was reduced synaptosomes isolated from the CNS. 5-A n 4 A Pn5 p<.05 0.05 LI * 4- U) 4...Lffect of’ pressure of 3.4-miethylenledioxy-miethamiiphetamnine ( MDMA ) and re- on the release of radioaetive glycine and (IABA from spinal lated

  18. Immunocytochemical localization of a Manduca sexta gamma-aminobutyric acid transporter.

    PubMed

    Umesh, Anita; Gill, Sarjeet S

    2002-07-08

    Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in insect central and peripheral nervous systems. Although much work has focused on the downstream targets of GABA, signal termination at insect GABAergic synapses has received very little attention. One of the major mechanisms of terminating synaptic transmission involves transport of the neurotransmitter molecules into presynaptic neurons or surrounding glia. Here we report the immunolocalization of a GABA transporter in the tobacco hornworm, Manduca sexta (MasGAT), using an affinity-purified antibody developed to the C-terminus. This is the first demonstration of an insect neurotransmitter transporter immunolocalization study. Results showed strong staining in the neuropil regions of embryonic, larval, and pharate adult central nervous system. Expression pattern in the pharate adult brain mostly mimicked that observed for GABA, with staining in parts of the optic and antennal lobes, mushroom body, lateral protocerebrum, and central complex. Certain longitudinal and lateral connectives of ganglia were observed to have immunostained fibers representing axons. These data support the view that GABA is involved in visual and olfactory processing in the insect brain. Copyright 2002 Wiley-Liss, Inc.

  19. [Effect of occupational stress on neurotransmitters in petroleum workers].

    PubMed

    Jiang, Yu; Lian, Yulong; Tao, Ning; Ge, Hua; Liu, Jiwen

    2015-09-01

    To explore the effects of occupational stress on neurotransmitters in petroleum workers. 178 petroleum workers with the length of service ≥ 1 year were recruited to the subjects by the questionnaire of OSI-R. The levels of 5-hydroxy tryptamine (5-HT), norepinephrine (NE), neuropeptide Y (NPY) and substance P (SP) in serum were measured. The subjects were classified into 3 groups according to the scores of occupational stress. The levels of 5-HT NE and SP for over 15 working years were higher than those of less than 15 years (P < 0. 05). There were differences (P < 0. 05) on 5-HT, NE, NPY and SP in different occupational stress degree groups, multiple comparison showed high. occupational stress group was higher than those of low occupational stress group. Multivariate correlation analysis showed that the occupational stress and sleep quality component scores correlated positively with the 5-HT, NE and SP (P < 0. 05) and correlated inversely with NPY in petroleum workers (P < 0. 05). Occupational stress in petroleum workers is correlated with serum monoamine and neuropeptides neurotransmitters, and it may affect serum levels of monoamine and neuropeptides neurotransmitters.

  20. Electrochemical techniques for subsecond neurotransmitter detection in live rodents.

    PubMed

    Hascup, Kevin N; Hascup, Erin R

    2014-08-01

    Alterations in neurotransmission have been implicated in numerous neurodegenerative and neuropsychiatric disorders, including Alzheimer disease, Parkinson disease, epilepsy, and schizophrenia. Unfortunately, few techniques support the measurement of real-time changes in neurotransmitter levels over multiple days, as is essential for ethologic and pharmacodynamic testing. Microdialysis is commonly used for these research paradigms, but its poor temporal and spatial resolution make this technique inadequate for measuring the rapid dynamics (milliseconds to seconds) of fast signaling neurotransmitters, such as glutamate and acetylcholine. Enzymatic microelectrode arrays (biosensors) coupled with electrochemical recording techniques have demonstrated fast temporal resolution (less than 1 s), excellent spatial resolution (micron-scale), low detection limits (≤200 nM), and minimal damage (50 to 100 μm) to surrounding brain tissue. Here we discuss the benefits, methods, and animal welfare considerations of using platinum microelectrodes on a ceramic substrate for enzyme-based electrochemical recording techniques for real-time in vivo neurotransmitter recordings in both anesthetized and awake, freely moving rodents.

  1. Fusion pores and their control of neurotransmitter and hormone release

    PubMed Central

    Chang, Che-Wei; Chiang, Chung-Wei

    2017-01-01

    Ca2+-triggered exocytosis functions broadly in the secretion of chemical signals, enabling neurons to release neurotransmitters and endocrine cells to release hormones. The biological demands on this process can vary enormously. Although synapses often release neurotransmitter in a small fraction of a millisecond, hormone release can be orders of magnitude slower. Vesicles usually contain multiple signaling molecules that can be released selectively and conditionally. Cells are able to control the speed, concentration profile, and content selectivity of release by tuning and tailoring exocytosis to meet different biological demands. Much of this regulation depends on the fusion pore—the aqueous pathway by which molecules leave a vesicle and move out into the surrounding extracellular space. Studies of fusion pores have illuminated how cells regulate secretion. Furthermore, the formation and growth of fusion pores serve as a readout for the progress of exocytosis, thus revealing key kinetic stages that provide clues about the underlying mechanisms. Herein, we review the structure, composition, and dynamics of fusion pores and discuss the implications for molecular mechanisms as well as for the cellular regulation of neurotransmitter and hormone release. PMID:28167663

  2. Profiling neurotransmitter receptor expression in the Ambystoma mexicanum brain.

    PubMed

    Reyes-Ruiz, Jorge Mauricio; Limon, Agenor; Korn, Matthew J; Nakamura, Paul A; Shirkey, Nicole J; Wong, Jamie K; Miledi, Ricardo

    2013-03-22

    Ability to regenerate limbs and central nervous system (CNS) is unique to few vertebrates, most notably the axolotl (Ambystoma sp.). However, despite the fact the neurotransmitter receptors are involved in axonal regeneration, little is known regarding its expression profile. In this project, RT-PCR and qPCR were performed to gain insight into the neurotransmitter receptors present in Ambystoma. Its functional ability was studied by expressing axolotl receptors in Xenopus laevis oocytes by either injection of mRNA or by direct microtransplantation of brain membranes. Oocytes injected with axolotl mRNA expressed ionotropic receptors activated by GABA, aspartate+glycine and kainate, as well as metabotropic receptors activated by acetylcholine and glutamate. Interestingly, we did not see responses following the application of serotonin. Membranes from the axolotl brain were efficiently microtransplanted into Xenopus oocytes and two types of native GABA receptors that differed in the temporal course of their responses and affinities to GABA were observed. Results of this study are necessary for further characterization of axolotl neurotransmitter receptors and may be useful for guiding experiments aimed at understanding activity-dependant limb and CNS regeneration. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  3. Neurotransmitter Influence on Human Meibomian Gland Epithelial Cells

    PubMed Central

    Kam, Wendy R.

    2011-01-01

    Purpose. A striking characteristic of the human meibomian gland is its rich sensory, sympathetic, and parasympathetic innervation, yet the functional relevance of these nerve fibers remains unknown. Acting on the hypothesis that neurotransmitters are released in the vicinity of the gland, act on glandular receptors, and influence the production, secretion, and/or delivery of meibomian gland secretions to the ocular surface, the goal in this study was to begin to determine whether neurotransmitters influence the meibomian gland. Methods. Immortalized human meibomian gland epithelial (SLHMG) cells were examined for the presence of vasoactive intestinal peptide (VIP) and muscarinic acetylcholine (mACh) receptor transcripts and proteins. Cells were also exposed to VIP, carbachol, forskolin, and/or 3-isobutyl-1-methylxanthine (IBMX) to determine whether these agents, alone or in combination, modulate the adenylyl cyclase pathway, the accumulation of intracellular free calcium ([Ca2+]i), or cell proliferation. Results. Results demonstrate that SLHMG cells transcribe and translate VIP and mACh receptors; VIP, with either IBMX or forskolin, activates the adenylyl cyclase pathway, and the effect of VIP and forskolin together is synergistic; both VIP and carbachol increase intracellular [Ca2+] in SLHMG cells; and VIP with forskolin stimulates SLHMG cell proliferation. Conclusions. This study shows that parasympathetic neurotransmitters and their agonists influence the function of human meibomian gland epithelial cells. It remains to be determined whether this action alters the production, secretion, and/or delivery of meibum to the ocular surface. PMID:21969302

  4. Neurotransmitters act as paracrine signals to regulate insulin secretion from the human pancreatic islet.

    PubMed

    Rodriguez-Diaz, Rayner; Menegaz, Danusa; Caicedo, Alejandro

    2014-08-15

    In this symposium review we discuss the role of neurotransmitters as paracrine signals that regulate pancreatic islet function. A large number of neurotransmitters and their receptors has been identified in the islet, but relatively little is known about their involvement in islet biology. Interestingly, neurotransmitters initially thought to be present in autonomic axons innervating the islet are also present in endocrine cells of the human islet. These neurotransmitters can thus be released as paracrine signals to help control hormone release. Here we propose that the role of neurotransmitters may extend beyond controlling endocrine cell function to work as signals modulating vascular flow and immune responses within the islet.

  5. Unsaturated Analogues of the Neurotransmitter GABA: trans-4-Aminocrotonic, cis-4-Aminocrotonic and 4-Aminotetrolic Acids.

    PubMed

    Johnston, Graham A R

    2016-03-01

    Analogues of the neurotransmitter GABA containing unsaturated bonds are restricted in the conformations they can attain. This review traces three such analogues from their synthesis to their use as neurochemicals. trans-4-Aminocrotonic acid was the first conformationally restricted analogue to be extensively studied. It acts like GABA across a range of macromolecules from receptors to transporters. It acts similarly to GABA on ionotropic receptors. cis-4-Aminocrotonic acid selectively activates bicuculline-insensitive GABAC receptors. 4-Aminotetrolic acid, containing a triple bond, activates bicuculline-sensitive GABAA receptors. These findings indicate that GABA activates GABAA receptors in extended conformations and GABAC receptors in folded conformations. These and related analogues are important for the molecular modelling of ionotropic GABA receptors and to the development of new agents acting selectively on these receptors.

  6. The importance of synapsin I and II for neurotransmitter levels and vesicular storage in cholinergic, glutamatergic and GABAergic nerve terminals.

    PubMed

    Bogen, Inger Lise; Haug, Kristin Huse; Roberg, Bjørg; Fonnum, Frode; Walaas, S Ivar

    2009-01-01

    The aim of this study was to examine the importance of the vesicle-associated synapsin I and II phosphoproteins for the accumulation of neurotransmitters in central cholinergic as compared to central glutamatergic and GABAergic nerve terminals. In brain homogenate samples from mice devoid of synapsin I and II, the levels of vesicular transporters for glutamate (VGLUT1-2) and GABA (VGAT) were decreased by 35-40% in striatum and cortex, while no change was apparent for the vesicular acetylcholine transporter (VAChT). The severe decrease in the levels of amino acid vesicular transporters caused only minor changes in the concentrations of the respective neurotransmitters in homogenates of the three selected brain areas from synapsin I- and II-deficient mice. However, when measured in a crude vesicular fraction, the concentrations of glutamate and GABA were decreased by 48-60% in synapsin-deficient mice, with a similar decrease in the levels of VGLUT1, VGLUT2 and VGAT. In comparison, the concentration of acetylcholine and the level of VAChT were not significantly different from wild-type in the vesicular fraction. No changes were seen in the activity of specific enzymes involved in the synthesis of acetylcholine, glutamate or GABA, however, immunoblotting indicated a decrease in the protein level of glutamic acid decarboxylase, isoform 65 (GAD(65)). In conclusion, the results indicate that neurotransmitter regulation in central cholinergic synapses may be less dependent on synapsin I and II compared to the marked alterations seen in the glutamatergic and GABAergic synapses.

  7. Stress, neurotransmitters, corticosterone and body-brain integration.

    PubMed

    Mora, Francisco; Segovia, Gregorio; Del Arco, Alberto; de Blas, Marta; Garrido, Pedro

    2012-10-02

    Stress can be defined as a brain-body reaction towards stimuli arising from the environment or from internal cues that are interpreted as a disruption of homeostasis. The organization of the response to a stressful situation involves not only the activity of different types of neurotransmitter systems in several areas of the limbic system, but also the response of neurons in these areas to several other chemicals and hormones, chiefly glucocorticoids, released from peripheral organs and glands. Thus, stress is probably the process through which body-brain integration plays a major role. Here we review first the responses to an acute stress in terms of neurotransmitters such as dopamine, acetylcholine, glutamate and GABA in areas of the brain involved in the regulation of stress responses. These areas include the prefrontal cortex, amygdala, hippocampus and nucleus accumbens and the interaction among those areas. Then, we consider the role of glucocorticoids and review some recent data about the interaction of these steroids with several neurotransmitters in those same areas of the brain. Also the actions of other substances (neuromodulators) released from peripheral organs such as the pancreas, liver or gonads (insulin, IGF-1, estrogens) are reviewed. The role of an environmental enrichment on these same responses is also discussed. Finally a section is devoted to put into perspective all these environmental-brain-body-brain interactions during stress and their consequences on aging. It is concluded that the integrative perspective framed in this review is relevant for better understanding of how the organism responds to stressful challenges and how this can be modified through different environmental conditions during the process of aging. This article is part of a Special Issue entitled: Brain Integration.

  8. The importance of glutamate, glycine, and {gamma}-aminobutyric acid transport and regulation in manganese, mercury and lead neurotoxicity

    SciTech Connect

    Fitsanakis, Vanessa A.; Aschner, Michael . E-mail: michael.aschner@vanderbilt.edu

    2005-05-01

    Historically, amino acids were studied in the context of their importance in protein synthesis. In the 1950s, the focus of research shifted as amino acids were recognized as putative neurotransmitters. Today, many amino acids are considered important neurochemicals. Although many amino acids play a role in neurotransmission, glutamate (Glu), glycine (Gly), and {gamma}-aminobutyric acid (GABA) are among the more prevalent and better understood. Glu, the major excitatory neurotransmitter, and Gly and GABA, the major inhibitory neurotransmitters, in the central nervous system, are known to be tightly regulated. Prolonged exposure to environmental toxicants, such as manganese (Mn), mercury (Hg), or lead (Pb), however, can lead to dysregulation of these neurochemicals and subsequent neurotoxicity. While the ability of these metals to disrupt the regulation of Glu, Gly and GABA have been studied, few articles have examined the collective role of these amino acids in the respective metal's mechanism of toxicity. For each of the neurotransmitters above, we will provide a brief synopsis of their regulatory function, including the importance of transport and re-uptake in maintaining their optimal function. Additionally, the review will address the hypothesis that aberrant homeostasis of any of these amino acids, or a combination of the three, plays a role in the neurotoxicity of Mn, Hg, or Pb.

  9. Name that neurotransmitter: using music to teach psychopharmacology concepts.

    PubMed

    Hermanns, Melinda; Lilly, Mary LuAnne; Wilson, Kathy; Russell, Nathan Andrew

    2012-09-01

    The purpose of this article is to discuss the use of music (i.e., two original songs, "Neurotransmitter Twitter" and "Parkinson's Shuffle") to teach aspects of psychopharmacology to students in the course Psychiatric/Mental Health Nursing. Songs were incorporated in both the clinical and classroom settings. This innovative teaching method allowed students the opportunity to revisit the information through multiple exposures of the content for reinforcement and enhancement of student learning in a fun, creative approach. Brain-based research will be discussed, along with the process of development.

  10. Neurotransmitters in the Gas Phase: La-Mb Studies

    NASA Astrophysics Data System (ADS)

    Cabezas, C.; Mata, S.; López, J. C.; Alonso, J. L.

    2011-06-01

    LA-MB-FTMW spectroscopy combines laser ablation with Fourier transform microwave spectroscopy in supersonic jets overcoming the problems of thermal decomposition associated with conventional heating methods. We present here the results on LA-MB-FTMW studies of some neurotransmitters. Six conformers of dopamine, four of adrenaline, five of noradrenaline and three conformers of serotonin have been characterized in the gas phase. The rotational and nuclear quadrupole coupling constants extracted from the analysis of the rotational spectrum are directly compared with those predicted by ab initio methods to achieve the conclusive identification of different conformers and the experimental characterization of the intramolecular forces at play which control conformational preferences.

  11. Carbon Nanotube-based microelectrodes for enhanced detection of neurotransmitters

    NASA Astrophysics Data System (ADS)

    Jacobs, Christopher B.

    Fast-scan cyclic voltammetry (FSCV) is one of the common techniques used for rapid measurement of neurotransmitters in vivo. Carbon-fiber microelectrodes (CFMEs) are typically used for neurotransmitter detection because of sub-second measurement capabilities, ability to measure changes in neurotransmitter concentration during neurotransmission, and the small size electrode diameter, which limits the amount of damage caused to tissue. Cylinder CFMEs, typically 50 -- 100 microm long, are commonly used for in vivo experiments because the electrode sensitivity is directly related to the electrode surface area. However the length of the electrode can limit the spatial resolution of neurotransmitter detection, which can restrict experiments in Drosophila and other small model systems. In addition, the electrode sensitivity toward dopamine and serotonin detection drops significantly for measurements at rates faster than 10 Hz, limiting the temporal resolution of CFMEs. While the use of FSCV at carbon-fiber microelectrodes has led to substantial strides in our understanding of neurotransmission, techniques that expand the capabilities of CFMEs are crucial to fully maximize the potential uses of FSCV. This dissertation introduces new methods to integrate carbon nanotubes (CNT) into microelectrodes and discusses the electrochemical enhancements of these CNT-microelectrodes. The electrodes are specifically designed with simple fabrication procedures so that highly specialized equipment is not necessary, and they utilize commercially available materials so that the electrodes could be easily integrated into existing systems. The electrochemical properties of CNT modified CFMEs are characterized using FSCV and the effect of CNT functionalization on these properties is explored in Chapter 2. For example, CFME modification using carboxylic acid functionalized CNTs yield about a 6-fold increase in dopamine oxidation current, but modification with octadecylamine CNTs results in a

  12. Beta-amyloid peptides undergo regulated co-secretion with neuropeptide and catecholamine neurotransmitters.

    PubMed

    Toneff, Thomas; Funkelstein, Lydiane; Mosier, Charles; Abagyan, Armen; Ziegler, Michael; Hook, Vivian

    2013-08-01

    Beta-amyloid (Aβ) peptides are secreted from neurons, resulting in extracellular accumulation of Aβ and neurodegeneration of Alzheimer's disease. Because neuronal secretion is fundamental for the release of neurotransmitters, this study assessed the hypothesis that Aβ undergoes co-release with neurotransmitters. Model neuronal-like chromaffin cells were investigated, and results illustrate regulated, co-secretion of Aβ(1-40) and Aβ(1-42) with peptide neurotransmitters (galanin, enkephalin, and NPY) and catecholamine neurotransmitters (dopamine, norepinephrine, and epinephrine). Regulated secretion from chromaffin cells was stimulated by KCl depolarization and nicotine. Forskolin, stimulating cAMP, also induced co-secretion of Aβ peptides with peptide and catecholamine neurotransmitters. These data suggested the co-localization of Aβ with neurotransmitters in dense core secretory vesicles (DCSV) that store and secrete such chemical messengers. Indeed, Aβ was demonstrated to be present in DCSV with neuropeptide and catecholamine transmitters. Furthermore, the DCSV organelle contains APP and its processing proteases, β- and γ-secretases, that are necessary for production of Aβ. Thus, Aβ can be generated in neurotransmitter-containing DCSV. Human IMR32 neuroblastoma cells also displayed regulated secretion of Aβ(1-40) and Aβ(1-42) with the galanin neurotransmitter. These findings illustrate that Aβ peptides are present in neurotransmitter-containing DCSV, and undergo co-secretion with neuropeptide and catecholamine neurotransmitters that regulate brain functions.

  13. Evidence that synaptosomal high-affinity carriers for amino acid neurotransmitters are glycosylated

    SciTech Connect

    Zaleska, M.M.; Erecinska, M.

    1987-05-01

    The effect of removal of surface sialic acid from synaptosomes on the high-affinity, Na/sup +/-dependent uptake systems for amino acid neurotransmitters was evaluated. Synaptosomes from rat forebrain were preincubated with neuraminidase from Vibrio cholerae for 20 min at 34/sup 0/. After washing and resuspension, their ability to transport /sup 14/C-GABA and the acidic amino acid, /sup 3/H-aspartate was studied. Pretreatment with neuraminidase resulted in a concentration-dependent inhibition of the uptake of both amino acids while the influx of /sup 3/H-L-leucine was unaffected. Inhibition was a function of the amount of sialic acid released from membranes. The analysis of the kinetic parameters of amino acid uptake revealed that inhibition resulted from a decrease of Vmax without any change in the Km. Neither the synaptosomal energy levels nor the internal concentration of potassium ions was affected by the pretreatment with neuraminidase. The maximum accumulation ratios for both amino acids remained largely unaltered. It is concluded that the GABA and acidic amino acid transporters are glycosylated and that sialic acid is involved in the operation of carrier proteins directly and not through modification of the driving forces responsible for amino acid transport.

  14. Substrate-induced Unlocking of the Inner Gate Determines the Catalytic Efficiency of a Neurotransmitter:Sodium Symporter*

    PubMed Central

    Billesbølle, Christian B.; Krüger, Mie B.; Shi, Lei; Quick, Matthias; Li, Zheng; Stolzenberg, Sebastian; Kniazeff, Julie; Gotfryd, Kamil; Mortensen, Jonas S.; Javitch, Jonathan A.; Weinstein, Harel; Loland, Claus J.; Gether, Ulrik

    2015-01-01

    Neurotransmitter:sodium symporters (NSSs) mediate reuptake of neurotransmitters from the synaptic cleft and are targets for several therapeutics and psychostimulants. The prokaryotic NSS homologue, LeuT, represents a principal structural model for Na+-coupled transport catalyzed by these proteins. Here, we used site-directed fluorescence quenching spectroscopy to identify in LeuT a substrate-induced conformational rearrangement at the inner gate conceivably leading to formation of a structural intermediate preceding transition to the inward-open conformation. The substrate-induced, Na+-dependent change required an intact primary substrate-binding site and involved increased water exposure of the cytoplasmic end of transmembrane segment 5. The findings were supported by simulations predicting disruption of an intracellular interaction network leading to a discrete rotation of transmembrane segment 5 and the adjacent intracellular loop 2. The magnitude of the spectroscopic response correlated inversely with the transport rate for different substrates, suggesting that stability of the intermediate represents an unrecognized rate-limiting barrier in the NSS transport mechanism. PMID:26363074

  15. Substrate-induced unlocking of the inner gate determines the catalytic efficiency of a neurotransmitter:sodium symporter.

    PubMed

    Billesbølle, Christian B; Krüger, Mie B; Shi, Lei; Quick, Matthias; Li, Zheng; Stolzenberg, Sebastian; Kniazeff, Julie; Gotfryd, Kamil; Mortensen, Jonas S; Javitch, Jonathan A; Weinstein, Harel; Loland, Claus J; Gether, Ulrik

    2015-10-30

    Neurotransmitter:sodium symporters (NSSs) mediate reuptake of neurotransmitters from the synaptic cleft and are targets for several therapeutics and psychostimulants. The prokaryotic NSS homologue, LeuT, represents a principal structural model for Na(+)-coupled transport catalyzed by these proteins. Here, we used site-directed fluorescence quenching spectroscopy to identify in LeuT a substrate-induced conformational rearrangement at the inner gate conceivably leading to formation of a structural intermediate preceding transition to the inward-open conformation. The substrate-induced, Na(+)-dependent change required an intact primary substrate-binding site and involved increased water exposure of the cytoplasmic end of transmembrane segment 5. The findings were supported by simulations predicting disruption of an intracellular interaction network leading to a discrete rotation of transmembrane segment 5 and the adjacent intracellular loop 2. The magnitude of the spectroscopic response correlated inversely with the transport rate for different substrates, suggesting that stability of the intermediate represents an unrecognized rate-limiting barrier in the NSS transport mechanism.

  16. Neurotransmitter CART as a New Therapeutic Candidate for Parkinson’s Disease

    PubMed Central

    Mao, Peizhong; Meshul, Charles K.; Thuillier, Philippe; Reddy, P. Hemachandra

    2013-01-01

    Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. To date, there is no effective treatment that halts its progression. Increasing evidence indicates that mitochondria play an important role in the development of PD. Hence mitochondria-targeted approaches or agents may have therapeutic promise for treatment of the disease. Neuropeptide CART (cocaine-amphetamine-regulated transcript), a hypothalamus and midbrain enriched neurotransmitter with an antioxidant property, can be found in mitochondria, which is the main source of reactive oxygen species. Systemic administration of CART has been found to ameliorate dopaminergic neuronal loss and improve motor functions in a mouse model of PD. In this article, we summarize recent progress in studies investigating the relationship between CART, dopamine, and the pathophysiology of PD, with a focus on mitochondria-related topics. PMID:23543038

  17. Phorbol esters and neurotransmitter release: more than just protein kinase C?

    PubMed Central

    Silinsky, Eugene M; Searl, Timothy J

    2003-01-01

    This review focuses on the effects of phorbol esters and the role of phorbol ester receptors in the secretion of neurotransmitter substances. We begin with a brief background on the historical use of phorbol esters as tools to decipher the role of the enzyme protein kinase C in signal transduction cascades. Next, we illustrate the structural differences between active and inactive phorbol esters and the mechanism by which the binding of phorbol to its recognition sites (C1 domains) on a particular protein acts to translocate that protein to the membrane. We then discuss the evidence that the most important nerve terminal receptor for phorbol esters (and their endogenous counterpart diacylglycerol) is likely to be Munc13. Indeed, Munc13 and its invertebrate homologues are the main players in priming the secretory apparatus for its critical function in the exocytosis process. PMID:12711617

  18. Natural polyphenols: Influence on membrane transporters

    PubMed Central

    Hussain, Saad Abdulrahman; Sulaiman, Amal Ajaweed; Alhaddad, Hasan; Alhadidi, Qasim

    2016-01-01

    Accumulated evidence has focused on the use of natural polyphenolic compounds as nutraceuticals since they showed a wide range of bioactivities and exhibited protection against variety of age-related disorders. Polyphenols have variable potencies to interact, and hence alter the activities of various transporter proteins, many of them classified as anion transporting polypeptide-binding cassette transporters like multidrug resistance protein and p-glycoprotein. Some of the efflux transporters are, generally, linked with anticancer and antiviral drug resistance; in this context, polyphenols may be beneficial in modulating drug resistance by increasing the efficacy of anticancer and antiviral drugs. In addition, these effects were implicated to explain the influence of dietary polyphenols on drug efficacy as result of food-drug interactions. However, limited data are available about the influence of these components on uptake transporters. Therefore, the objective of this article is to review the potential efficacies of polyphenols in modulating the functional integrity of uptake transporter proteins, including those terminated the effect of neurotransmitters, and their possible influence in neuropharmacology. PMID:27069731

  19. Recent advances in transport of water-soluble vitamins in organs of the digestive system: a focus on the colon and the pancreas.

    PubMed

    Said, Hamid M

    2013-11-01

    This review focuses on recent advances in our understanding of the mechanisms and regulation of water-soluble vitamin (WSV) transport in the large intestine and pancreas, two important organs of the digestive system that have only recently received their fair share of attention. WSV, a group of structurally unrelated compounds, are essential for normal cell function and development and, thus, for overall health and survival of the organism. Humans cannot synthesize WSV endogenously; rather, WSV are obtained from exogenous sources via intestinal absorption. The intestine is exposed to two sources of WSV: a dietary source and a bacterial source (i.e., WSV generated by the large intestinal microbiota). Contribution of the latter source to human nutrition/health has been a subject of debate and doubt, mostly based on the absence of specialized systems for efficient uptake of WSV in the large intestine. However, recent studies utilizing a variety of human and animal colon preparations clearly demonstrate that such systems do exist in the large intestine. This has provided strong support for the idea that the microbiota-generated WSV are of nutritional value to the host, and especially to the nutritional needs of the local colonocytes and their health. In the pancreas, WSV are essential for normal metabolic activities of all its cell types and for its exocrine and endocrine functions. Significant progress has also been made in understanding the mechanisms involved in the uptake of WSV and the effect of chronic alcohol exposure on the uptake processes.

  20. Recent advances in transport of water-soluble vitamins in organs of the digestive system: a focus on the colon and the pancreas

    PubMed Central

    2013-01-01

    This review focuses on recent advances in our understanding of the mechanisms and regulation of water-soluble vitamin (WSV) transport in the large intestine and pancreas, two important organs of the digestive system that have only recently received their fair share of attention. WSV, a group of structurally unrelated compounds, are essential for normal cell function and development and, thus, for overall health and survival of the organism. Humans cannot synthesize WSV endogenously; rather, WSV are obtained from exogenous sources via intestinal absorption. The intestine is exposed to two sources of WSV: a dietary source and a bacterial source (i.e., WSV generated by the large intestinal microbiota). Contribution of the latter source to human nutrition/health has been a subject of debate and doubt, mostly based on the absence of specialized systems for efficient uptake of WSV in the large intestine. However, recent studies utilizing a variety of human and animal colon preparations clearly demonstrate that such systems do exist in the large intestine. This has provided strong support for the idea that the microbiota-generated WSV are of nutritional value to the host, and especially to the nutritional needs of the local colonocytes and their health. In the pancreas, WSV are essential for normal metabolic activities of all its cell types and for its exocrine and endocrine functions. Significant progress has also been made in understanding the mechanisms involved in the uptake of WSV and the effect of chronic alcohol exposure on the uptake processes. PMID:23989008

  1. Localized neurotransmitter release for use in a prototype retinal interface.

    PubMed

    Peterman, Mark C; Bloom, David M; Lee, Christina; Bent, Stacey F; Marmor, Michael F; Blumenkranz, Mark S; Fishman, Harvey A

    2003-07-01

    Current neural prostheses use electricity as the mode of stimulation, yet information transfer in neural circuitry is primarily through chemical transmitters. To address this disparity, this study was conducted to devise a prototype interface for a retinal prosthetic based on localized chemical delivery. The goal was to determine whether fluidic delivery through microfabricated apertures could be used to stimulate at single-cell dimensions. A drug delivery system was microfabricated based on a 5- or 10- microm aperture in a 500-nm thick silicon nitride membrane to localize and limit transmitter release. The aperture overlies a microfluidic delivery channel in a silicone elastomer. To demonstrate the effectiveness of this transmitter-based prosthesis, rat pheochromocytoma cells (PC12 cell line) were grown on the surface of the device to test the precision of stimulation, using bradykinin as a stimulant and measuring fluorescence from the calcium indicator, fluo-4. The extent of stimulation could be controlled accurately by varying the concentration of stimulant, from a single cell adjacent to the aperture to a broad area of cells. The stimulation radius was as small as 10 microm, corresponding to stimulation volumes as small as 2 pL. The relationship between the extent of stimulation and concentration was linear. The demonstration of localized chemical stimulation of excitable cells illustrates the potential of this technology for retinal prostheses. Although this is only a proof of concept of neurotransmitter stimulation for a retinal prosthesis, it is a significant first step toward mimicking neurotransmitter release during synaptic transmission.

  2. [Mechanisms of neurotransmitter release facilitation in strontium solutions].

    PubMed

    Mukhamed'iarov, M A; Kochunova, Iu O; Telina, E N; Zefirov, A L

    2008-02-01

    Mechanisms of neurotransmitter release facilitation were studied using electrophysiological recording of end-plate currents (EPC) and nerve ending (NE) responses after substitution of extracellular Ca ions with Sr ions at the frog neuromuscular junction. The solutions with 0.5 mM concentration of Ca ions (calcium solution) or 1 mM concentration of Sr ions (strontium solution) were used where baseline neurotransmitter release (at low-frequency stimulation) is equal. Decay of paired-pulse facilitation of EPC at calcium solutions with increase of interpulse interval from 5 to 500 ms was well described by three-exponential function consisting of early, first and second components. Facilitation at strontium solutions was significantly diminished due mainly to decrease of early and first components. At the same time, EPC facilitation with rhythmic stimulation (10 or 50 imp/s) at strontium solutions was significantly increased. Also more pronounced decrease of NE response 3rd phase, reflecting potassium currents was detected under rhythmic stimulation of 50 imp/s at strontium solutions comparing to calcium solutions. It was concluded that facilitation sites underlying first and early components had lower affinity to Sr ions than to Ca ions. The enhancement of frequency facilitation at strontium solutions is mediated by two mechanisms: more pronounced broadening of NE action potential and increase of bivalent cation influx due to feebly marked activation of Ca(2+)-dependent potassium current by Sr ions, and slower dynamics of Sr(2+) removal from NE axoplasm comparing to Ca(2+).

  3. Cytokine Targets in the Brain: Impact on Neurotransmitters and Neurocircuits

    PubMed Central

    Miller, Andrew H.; Haroon, Ebrahim; Raison, Charles L.; Felger, Jennifer C.

    2014-01-01

    Increasing attention has been paid to the role of inflammation in a host of illnesses including neuropsychiatric disorders such as depression and anxiety. Activation of the inflammatory response leads to release of inflammatory cytokines and mobilization of immune cells both of which have been shown to access the brain and alter behavior. The mechanisms of the effects of inflammation on the brain have become an area of intensive study. Data indicate that cytokines and their signaling pathways including p38 mitogen activated protein kinase have significant effects on the metabolism of multiple neurotransmitters such as serotonin, dopamine and glutamate through impact on their synthesis, release and reuptake. Cytokines also activate the kynurenine pathway which not only depletes tryptophan, the primary amino acid precursor of serotonin, but also generates neuroactive metabolites that can significantly influence the regulation of dopamine and glutamate. Through their effects on neurotransmitter systems, cytokines impact neurocircuits in the brain including the basal ganglia and anterior cingulate cortex, leading to significant changes in motor activity and motivation as well as anxiety, arousal and alarm. In the context of environmental challenge from the microbial world, these effects of inflammatory cytokines on the brain represent an orchestrated suite of behavioral and immune responses that subserve evolutionary priorities to shunt metabolic resources away from environmental exploration to fighting infection and wound healing, while also maintaining vigilance against attack, injury and further pathogen exposure. Chronic activation of this innate behavioral and immune response may lead to depression and anxiety disorders in vulnerable individuals. PMID:23468190

  4. Detection and Monitoring of Neurotransmitters - a Spectroscopic Analysis

    NASA Astrophysics Data System (ADS)

    Manciu, Felicia; Lee, Kendall; Durrer, William; Bennet, Kevin

    2012-10-01

    In this work we demonstrate the capability of confocal Raman mapping spectroscopy for simultaneously and locally detecting important compounds in neuroscience such as dopamine, serotonin, and adenosine. The Raman results show shifting of the characteristic vibrations of the compounds, observations consistent with previous spectroscopic studies. Although some vibrations are common in these neurotransmitters, Raman mapping was achieved by detecting non-overlapping characteristic spectral signatures of the compounds, as follows: for dopamine the vibration attributed to C-O stretching, for serotonin the indole ring stretching vibration, and for adenosine the adenine ring vibrations. Without damage, dyeing, or preferential sample preparation, confocal Raman mapping provided positive detection of each neurotransmitter, allowing association of the high-resolution spectra with specific micro-scale image regions. Such information is particularly important for complex, heterogeneous samples, where modification of the chemical or physical composition can influence the neurotransmission processes. We also report an estimated dopamine diffusion coefficient two orders of magnitude smaller than that calculated by the flow-injection method.

  5. Re-examining how complexin inhibits neurotransmitter release

    PubMed Central

    Trimbuch, Thorsten; Xu, Junjie; Flaherty, David; Tomchick, Diana R; Rizo, Josep; Rosenmund, Christian

    2014-01-01

    Complexins play activating and inhibitory functions in neurotransmitter release. The complexin accessory helix inhibits release and was proposed to insert into SNARE complexes to prevent their full assembly. This model was supported by ‘superclamp’ and ‘poor-clamp’ mutations that enhanced or decreased the complexin-I inhibitory activity in cell–cell fusion assays, and by the crystal structure of a superclamp mutant bound to a synaptobrevin-truncated SNARE complex. NMR studies now show that the complexin-I accessory helix does not insert into synaptobrevin-truncated SNARE complexes in solution, and electrophysiological data reveal that superclamp mutants have slightly stimulatory or no effects on neurotransmitter release, whereas a poor-clamp mutant inhibits release. Importantly, increasing or decreasing the negative charge of the complexin-I accessory helix inhibits or stimulates release, respectively. These results suggest a new model whereby the complexin accessory helix inhibits release through electrostatic (and perhaps steric) repulsion enabled by its location between the vesicle and plasma membranes. DOI: http://dx.doi.org/10.7554/eLife.02391.001 PMID:24842998

  6. MRI sensing of neurotransmitters with a crown ether appended Gd(3+) complex.

    PubMed

    Oukhatar, Fatima; Même, Sandra; Même, William; Szeremeta, Frédéric; Logothetis, Nikos K; Angelovski, Goran; Tóth, Éva

    2015-02-18

    Molecular magnetic resonance imaging (MRI) approaches that detect biomarkers associated with neural activity would allow more direct observation of brain function than current functional MRI based on blood-oxygen-level-dependent contrast. Our objective was to create a synthetic molecular platform with appropriate recognition moieties for zwitterionic neurotransmitters that generate an MR signal change upon neurotransmitter binding. The gadolinium complex (GdL) we report offers ditopic binding for zwitterionic amino acid neurotransmitters, via interactions (i) between the positively charged and coordinatively unsaturated metal center and the carboxylate function and (ii) between a triazacrown ether and the amine group of the neurotransmitters. GdL discriminates zwitterionic neurotransmitters from monoamines. Neurotransmitter binding leads to a remarkable relaxivity change, related to a decrease in hydration number. GdL was successfully used to monitor neural activity in ex vivo mouse brain slices by MRI.

  7. Pituitary adenylate cyclase-activating polypeptide is a sympathoadrenal neurotransmitter involved in catecholamine regulation and glucohomeostasis.

    PubMed

    Hamelink, Carol; Tjurmina, Olga; Damadzic, Ruslan; Young, W Scott; Weihe, Eberhard; Lee, Hyeon-Woo; Eiden, Lee E

    2002-01-08

    The adrenal gland is important for homeostatic responses to metabolic stress: hypoglycemia stimulates the splanchnic nerve, epinephrine is released from adrenomedullary chromaffin cells, and compensatory glucogenesis ensues. Acetylcholine is the primary neurotransmitter mediating catecholamine secretion from the adrenal medulla. Accumulating evidence suggests that a secretin-related neuropeptide also may function as a transmitter at the adrenomedullary synapse. Costaining with highly specific antibodies against the secretin-related neuropeptide pituitary adenylate cyclase-activating peptide (PACAP) and the vesicular acetylcholine transporter (VAChT) revealed that PACAP is found in nerve terminals at all mouse adrenomedullary cholinergic synapses. Mice with a targeted deletion of the PACAP gene had otherwise normal cholinergic innervation and morphology of the adrenal medulla, normal adrenal catecholamine and blood glucose levels, and an intact initial catecholamine secretory response to insulin-induced hypoglycemia. However, insulin-induced hypoglycemia was more profound and longer-lasting in PACAP knock-outs, and was associated with a dose-related lethality absent in wild-type mice. Failure of PACAP-deficient mice to adequately counterregulate plasma glucose levels could be accounted for by impaired long-term secretion of epinephrine, secondary to a lack of induction of tyrosine hydroxylase, normally occurring after insulin hypoglycemia in wild-type mice, and a consequent depletion of adrenomedullary epinephrine stores. Thus, PACAP is needed to couple epinephrine biosynthesis to secretion during metabolic stress. PACAP appears to function as an "emergency response" cotransmitter in the sympathoadrenal axis, where the primary secretory response is controlled by a classical neurotransmitter but sustained under paraphysiological conditions by a neuropeptide.

  8. [Glutamatergic neurotransmitter system in regulation of the gastrointestinal tract motor activity].

    PubMed

    Alekseeva, E V; Popova, T S; Sal'nikov, P S

    2015-01-01

    The review include actual facts, demonstrating high probability of glutamatergic neurotransmitter system role in the regulation of the gastrointestinal tract motor activity. These facts suggest significant role of the glutamatergic neurotransmitter system dysfunction in forming motor activity disorders of the digestive tract, including in patients in critical condition. The analysis is based on results of multiple experimental and clinical researches of glutamic acid and other components of the glutamatergic neurotransmitter system in central nervous system and autonomic nervous system (with the accent on the enteral nervous system) in normal conditions and with functioning changes of the glutamatergic neurotransmitter system in case of inflammation, hupoxia, stress and in critical condition.

  9. A 10(9) neutrons/pulse transportable pulsed D-D neutron source based on flexible head plasma focus unit.

    PubMed

    Niranjan, Ram; Rout, R K; Srivastava, R; Kaushik, T C; Gupta, Satish C

    2016-03-01

    A 17 kJ transportable plasma focus (PF) device with flexible transmission lines is developed and is characterized. Six custom made capacitors are used for the capacitor bank (CB). The common high voltage plate of the CB is fixed to a centrally triggered spark gap switch. The output of the switch is coupled to the PF head through forty-eight 5 m long RG213 cables. The CB has a quarter time-period of 4 μs and an estimated current of 506 kA is delivered to the PF device at 17 kJ (60 μF, 24 kV) energy. The average neutron yield measured using silver activation detector in the radial direction is (7.1 ± 1.4) × 10(8) neutrons/shot over 4π sr at 5 mbar optimum D2 pressure. The average neutron yield is more in the axial direction with an anisotropy factor of 1.33 ± 0.18. The average neutron energies estimated in the axial as well as in the radial directions are (2.90 ± 0.20) MeV and (2.58 ± 0.20) MeV, respectively. The flexibility of the PF head makes it useful for many applications where the source orientation and the location are important factors. The influence of electromagnetic interferences from the CB as well as from the spark gap on applications area can be avoided by putting a suitable barrier between the bank and the PF head.

  10. The Fluorescence Methods to Study Neurotransmitters (Biomediators) in Plant Cells.

    PubMed

    Roshchina, Victoria V

    2016-05-01

    Fluorescence as a parameter for analysis of intracellular binding and localization of neurotransmitters also named biomediators (acetylcholine and biogenic amines such as catecholamines, serotonin, histamine) as well as their receptors in plant cells has been estimated basing on several world publications and own experiments of the author. The subjects of the consideration were 1. application of reagents forming fluorescent products (for catecholamines - glyoxylic acid, for histamine - formaldehyde or ortho-phthalic aldehyde) to show the presence and binding of the compounds in cells, 2. binding of their fluorescent agonists and antagonists with cell, 3. effects of the compounds, their agonists and antagonists on autofluorescence, 4. action of external factors on the accumulation of the compounds in cells. How neurotransmitters can bind to certain cellular compartments has been shown on intact individual cells (vegetative microspores, pollens, secretory cells) and isolated organelles. The staining with reagents on biogenic amines leads to the appearance blue or blue-green emission on the surface and excretions of intact cells as well in some DNA-containing organelles within cells. The difference between autofluorescence and histochemically induced fluorescence may reflect the occurrence and amount of biogenic amines in the cells studied. Ozone and salinity as external factors can regulate the emission of intact cells related to biogenic amines. After the treatment of isolated cellular organelles with glyoxylic acid blue emission with maximum 460-475 nm was seen in nuclei and chloroplasts (in control variants in this spectral region the noticeable emission was absent) and very expressive fluorescence (more than twenty times as compared to control) in the vacuoles. After exposure to ortho-phthalic aldehyde blue emission was more noticeable in nuclei and chloroplasts. Fluorescent agonists (muscarine, 6,7-diOHATN, BODIPY-dopamine or BODIPY-5HT) or antagonists (d

  11. Reserpine modulates neurotransmitter release to extend lifespan and alleviate age-dependent Aβ proteotoxicity in Caenorhabditis elegans.

    PubMed

    Saharia, Kopal; Arya, Upasna; Kumar, Ranjeet; Sahu, Rashmi; Das, Chinmaya Kumar; Gupta, Kuldeep; Dwivedi, Hemalata; Subramaniam, Jamuna R

    2012-02-01

    Aging is a debilitating process often associated with chronic diseases such as diabetes, cardiovascular and neurodegenerative diseases like Alzheimer's disease (AD). AD occurs at a very high incidence posing a huge burden to the society. Model organisms such as C. elegans become essential to understand aging or lifespan extension - the etiology, molecular mechanism and identification of new drugs against age associated diseases. The AD model, manifesting Aβ proteotoxicity, in C. elegans is well established and has provided valuable insights. Earlier, we have reported that Reserpine, an FDA-approved antihypertensive drug, increases C. elegans lifespan with a high quality of life and ameliorates Aβ toxicity in C. elegans. But reserpine does not seem to act through the known lifespan extension pathways or inhibition of its known target, vesicular monoamine transporter, VMAT. Reserpine's mode of action and the pathways it activates are not known. Here, we have evaluated the presynaptic neurotransmitter(s) release pathway and identified acetylcholine (ACh) as the crucial player for reserpine's action. The corroborating evidences are: i) lack of lifespan extension in the ACh loss of function (hypomorphic) - synthesis (cha-1) and transport (unc-17) mutants; ii) mitigation of chronic aldicarb effect; iii) lifespan extension in dopamine (cat-2) and dopamine and serotonin (bas-1) biosynthetic mutants; iv) no rescue from exogenous serotonin induced paralysis in the AD model worms; upon reserpine treatment. Thus, modulation of acetylcholine is essential for reserpine's action. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Mimicking subsecond neurotransmitter dynamics with femtosecond laser stimulated nanosystems

    NASA Astrophysics Data System (ADS)

    Nakano, Takashi; Chin, Catherine; Myint, David Mo Aung; Tan, Eng Wui; Hale, Peter John; Krishna M., Bala Murali; Reynolds, John N. J.; Wickens, Jeff; Dani, Keshav M.

    2014-06-01

    Existing nanoscale chemical delivery systems target diseased cells over long, sustained periods of time, typically through one-time, destructive triggering. Future directions lie in the development of fast and robust techniques capable of reproducing the pulsatile chemical activity of living organisms, thereby allowing us to mimic biofunctionality. Here, we demonstrate that by applying programmed femtosecond laser pulses to robust, nanoscale liposome structures containing dopamine, we achieve sub-second, controlled release of dopamine - a key neurotransmitter of the central nervous system - thereby replicating its release profile in the brain. The fast delivery system provides a powerful new interface with neural circuits, and to the larger range of biological functions that operate on this short timescale.

  13. Orquestic regulation of neurotransmitters on reward-seeking behavior.

    PubMed

    Arias-Carrión, Oscar; Caraza-Santiago, Xanic; Salgado-Licona, Sergio; Salama, Mohamed; Machado, Sergio; Nardi, Antonio Egidio; Menéndez-González, Manuel; Murillo-Rodríguez, Eric

    2014-01-01

    The ventral tegmental area is strongly associated with the reward system. Dopamine is released in areas such as the nucleus accumbens and prefrontal cortex as a result of rewarding experiences such as food, sex, and neutral stimuli that become associated with them. Electrical stimulation of the ventral tegmental area or its output pathways can itself serve as a potent reward. Different drugs that increase dopamine levels are intrinsically rewarding. Although the dopaminergic system represent the cornerstone of the reward system, other neurotransmitters such as endogenous opioids, glutamate, γ-Aminobutyric acid, acetylcholine, serotonin, adenosine, endocannabinoids, orexins, galanin and histamine all affect this mesolimbic dopaminergic system. Consequently, genetic variations of neurotransmission are thought influence reward processing that in turn may affect distinctive social behavior and susceptibility to addiction. Here, we discuss current evidence on the orquestic regulation of different neurotranmitters on reward-seeking behavior and its potential effect on drug addiction.

  14. Orquestic regulation of neurotransmitters on reward-seeking behavior

    PubMed Central

    2014-01-01

    The ventral tegmental area is strongly associated with the reward system. Dopamine is released in areas such as the nucleus accumbens and prefrontal cortex as a result of rewarding experiences such as food, sex, and neutral stimuli that become associated with them. Electrical stimulation of the ventral tegmental area or its output pathways can itself serve as a potent reward. Different drugs that increase dopamine levels are intrinsically rewarding. Although the dopaminergic system represent the cornerstone of the reward system, other neurotransmitters such as endogenous opioids, glutamate, γ-Aminobutyric acid, acetylcholine, serotonin, adenosine, endocannabinoids, orexins, galanin and histamine all affect this mesolimbic dopaminergic system. Consequently, genetic variations of neurotransmission are thought influence reward processing that in turn may affect distinctive social behavior and susceptibility to addiction. Here, we discuss current evidence on the orquestic regulation of different neurotranmitters on reward-seeking behavior and its potential effect on drug addiction. PMID:25061480

  15. Clinical neuroanatomy and neurotransmitter-mediated regulation of penile erection.

    PubMed

    Jung, Junyang; Jo, Hyun Woo; Kwon, Hyunseob; Jeong, Na Young

    2014-06-01

    Erectile dysfunction (ED) has an adverse impact on men's quality of life. Penile erection, which is regulated by nerves that are innervated into the erectile tissue, can be affected by functional or anatomical trauma of the perineal region, including specific structures of the penis, causing ED. Penile erection is neurologically controlled by the autonomic nervous system. Therefore, it is of utmost importance to understand the neurogenic structure of the erectile tissue and the types of neurotransmitters involved in the penile erection process. Here, we highlight the basic clinical anatomy and erectile function of the penis. Understanding the clinical connotation of the relationship between penile erectile structure and function may provide fresh insights for identifying the main mechanisms involved in ED and help develop surgical techniques for the treatment of ED.

  16. Clinical Neuroanatomy and Neurotransmitter-Mediated Regulation of Penile Erection

    PubMed Central

    Jo, Hyun Woo; Kwon, Hyunseob

    2014-01-01

    Erectile dysfunction (ED) has an adverse impact on men's quality of life. Penile erection, which is regulated by nerves that are innervated into the erectile tissue, can be affected by functional or anatomical trauma of the perineal region, including specific structures of the penis, causing ED. Penile erection is neurologically controlled by the autonomic nervous system. Therefore, it is of utmost importance to understand the neurogenic structure of the erectile tissue and the types of neurotransmitters involved in the penile erection process. Here, we highlight the basic clinical anatomy and erectile function of the penis. Understanding the clinical connotation of the relationship between penile erectile structure and function may provide fresh insights for identifying the main mechanisms involved in ED and help develop surgical techniques for the treatment of ED. PMID:24987557

  17. Wireless Power Transfer for Autonomous Wearable Neurotransmitter Sensors

    PubMed Central

    Nguyen, Cuong M.; Kota, Pavan Kumar; Nguyen, Minh Q.; Dubey, Souvik; Rao, Smitha; Mays, Jeffrey; Chiao, J.-C.

    2015-01-01

    In this paper, we report a power management system for autonomous and real-time monitoring of the neurotransmitter L-glutamate (L-Glu). A low-power, low-noise, and high-gain recording module was designed to acquire signal from an implantable flexible L-Glu sensor fabricated by micro-electro-mechanical system (MEMS)-based processes. The wearable recording module was wirelessly powered through inductive coupling transmitter antennas. Lateral and angular misalignments of the receiver antennas were resolved by using a multi-transmitter antenna configuration. The effective coverage, over which the recording module functioned properly, was improved with the use of in-phase transmitter antennas. Experimental results showed that the recording system was capable of operating continuously at distances of 4 cm, 7 cm and 10 cm. The wireless power management system reduced the weight of the recording module, eliminated human intervention and enabled animal experimentation for extended durations. PMID:26404311

  18. Teaching medical students basic neurotransmitter pharmacology using primary research resources.

    PubMed

    Halliday, Amy C; Devonshire, Ian M; Greenfield, Susan A; Dommett, Eleanor J

    2010-12-01

    Teaching pharmacology to medical students has long been seen as a challenge, and one to which a number of innovative approaches have been taken. In this article, we describe and evaluate the use of primary research articles in teaching second-year medical students both in terms of the information learned and the use of the papers themselves. We designed a seminar where small groups of students worked on different neurotransmitters before contributing information to a plenary session. Student feedback suggested that when the information was largely novel, students learned considerably more. Crucially, this improvement in knowledge was seen even when they had not directly studied a particular transmitter in their work groups, suggesting a shared learning experience. Moreover, the majority of students reported that using primary research papers was easy and useful, with over half stating that they would use them in future study.

  19. Terahertz identification and quantification of neurotransmitter and neurotrophy mixture

    PubMed Central

    Peng, Yan; Yuan, Xiaorong; Zou, Xiang; Chen, Wanqing; Huang, Hui; Zhao, Hongwei; Song, Bo; Chen, Liang; Zhu, Yiming

    2016-01-01

    Terahertz spectroscopy has been widely used for investigating the fingerprint spectrum of different substances. For cancerous tissues, the greatest difficulty is the absorption peaks of various substances contained in tissues overlap with each other, which are hard to identify and quantitative analyze. As a result, it is very hard to measure the presence of cancer cell and then to diagnose accurately. In this paper, we select three typical neurotransmitters (γ-aminobutyric acid, L-glutamic acid, dopamine hydrochloride) and two typical metabolites (inositol and creatine) in neurons to measure their terahertz spectra with different mixture ratios. By choosing characteristic absorption peaks, removing baseline and using the least square method, we can identify the components and proportions of each mixture, where the goodness of fit to practical situation is up to 94%. These results provide important evidences for identifying nerve substances and obtaining exact quantitative analysis. PMID:27895988

  20. Wireless multichannel integrated potentiostat for distributed neurotransmitter sensing.

    PubMed

    Murari, Kartikeya; Sauer, Christian; Stanacevic, Milutin; Cauwenberghs, Gert; Thakor, Nitish

    2005-01-01

    Sensing neurotransmitters is critical in studying neural pathways and neurological disorders. An integrated device is presented which incorporates a potentiostat and a power harvesting and telemetry module. The potentiostat features 16 channels with multiple scales from microamperes to picoamperes. The wireless module is able to harvest power through inductively coupled coils and uses the same link to transmit data to and from the potentiostat. An integrated prototype is fabricated in CMOS technology, and experimentally characterized. Test results show RF powering introduces noise levels of 0.42% and 0.18% on potentiostat current scales of 500pA and 4nA respectively. Real-time multi-channel acquisition of dopamine concentration in vitro is performed with carbon fiber sensors.

  1. Attenuation of forgetting by pharmacological stimulation of aminergic neurotransmitter systems.

    PubMed

    Quartermain, D; Judge, M E; Leo, P

    1988-05-01

    Mice were trained in one-way active avoidance to a criterion of 3/4 avoidances and tested under extinction conditions one week later when substantial forgetting had occurred. Thirty min prior to testing animals were injected with either saline or different doses of drugs which activate the noradrenergic (phenylephrine, salbutamol, clonidine) dopaminergic (L-dopa(Sinemet) transdihydrolisuride, apomorphine) and serotonergic (fluoxetine, 5-methoxy DMT) neurotransmitter systems. Results showed that all agents alleviated forgetting in a dose dependent fashion. Untrained mice treated with the most effective dose of representative drugs from each class did not exhibit avoidance behavior at testing indicating that the improved performance of trained animals was probably not the result of increased activity or other non-memorial effects of the drugs. It was concluded that pharmacological agents which stimulate monoamine systems may improve memory retrieval by activating a non-specific neural system which controls arousal, attention and motor readiness.

  2. Wireless Power Transfer for Autonomous Wearable Neurotransmitter Sensors.

    PubMed

    Nguyen, Cuong M; Kota, Pavan Kumar; Nguyen, Minh Q; Dubey, Souvik; Rao, Smitha; Mays, Jeffrey; Chiao, J-C

    2015-09-23

    In this paper, we report a power management system for autonomous and real-time monitoring of the neurotransmitter L-glutamate (L-Glu). A low-power, low-noise, and high-gain recording module was designed to acquire signal from an implantable flexible L-Glu sensor fabricated by micro-electro-mechanical system (MEMS)-based processes. The wearable recording module was wirelessly powered through inductive coupling transmitter antennas. Lateral and angular misalignments of the receiver antennas were resolved by using a multi-transmitter antenna configuration. The effective coverage, over which the recording module functioned properly, was improved with the use of in-phase transmitter antennas. Experimental results showed that the recording system was capable of operating continuously at distances of 4 cm, 7 cm and 10 cm. The wireless power management system reduced the weight of the recording module, eliminated human intervention and enabled animal experimentation for extended durations.

  3. Neurotransmitter GABA activates muscle but not α7 nicotinic receptors.

    PubMed

    Dionisio, Leonardo; Bergé, Ignacio; Bravo, Matías; Esandi, María Del Carmen; Bouzat, Cecilia

    2015-01-01

    Cys-loop receptors are neurotransmitter-activated ion channels involved in synaptic and extrasynaptic transmission in the brain and are also present in non-neuronal cells. As GABAA and nicotinic receptors (nAChR) belong to this family, we explored by macroscopic and single-channel recordings whether the inhibitory neurotransmitter GABA has the ability to activate excitatory nAChRs. GABA differentially activates nAChR subtypes. It activates muscle nAChRs, with maximal peak currents of about 10% of those elicited by acetylcholine (ACh) and 15-fold higher EC50 with respect to ACh. At the single-channel level, the weak agonism is revealed by the requirement of 20-fold higher concentration of GABA for detectable channel openings, a major population of brief openings, and absence of clusters of openings when compared with ACh. Mutations at key residues of the principal binding-site face of muscle nAChRs (αY190 and αG153) affect GABA activation similarly as ACh activation, whereas a mutation at the complementary face (εG57) shows a selective effect for GABA. Studies with subunit-lacking receptors show that GABA can activate muscle nAChRs through the α/δ interface. Interestingly, single-channel activity elicited by GABA is similar to that elicited by ACh in gain-of-function nAChR mutants associated to congenital myasthenic syndromes, which could be important in the progression of the disorders due to steady exposure to serum GABA. In contrast, GABA cannot elicit single-channel or macroscopic currents of α7 or the chimeric α7-serotonin-type 3 receptor, a feature important for preserving an adequate excitatory/inhibitory balance in the brain as well as for avoiding activation of non-neuronal receptors by serum GABA. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  4. Mutations in human monoamine-related neurotransmitter pathway genes.

    PubMed

    Haavik, Jan; Blau, Nenad; Thöny, Beat

    2008-07-01

    Biosynthesis and metabolism of serotonin and catecholamines involve at least eight individual enzymes that are mainly expressed in tissues derived from the neuroectoderm, e.g., the central nervous system (CNS), pineal gland, adrenal medulla, enterochromaffin tissue, sympathetic nerves, and ganglia. Some of the enzymes appear to have additional biological functions and are also expressed in the heart and various other internal organs. The biosynthetic enzymes are tyrosine hydroxylase (TH), tryptophan hydroxylases type 1 and 2 (TPH1, TPH2), aromatic amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DbetaH), and phenylethanolamine N-methyltransferase (PNMT), and the specific catabolic enzymes are monoamine oxidase A (MAO-A) and catechol O-methyltransferase (COMT). For the TH, DDC, DBH, and MAOA genes, many single nucleotide polymorphisms (SNPs) with unknown function, and small but increasing numbers of cases with autosomal recessive mutations have been recognized. For the remaining genes (TPH1, TPH2, PNMT, and COMT) several different genetic markers have been suggested to be associated with regulation of mood, pain perception, and aggression, as well as psychiatric disturbances such as schizophrenia, depression, suicidality, and attention deficit/hyperactivity disorder. The genetic markers may either have a functional role of their own, or be closely linked to other unknown functional variants. In the future, molecular testing may become important for the diagnosis of such conditions. Here we present an overview on mutations and polymorphisms in the group of genes encoding monoamine neurotransmitter metabolizing enzymes. At the same time we propose a unified nomenclature for the nucleic acid aberrations in these genes. New variations or details on mutations will be updated in the Pediatric Neurotransmitter Disorder Data Base (PNDDB) database (www.bioPKU.org).

  5. Macrocyclic Gd(3+) complexes with pendant crown ethers designed for binding zwitterionic neurotransmitters.

    PubMed

    Oukhatar, Fatima; Meudal, Hervé; Landon, Céline; Logothetis, Nikos K; Platas-Iglesias, Carlos; Angelovski, Goran; Tóth, Éva

    2015-07-27

    A series of Gd(3+) complexes exhibiting a relaxometric response to zwitterionic amino acid neurotransmitters was synthesized. The design concept involves ditopic interactions 1) between a positively charged and coordinatively unsaturated Gd(3+) chelate and the carboxylate group of the neurotransmitters and 2) between an azacrown ether appended to the chelate and the amino group of the neurotransmitters. The chelates differ in the nature and length of the linker connecting the cyclen-type macrocycle that binds the Ln(3+) ion and the crown ether. The complexes are monohydrated, but they exhibit high proton relaxivities (up to 7.7 mM(-1)  s(-1) at 60 MHz, 310 K) due to slow molecular tumbling. The formation of ternary complexes with neurotransmitters was monitored by (1) H relaxometric titrations of the Gd(3+) complexes and by luminescence measurements on the Eu(3+) and Tb(3+) analogues at pH 7.4. The remarkable relaxivity decrease (≈80 %) observed on neurotransmitter binding is related to the decrease in the hydration number, as evidenced by luminescence lifetime measurements on the Eu(3+) complexes. These complexes show affinity for amino acid neurotransmitters in the millimolar range, which can be suited to imaging concentrations of synaptically released neurotransmitters. They display good selectivity over non-amino acid neurotransmitters (acetylcholine, serotonin, and noradrenaline) and hydrogenphosphate, but selectivity over hydrogencarbonate was not achieved.

  6. Mechanism of the association between Na+ binding and conformations at the intracellular gate in neurotransmitter:sodium symporters

    DOE PAGES

    Stolzenberg, Sebastian; Quick, Matthias; Zhao, Chunfeng; ...

    2015-04-13

    Neurotransmitter:sodium symporters (NSSs) terminate neurotransmission by Na+-dependent reuptake of released neurotransmitters. Previous studies suggested that Na+-binding reconfigures dynamically coupled structural elements in an allosteric interaction network (AIN) responsible for function-related conformational changes, but the intramolecular pathway of this mechanism has remained uncharted. Here we describe a new approach for the modeling and analysis of intramolecular dynamics in the bacterial NSS homolog LeuT. From microsecond-scale molecular dynamics simulations and cognate experimental verifications in both LeuT and human dopamine transporter (hDAT), we apply the novel method to identify the composition and the dynamic properties of their conserved AIN. In LeuT, two differentmore » perturbations disrupting Na+ binding and transport (i.e. replacing Na+ with Li+ or the Y268A mutation at the intracellular gate) affect the AIN in strikingly similar ways. In contrast, other mutations that affect the intracellular gate (i.e. R5A and D369A) do not significantly impair Na+ cooperativity and transport. Our analysis shows these perturbations to have much lesser effects on the AIN, underscoring the sensitivity of this novel method to the mechanistic nature of the perturbation. Notably, this set of observations holds as well for hDAT, where the aligned Y335A, R60A, and D436A mutations also produce different impacts on Na+ dependence. Furthermore, the detailed AIN generated from our method is shown to connect Na+ binding with global conformational changes that are critical for the transport mechanism. Lastly, that the AIN between the Na+ binding sites and the intracellular gate in bacterial LeuT resembles that in eukaryotic hDAT highlights the conservation of allosteric pathways underlying NSS function.« less

  7. Mechanism of the Association between Na+ Binding and Conformations at the Intracellular Gate in Neurotransmitter:Sodium Symporters.

    PubMed

    Stolzenberg, Sebastian; Quick, Matthias; Zhao, Chunfeng; Gotfryd, Kamil; Khelashvili, George; Gether, Ulrik; Loland, Claus J; Javitch, Jonathan A; Noskov, Sergei; Weinstein, Harel; Shi, Lei

    2015-05-29

    Neurotransmitter:sodium symporters (NSSs) terminate neurotransmission by Na(+)-dependent reuptake of released neurotransmitters. Previous studies suggested that Na(+)-binding reconfigures dynamically coupled structural elements in an allosteric interaction network (AIN) responsible for function-related conformational changes, but the intramolecular pathway of this mechanism has remained uncharted. We describe a new approach for the modeling and analysis of intramolecular dynamics in the bacterial NSS homolog LeuT. From microsecond-scale molecular dynamics simulations and cognate experimental verifications in both LeuT and human dopamine transporter (hDAT), we apply the novel method to identify the composition and the dynamic properties of their conserved AIN. In LeuT, two different perturbations disrupting Na(+) binding and transport (i.e. replacing Na(+) with Li(+) or the Y268A mutation at the intracellular gate) affect the AIN in strikingly similar ways. In contrast, other mutations that affect the intracellular gate (i.e. R5A and D369A) do not significantly impair Na(+) cooperativity and transport. Our analysis shows these perturbations to have much lesser effects on the AIN, underscoring the sensitivity of this novel method to the mechanistic nature of the perturbation. Notably, this set of observations holds as well for hDAT, where the aligned Y335A, R60A, and D436A mutations also produce different impacts on Na(+) dependence. Thus, the detailed AIN generated from our method is shown to connect Na(+) binding with global conformational changes that are critical for the transport mechanism. That the AIN between the Na(+) binding sites and the intracellular gate in bacterial LeuT resembles that in eukaryotic hDAT highlights the conservation of allosteric pathways underlying NSS function.

  8. RECENT DEVELOPMENTS IN ELECTROCHEMICAL SENSORS FOR THE DETECTION OF NEUROTRANSMITTERS FOR APPLICATIONS IN BIOMEDICINE

    PubMed Central

    Özel, Rıfat Emrah; Hayat, Akhtar; Andreescu, Silvana

    2015-01-01

    Neurotransmitters are important biological molecules that are essential to many neurophysiological processes including memory, cognition, and behavioral states. The development of analytical methodologies to accurately detect neurotransmitters is of great importance in neurological and biological research. Specifically designed microelectrodes or microbiosensors have demonstrated potential for rapid, real-time measurements with high spatial resolution. Such devices can facilitate study of the role and mechanism of action of neurotransmitters and can find potential uses in biomedicine. This paper reviews the current status and recent advances in the development and application of electrochemical sensors for the detection of small-molecule neurotransmitters. Measurement challenges and opportunities of electroanalytical methods to advance study and understanding of neurotransmitters in various biological models and disease conditions are discussed. PMID:26973348

  9. RECENT DEVELOPMENTS IN ELECTROCHEMICAL SENSORS FOR THE DETECTION OF NEUROTRANSMITTERS FOR APPLICATIONS IN BIOMEDICINE.

    PubMed

    Özel, Rıfat Emrah; Hayat, Akhtar; Andreescu, Silvana

    2015-05-03

    Neurotransmitters are important biological molecules that are essential to many neurophysiological processes including memory, cognition, and behavioral states. The development of analytical methodologies to accurately detect neurotransmitters is of great importance in neurological and biological research. Specifically designed microelectrodes or microbiosensors have demonstrated potential for rapid, real-time measurements with high spatial resolution. Such devices can facilitate study of the role and mechanism of action of neurotransmitters and can find potential uses in biomedicine. This paper reviews the current status and recent advances in the development and application of electrochemical sensors for the detection of small-molecule neurotransmitters. Measurement challenges and opportunities of electroanalytical methods to advance study and understanding of neurotransmitters in various biological models and disease conditions are discussed.

  10. [Preliminary research on multi-neurotransmitters' change regulation in 120 depression patients' brains].

    PubMed

    Chi, Ming; Qing, Xue-Mei; Pan, Yan-Shu; Xu, Feng-Quan; Liu, Chao; Zhang, Cheng; Xu, Zhen-Hua

    2014-04-01

    In view of the effective traditional Chinese medicine (TCM) in the treatment of clinical depression, the mechanism is not clear, this study attempts to research the cause of depression in a complex situation to lay the foundation for the next step of TCM curative effect evaluation. Based on the brain wave of 120 depression patients and 40 ordinary person, the change regulation of acetylcholine, dopamine, norepinephrine, depression neurotransmitters and excited neurotransmitters in the whole and various encephalic regions' multi-neurotransmitters of depression patients-serotonin are analysed by search of encephalo-telex (SET) system, which lays the foundation for the diagnosis of depression. The result showed that: contrased with the normal person group, the mean value of the six neurotransmitters in depression patients group are: (1) in the whole encephalic region of depression patients group the dopamine fall (P < 0.05), and in the double centralregions, right temporal region and right parietal region distinct fall (P < 0.01); (2) in the right temporal region of depression patients group the serotonin rise (P < 0.05); (3) in the right central region, left parietal region of depression patients group the acetylcholine fall (P < 0.05), left rear temporal region fall obviously (P < 0.01). The correlation research between antagonizing pairs of neurotransmitters and neurotransmitters: (1) the three antagonizing pairs of neurotransmitters-serotonin and dopamine, acetylcholine and norepinephrine, depression neurotransmitters and excited neurotransmitters, in ordinary person group and depression patients group are characterizeed by middle or strong negative correlation. Serotonin and dopamine, which are characterized by weak negative correlation in the right rear temporal region of ordinary person group, are characterized by strong negative correlation in the other encephalic regions and the whole encephalic (ordinary person group except the right rear temporal region

  11. Inhibitory and excitatory amino acid neurotransmitters are utilized by the projection from the dorsal deep mesencephalic nucleus to the sublaterodorsal nucleus REM sleep induction zone

    PubMed Central

    Liang, Chang-Lin; Nguyen, Tin Quang; Marks, Gerald A.

    2014-01-01

    The sublaterodorsal nucleus (SLD) in the pons of the rat is a locus supporting short-latency induction of a REM sleep-like state following local application of a GABAA receptor antagonist or kainate, glutamate receptor agonist. One putatively relevant source of these neurotransmitters is from the region of the deep mesencephalic nucleus (DpMe) just ventrolateral to the periaquiductal gray, termed the dorsal DpMe (dDpMe). Here, the amino acid neurotransmitter innervation of SLD from dDpMe was studied utilizing anterograde tract-tracing with biotinylated dextranamine (BDA) and fluorescence immunohistochemistry visualized with laser scanning confocal microscopy. Both markers for inhibitory and excitatory amino acid neurotransmitters were found in varicose axon fibers in SLD originating from dDpMe. Vesicular glutamate transporter2 (VGLUT2) represented the largest number of anterogradely labeled varicosities followed by vesicular GABA transporter (VGAT). Numerous VGAT and VGLUT2 labeled varicosities were observed apposed to dDpMe-labeled axon fibers indicating both excitatory and inhibitory presynaptic, local modulation within the SLD. Some double-labeled BDA/VGAT varicosities were seen apposed to small somata labeled for glutamate consistent with being presynaptic to the phenotype of REM sleep-active SLD neurons. Results found support the current theoretical framework of the interaction of dDpMe and SLD in control of REM sleep, while also indicating operation of mechanisms with a greater level of complexity. PMID:24751569

  12. Single molecule imaging of conformational dynamics in sodium-coupled transporters

    NASA Astrophysics Data System (ADS)

    Terry, Daniel S.

    Neurotransmitter:sodium symporter (NSS) proteins remove neurotransmitters released into the synapse through a transport process driven by the physiological sodium ion (Na+) gradient. NSSs for dopamine, noradrenaline, and serotonin are targeted by the psychostimulants cocaine and amphetamines, as well as by antidepressants. The crystal structure of LeuT, a prokaryotic NSS homologue, revealed the NSS molecular architecture and has been the basis for extensive structural, biochemical, and computational investigations of the mechanism of transporter proteins with a LeuT-like fold. In this dissertation, the conformational states sampled by LeuT are explored using single-molecule fluorescence resonance energy transfer imaging methods, with special focus on the motions of transmembrane helix 1a that lead to inward release of substrate. We also explored how dynamics are modulated by substrate, Na+, and protons to produce efficient transport. These advances represent a first of a kind study of the dynamics of an integral membrane protein at a truly single-molecule scale. Advances in instrumentation, analysis tools, and organic fluorophores were all required to achieve these goals, and such advances are also described. While these experiments were performed with detergent-solubilized protein, preliminary work suggests that imaging of LeuT in proteoliposomes is feasible and a fluorescence sensor assay could be used to simultaneously detect conformational dynamics and transport function.

  13. Single Molecule Imaging of Conformational Dynamics in Sodium-Coupled Transporters

    ERIC Educational Resources Information Center

    Terry, Daniel S.

    2013-01-01

    Neurotransmitter:sodium symporter (NSS) proteins remove neurotransmitters released into the synapse through a transport process driven by the physiological sodium ion (Na[superscript +]) gradient. NSSs for dopamine, noradrenaline, and serotonin are targeted by the psychostimulants cocaine and amphetamines, as well as by antidepressants. The…

  14. Single Molecule Imaging of Conformational Dynamics in Sodium-Coupled Transporters

    ERIC Educational Resources Information Center

    Terry, Daniel S.

    2013-01-01

    Neurotransmitter:sodium symporter (NSS) proteins remove neurotransmitters released into the synapse through a transport process driven by the physiological sodium ion (Na[superscript +]) gradient. NSSs for dopamine, noradrenaline, and serotonin are targeted by the psychostimulants cocaine and amphetamines, as well as by antidepressants. The…

  15. What is an antidepressant binding site doing in a bacterial transporter?

    PubMed

    Rudnick, Gary

    2007-09-21

    LeuT is a bacterial amino acid transporter belonging to a large family of membrane proteins, including the neurotransmitter transporters that are targets for antidepressant drugs. The high-resolution structure of LeuT has provided an important model for understanding structure and function in this family. Two recent papers found that LeuT can bind tricyclic antidepressants, raising the possibility that it may also serve as a model for the pharmacological properties of neurotransmitter transporters.

  16. REM Sleep at its Core – Circuits, Neurotransmitters, and Pathophysiology

    PubMed Central

    Fraigne, Jimmy J.; Torontali, Zoltan A.; Snow, Matthew B.; Peever, John H.

    2015-01-01

    Rapid eye movement (REM) sleep is generated and maintained by the interaction of a variety of neurotransmitter systems in the brainstem, forebrain, and hypothalamus. Within these circuits lies a core region that is active during REM sleep, known as the subcoeruleus nucleus (SubC) or sublaterodorsal nucleus. It is hypothesized that glutamatergic SubC neurons regulate REM sleep and its defining features such as muscle paralysis and cortical activation. REM sleep paralysis is initiated when glutamatergic SubC cells activate neurons in the ventral medial medulla, which causes release of GABA and glycine onto skeletal motoneurons. REM sleep timing is controlled by activity of GABAergic neurons in the ventrolateral periaqueductal gray and dorsal paragigantocellular reticular nucleus as well as melanin-concentrating hormone neurons in the hypothalamus and cholinergic cells in the laterodorsal and pedunculo-pontine tegmentum in the brainstem. Determining how these circuits interact with the SubC is important because breakdown in their communication is hypothesized to underlie narcolepsy/cataplexy and REM sleep behavior disorder (RBD). This review synthesizes our current understanding of mechanisms generating healthy REM sleep and how dysfunction of these circuits contributes to common REM sleep disorders such as cataplexy/narcolepsy and RBD. PMID:26074874

  17. Fast neurotransmitter release regulated by the endocytic scaffold intersectin

    PubMed Central

    Sakaba, Takeshi; Kononenko, Natalia L.; Bacetic, Jelena; Pechstein, Arndt; Schmoranzer, Jan; Yao, Lijun; Barth, Holger; Shupliakov, Oleg; Kobler, Oliver; Aktories, Klaus; Haucke, Volker

    2013-01-01

    Sustained fast neurotransmission requires the rapid replenishment of release-ready synaptic vesicles (SVs) at presynaptic active zones. Although the machineries for exocytic fusion and for subsequent endocytic membrane retrieval have been well characterized, little is known about the mechanisms underlying the rapid recruitment of SVs to release sites. Here we show that the Down syndrome-associated endocytic scaffold protein intersectin 1 is a crucial factor for the recruitment of release-ready SVs. Genetic deletion of intersectin 1 expression or acute interference with intersectin function inhibited the replenishment of release-ready vesicles, resulting in short-term depression, without significantly affecting the rate of endocytic membrane retrieval. Acute perturbation experiments suggest that intersectin-mediated vesicle replenishment involves the association of intersectin with the fissioning enzyme dynamin and with the actin regulatory GTPase CDC42. Our data indicate a role for the endocytic scaffold intersectin in fast neurotransmitter release, which may be of prime importance for information processing in the brain. PMID:23633571

  18. Delayed release of neurotransmitter from cerebellar granule cells.

    PubMed

    Atluri, P P; Regehr, W G

    1998-10-15

    At fast chemical synapses the rapid release of neurotransmitter that occurs within a few milliseconds of an action potential is followed by a more sustained elevation of release probability, known as delayed release. Here we characterize the role of calcium in delayed release and test the hypothesis that facilitation and delayed release share a common mechanism. Synapses between cerebellar granule cells and their postsynaptic targets, stellate cells and Purkinje cells, were studied in rat brain slices. Presynaptic calcium transients were measured with calcium-sensitive fluorophores, and delayed release was detected with whole-cell recordings. Calcium influx, presynaptic calcium dynamics, and the number of stimulus pulses were altered to assess their effect on delayed release and facilitation. Following single stimuli, delayed release can be separated into two components: one lasting for tens of milliseconds that is steeply calcium-dependent, the other lasting for hundreds of milliseconds that is driven by low levels of calcium with a nearly linear calcium dependence. The amplitude, calcium dependence, and magnitude of delayed release do not correspond to those of facilitation, indicating that these processes are not simple reflections of a shared mechanism. The steep calcium dependence of delayed release, combined with the large calcium transients observed in these presynaptic terminals, suggests that for physiological conditions delayed release provides a way for cells to influence their postsynaptic targets long after their own action potential activity has subsided.

  19. Neurotransmitter-precursor-supplement intervention for detoxified heroin addicts.

    PubMed

    Chen, Dingyan; Liu, Yan; He, Wulong; Wang, Hongxing; Wang, Zengzhen

    2012-06-01

    This study examined the effects of combined administration of tyrosine, lecithin, L-glutamine and L-5-hydroxytryptophan (5-HTP) on heroin withdrawal syndromes and mental symptoms in detoxified heroin addicts. In the cluster-randomized placebo-controlled trial, 83 detoxified heroin addicts were recruited from a detoxification treatment center in Wuhan, China. Patients in the intervention group (n=41) were given the combined treatment with tyrosine, lecithin, L-glutamine and 5-HTP and those in the control group (n=42) were administered the placebo. The sleep status and the withdrawal symptoms were observed daily throughout the study, and the mood states were monitored pre- and post-intervention. The results showed that the insomnia and withdrawal scores were significantly improved over time in participants in the intervention group as compared with those in the control group. A greater reduction in tension-anxiety, depression-dejection, anger-hostility, fatigue-inertia and total mood disturbance, and a greater increase in their vigor-activity symptoms were found at day 6 in the intervention group than in the control group (all P<0.05). It was concluded that the neurotransmitter-precursor-supplement intervention is effective in alleviating the withdrawal and mood symptoms and it may become a supplementary method for patients' recovery from heroin addiction.

  20. REM Sleep at its Core - Circuits, Neurotransmitters, and Pathophysiology.

    PubMed

    Fraigne, Jimmy J; Torontali, Zoltan A; Snow, Matthew B; Peever, John H

    2015-01-01

    Rapid eye movement (REM) sleep is generated and maintained by the interaction of a variety of neurotransmitter systems in the brainstem, forebrain, and hypothalamus. Within these circuits lies a core region that is active during REM sleep, known as the subcoeruleus nucleus (SubC) or sublaterodorsal nucleus. It is hypothesized that glutamatergic SubC neurons regulate REM sleep and its defining features such as muscle paralysis and cortical activation. REM sleep paralysis is initiated when glutamatergic SubC cells activate neurons in the ventral medial medulla, which causes release of GABA and glycine onto skeletal motoneurons. REM sleep timing is controlled by activity of GABAergic neurons in the ventrolateral periaqueductal gray and dorsal paragigantocellular reticular nucleus as well as melanin-concentrating hormone neurons in the hypothalamus and cholinergic cells in the laterodorsal and pedunculo-pontine tegmentum in the brainstem. Determining how these circuits interact with the SubC is important because breakdown in their communication is hypothesized to underlie narcolepsy/cataplexy and REM sleep behavior disorder (RBD). This review synthesizes our current understanding of mechanisms generating healthy REM sleep and how dysfunction of these circuits contributes to common REM sleep disorders such as cataplexy/narcolepsy and RBD.

  1. The neurotransmitter dopamine modulates vascular permeability in the endothelium

    PubMed Central

    Bhattacharya, Resham; Sinha, Sutapa; Yang, Su-Ping; Patra, Chittaranjan; Dutta, Shamit; Wang, Enfeng; Mukhopadhyay, Debabrata

    2008-01-01

    Background Vascular permeability factor/Vascular endothelial growth factor (VPF/VEGF), a multifunctional cytokine, is a potent inducer of vascular permeability, an important early step in angiogenesis. It is known that the neurotransmitter dopamine can inhibit VPF/VEGF mediated angiogenesis, in particular microvascular permeability, but the effectors of this action remain unclear. Results Here, we define the signaling pathway modulated by dopamine that inhibits VPF/VEGF induced vascular permeability in endothelial cells. Signals from VPF/VEGF lead to changes in the phosphorylation of tight junction protein zonula occludens (ZO-1) and adherens junction proteins like VE-cadherin and associated catenins, thus weakening endothelial cell-cell adhesion and increasing vascular permeability. We found VEGF receptor-2 (VEGFR-2) to be part of a multi-protein complex involving ZO-1, VE-cadherin and β-catenin. VPF/VEGF induced phosphorylations of VE-cadherin, β-catenin and ZO-1 were inhibited by dopamine treatment. Association of occludin with ZO-1 and ZO-1 with VE-cadherin were significantly inhibited by dopamine in VEGF treated cells. Furthermore, we identified Src as an important target for dopamine-mediated inhibition of VPF/VEGF induced permeability. Conclusion Taken together, our results provide molecular insights of dopamine function in the vascular endothelium and suggest a central role of Src in regulating key molecules that control vascular permeability. PMID:18662404

  2. Endogenous opioid peptides as neurotransmitters in the rat hippocampus

    SciTech Connect

    Neumaier, J.F.

    1989-01-01

    The role of endogenous opioid peptides as neurotransmitters in the rat hippocampus was investigated by using extracellular recording and radioligand binding techniques in the hippocampal slice preparation. Synaptic conductances from endogenously released opioid peptides have been difficult to detect. This problem was approach by designing a novel assay of opioid peptide release, in which release was detected by measuring binding competition between endogenous opioids and added radioligand. Membrane depolarization displaced ({sup 3}H)-diprenorphine binding in a transient, calcium-dependent, and peptidase-sensitive manner. Autoradiographic localization of the sites of ({sup 3}H)-diprenorphine binding displacement showed that significant opioid peptide release and receptor occupancy occurred in each major subregion of the hippocampal slices. This assay method can not be used to define optimal electrical stimulation conditions for releasing endogenous opioids. The binding displacement method was extended to the study of the sigma receptor. Depolarization of hippocampal slices was found to reduce the binding of the sigma-selective radioligand ({sup 3}H)-ditolylguanidine in a transient and calcium-dependent manner with no apparent direct effects on sigma receptor affinity.

  3. Neurotransmitter-mediated collective rhythms in grouped Drosophila circadian clocks.

    PubMed

    Junwei Wang; Jiajun Zhang; Zhanjiang Yuan; Aimin Chen; Tianshou Zhou

    2008-12-01

    Over the past decades, fly Drosophila melanogaster has being used as a premier model organism to study molecular and genetic bases of circadian rhythms. Here the authors propose a multicellular heterogeneous model for which the network of Drosophila circadian oscillators consists of two groups, the self-sustained lateral neurons (LNs) communicating to each other and the damped dorsal neurons (DNs) receiving neurotransmitters only from the LNs without interaction within this group. By simulating different experimental conditions, the authors find that the proposed model, except for being capable of reproducing some known experimental results well, also can predict some interesting phenomena: 1) The DNs need neuronal projections from the LNs to be rhythmic and to synchronize; 2) the effect of communication on mean amplitude and mean period of two oscillatory groups is different; 3) communication delay can facilitate the network synchronization of the LNs; and 4) only the LNs lose rhythmicity under constant light conditions. These results reveal the mechanism of an integrated pacemaker that would govern behavioral and physiological rhythmicity of the model organism.

  4. Polyethylenimine Carbon Nanotube Fiber Electrodes for Enhanced Detection of Neurotransmitters

    PubMed Central

    2015-01-01

    Carbon nanotube (CNT)-based microelectrodes have been investigated as alternatives to carbon-fiber microelectrodes for the detection of neurotransmitters because they are sensitive, exhibit fast electron transfer kinetics, and are more resistant to surface fouling. Wet spinning CNTs into fibers using a coagulating polymer produces a thin, uniform fiber that can be fabricated into an electrode. CNT fibers formed in poly(vinyl alcohol) (PVA) have been used as microelectrodes to detect dopamine, serotonin, and hydrogen peroxide. In this study, we characterize microelectrodes with CNT fibers made in polyethylenimine (PEI), which have much higher conductivity than PVA-CNT fibers. PEI-CNT fibers have lower overpotentials and higher sensitivities than PVA-CNT fiber microelectrodes, with a limit of detection of 5 nM for dopamine. The currents for dopamine were adsorption controlled at PEI-CNT fiber microelectrodes, independent of scan repetition frequency, and stable for over 10 h. PEI-CNT fiber microelectrodes were resistant to surface fouling by serotonin and the metabolite interferant 5-hydroxyindoleacetic acid (5-HIAA). No change in sensitivity was observed for detection of serotonin after 30 flow injection experiments or after 2 h in 5-HIAA for PEI-CNT electrodes. The antifouling properties were maintained in brain slices when serotonin was exogenously applied multiple times or after bathing the slice in 5-HIAA. Thus, PEI-CNT fiber electrodes could be useful for the in vivo monitoring of neurochemicals. PMID:25117550

  5. Benefits of Neuronal Preferential Systemic Gene Therapy for Neurotransmitter Deficiency

    PubMed Central

    Lee, Ni-Chung; Muramatsu, Shin-Ichi; Chien, Yin-Hsiu; Liu, Wen-Shin; Wang, Wei-Hua; Cheng, Chia-Hao; Hu, Meng-Kai; Chen, Pin-Wen; Tzen, Kai-Yuan; Byrne, Barry J; Hwu, Wuh-Liang

    2015-01-01

    Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disease that impairs synthesis of dopamine and serotonin. Children with AADC deficiency exhibit severe motor, behavioral, and autonomic dysfunctions. We previously generated an IVS6+4A>T knock-in mouse model of AADC deficiency (DdcKI mice) and showed that gene therapy at the neonatal stage can rescue this phenotype. In the present study, we extended this treatment to systemic therapy on young mice. After intraperitoneal injection of AADC viral vectors into 7-day-old DdcKI mice, the treated mice exhibited improvements in weight gain, survival, motor function, autonomic function, and behavior. The yfAAV9/3-Syn-I-mAADC-treated mice showed greater neuronal transduction and higher brain dopamine levels than AAV9-CMV-hAADC-treated mice, whereas AAV9-CMV-hAADC-treated mice exhibited hyperactivity. Therefore, neurotransmitter-deficient animals can be rescued at a young age using systemic gene therapy, although a vector for preferential neuronal expression may be necessary to avoid hyperactivity caused by this treatment. PMID:26137853

  6. Calcitonin gene related peptide as inhibitory neurotransmitter in the ureter.

    PubMed

    Maggi, C A; Giuliani, S; Meini, S; Santicioli, P

    1995-07-01

    A dense plexus of calcitonin gene related peptide (CGRP) containing nerve fibres is present in the mammalian ureter, from which CGRP is released by depolarizing stimuli, including chemical normally present in the urine. CGRP exerts a profound, receptor-mediated, inhibitory effect on the evoked motility of the ureter by suppressing latent pacemakers in the smooth muscle. This effect is largely glibenclamide sensitive, indicating the activation of potassium (K) channels in its genesis. Electrical stimulation of intramural nerves in the guinea-pig ureter produces a transient membrane hyperpolarization, which is blocked by glibenclamide or by capsaicin pretreatment, enhanced in a low-K medium, and inhibited by a CGRP receptor antagonist. Thus endogenous CGRP acts as a neurotransmitter K channel opener in the ureter. The refractory period of the guinea-pig ureter is markedly and similarly reduced by capsaicin pretreatment or administration of a CGRP receptor antagonist, indicating that endogenous CGRP can modulate the maximal frequency of ureteral peristalsis. Using a three-chamber organ bath that enabled the separate perfusion of the renal, middle, and bladder regions of the organ, evidence was obtained that CGRP blocks propagation of impulses along the ureter through a glibenclamide-sensitive mechanism. These findings indicate a role of CGRP in the local regulation of ureteral motility and peristalsis.

  7. Potential Antidepressant Role of Neurotransmitter CART: Implications for Mental Disorders

    PubMed Central

    Mao, Peizhong

    2011-01-01

    Depression is one of the most prevalent and debilitating public health concerns. Although no single cause of depression has been identified, it appears that interaction among genetic, epigenetic, biochemical, environmental, and psychosocial factors may explain its etiology. Further, only a fraction of depressed patients show full remission while using current antidepressants. Therefore, identifying common pathways of the disorder and using that knowledge to develop more effective pharmacological treatments are two primary targets of research in this field. Brain-enriched neurotransmitter CART (cocaine- and amphetamine-regulated transcript) has multiple functions related to emotions. It is a potential neurotrophic factor and is involved in the regulation of hypothalamic-pituitary-adrenal axis and stress response as well as in energy homeostasis. CART is also highly expressed in limbic system, which is considered to have an important role in regulating mood. Notably, adolescents carrying a missense mutation in the CART gene exhibit increased depression and anxiety. Hence, CART peptide may be a novel promising antidepressant agent. In this paper, we summarize recent progress in depression and CART. In particular, we emphasize a new antidepressant function for CART. PMID:21785720

  8. Flavonoid nutraceuticals and ionotropic receptors for the inhibitory neurotransmitter GABA.

    PubMed

    Johnston, Graham A R

    2015-10-01

    Flavonoids that are found in nutraceuticals have many and varied effects on the activation of ionotropic receptors for GABA, the major inhibitory neurotransmitter in our brains. They can act as positive or negative modulators enhancing or reducing the effect of GABA. They can act as allosteric agonists. They can act to modulate the action of other modulators. There is considerable evidence that these flavonoids are able to enter the brain to influence brain function. They may have a range of effects including relief of anxiety, improvement in cognition, acting as neuroprotectants and as sedatives. All of these effects are sought after in nutraceuticals. A number of studies have likened flavonoids to the widely prescribed benzodiazepines as 'a new family of benzodiazepine receptor ligands'. They are much more than that with many flavonoid actions on ionotropic GABA receptors being insensitive to the classic benzodiazepine antagonist flumazenil and thus independent of the classic benzodiazepine actions. It is time to consider flavonoids in their own right as important modulators of these vital receptors in brain function. Flavonoids are rarely consumed as a single flavonoid except as dietary supplements. The effects of mixtures of flavonoids and other modulators on GABAA receptors need to be more thoroughly investigated.

  9. Pyrethroid insecticides evoke neurotransmitter release from rabbit striatal slices

    SciTech Connect

    Eells, J.T.; Dubocovich, M.L.

    1988-08-01

    The effects of the synthetic pyrethroid insecticide fenvalerate ((R,S)-alpha-cyano-3-phenoxybenzyl(R,S)-2-(4-chlorophenyl)-3- methylbutyrate) on neurotransmitter release in rabbit brain slices were investigated. Fenvalerate evoked a calcium-dependent release of (/sup 3/H)dopamine and (/sup 3/H)acetylcholine from rabbit striatal slices that was concentration-dependent and specific for the toxic stereoisomer of the insecticide. The release of (/sup 3/H)dopamine and (/sup 3/H)acetylcholine by fenvalerate was modulated by D2 dopamine receptor activation and antagonized completely by the sodium channel blocker, tetrodotoxin. These findings are consistent with an action of fenvalerate on the voltage-dependent sodium channels of the presynaptic membrane resulting in membrane depolarization, and the release of dopamine and acetylcholine by a calcium-dependent exocytotic process. In contrast to results obtained in striatal slices, fenvalerate did not elicit the release of (/sup 3/H)norepinephrine or (/sup 3/H)acetylcholine from rabbit hippocampal slices indicative of regional differences in sensitivity to type II pyrethroid actions.

  10. Does chronic nicotine alter neurotransmitter receptors involved in Parkinson's disease

    SciTech Connect

    Reilly, M.A.; Lapin, E.P.; Lajtha, A.; Maker, H.S.

    1986-03-05

    Cigarette smokers are fewer in number among Parkinson's Disease (PD) patients than among groups of persons who do not have PD. Several hypotheses have been proposed to explain this observation. One which must be tested is the possibility that some pharmacologic agent present in cigarette smoke may interact with some central nervous system component involved in PD. To this end, they have investigated the effect of chronic nicotine administration on receptors for some of the neurotransmitters that are affected in PD. Rats were injected for six weeks with saline or nicotine 0.8 mg/kg S.C., then killed and brains removed and dissected. The binding of (/sup 3/H)-ketanserin to serotonin receptors in frontal cortex and of (/sup 3/H)-domperidone to dopamine receptors in caudate was not affected. However, the binding of (/sup 3/H)-domperidone in nucleus accumbens was altered: the K/sub d/ increased from 0.16 +/- 0.02 nM to 0.61 +/- 0.07 nM, and the B/sub max/ increased from 507 +/- 47 fmol/mg protein to 910 +/- 43 fmol/mg (p < 0.001 for both comparisons). These values are based on three ligand concentrations. Additional studies are in progress to substantiate the data. It is concluded that chronic nicotine administration may alter dopamine receptors in nucleus accumbens.

  11. Early Antipsychotic Treatment in Juvenile Rats Elicits Long-Term Alterations to the Dopamine Neurotransmitter System.

    PubMed

    De Santis, Michael; Lian, Jiamei; Huang, Xu-Feng; Deng, Chao

    2016-11-22

    Prescription of antipsychotic drugs (APDs) to children has substantially increased in recent years. Whilst current investigations into potential long-term effects have uncovered some alterations to adult behaviours, further investigations into potential changes to neurotransmitter systems are required. The current study investigated potential long-term changes to the adult dopamine (DA) system following aripiprazole, olanzapine and risperidone treatment in female and male juvenile rats. Levels of tyrosine hydroxylase (TH), phosphorylated-TH (p-TH), dopamine active transporter (DAT), and D₁ and D₂ receptors were measured via Western blot and/or receptor autoradiography. Aripiprazole decreased TH and D₁ receptor levels in the ventral tegmental area (VTA) and p-TH levels in the prefrontal cortex (PFC) of females, whilst TH levels decreased in the PFC of males. Olanzapine decreased PFC p-TH levels and increased D₂ receptor expression in the PFC and nucleus accumbens (NAc) in females only. Additionally, risperidone treatment increased D₁ receptor levels in the hippocampus of females, whilst, in males, p-TH levels increased in the PFC and hippocampus, D₁ receptor expression decreased in the NAc, and DAT levels decreased in the caudate putamen (CPu), and elevated in the VTA. These results suggest that early treatment with various APDs can cause different long-term alterations in the adult brain, across both treatment groups and genders.

  12. Fluorescent false neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum

    PubMed Central

    Pereira, Daniela B.; Schmitz, Yvonne; Mészáros, József; Merchant, Paolomi; Hu, Gang; Li, Shu; Henke, Adam; Lizardi-Ortiz, José E.; Karpowicz, Richard J.; Morgenstern, Travis J.; Sonders, Mark S.; Kanter, Ellen; Rodriguez, Pamela C.; Mosharov, Eugene V.; Sames, Dalibor; Sulzer, David

    2016-01-01

    Neurotransmission at dopaminergic synapses has been studied with techniques that provide high temporal resolution but cannot resolve individual synapses. To elucidate the spatial dynamics and heterogeneity of individual dopamine boutons, we developed fluorescent false neurotransmitter 200 (FFN200), a vesicular monoamine transporter 2 (VMAT2) substrate that is the first probe to selectively trace monoamine exocytosis in both neuronal cell culture and brain tissue. By monitoring electrically-evoked Ca2+ transients with GCaMP3 and FFN200 release simultaneously, we find that only a small fraction of dopamine boutons that exhibit Ca2+ influx engage in exocytosis, a result confirmed with activity-dependent loading of the endocytic probe FM 1-43. Thus, only a low fraction of striatal dopamine axonal sites with uptake-competent VMAT2 vesicles are capable of transmitter release. This is consistent with the presence of functionally “silent” dopamine vesicle clusters and represents a first report suggestive of presynaptically silent neuromodulatory synapses. PMID:26900925

  13. Early Antipsychotic Treatment in Juvenile Rats Elicits Long-Term Alterations to the Dopamine Neurotransmitter System

    PubMed Central

    De Santis, Michael; Lian, Jiamei; Huang, Xu-Feng; Deng, Chao

    2016-01-01

    Prescription of antipsychotic drugs (APDs) to children has substantially increased in recent years. Whilst current investigations into potential long-term effects have uncovered some alterations to adult behaviours, further investigations into potential changes to neurotransmitter systems are required. The current study investigated potential long-term changes to the adult dopamine (DA) system following aripiprazole, olanzapine and risperidone treatment in female and male juvenile rats. Levels of tyrosine hydroxylase (TH), phosphorylated-TH (p-TH), dopamine active transporter (DAT), and D1 and D2 receptors were measured via Western blot and/or receptor autoradiography. Aripiprazole decreased TH and D1 receptor levels in the ventral tegmental area (VTA) and p-TH levels in the prefrontal cortex (PFC) of females, whilst TH levels decreased in the PFC of males. Olanzapine decreased PFC p-TH levels and increased D2 receptor expression in the PFC and nucleus accumbens (NAc) in females only. Additionally, risperidone treatment increased D1 receptor levels in the hippocampus of females, whilst, in males, p-TH levels increased in the PFC and hippocampus, D1 receptor expression decreased in the NAc, and DAT levels decreased in the caudate putamen (CPu), and elevated in the VTA. These results suggest that early treatment with various APDs can cause different long-term alterations in the adult brain, across both treatment groups and genders. PMID:27879654

  14. Novel repeat polymorphisms of the dopaminergic neurotransmitter genes among dogs and wolves.

    PubMed

    Hejjas, Krisztina; Vas, Judit; Kubinyi, Eniko; Sasvari-Szekely, Maria; Miklosi, Adam; Ronai, Zsolt

    2007-12-01

    Genetic polymorphisms of the neurotransmission systems are intensively studied in the human because of a possible influence on personality traits and the risk of psychiatric disorders. The investigation of genetic variations of the dog genome has recently been a promising approach, as a considerable similarity can be observed between dogs and humans, in both genetic and social aspects, suggesting that the dog could become an appropriate animal model of human behavioral genetic studies. The aim of our study was the identification and analysis of variable number of tandem repeats polymorphisms (VNTRs) in the genes of the dopaminergic neurotransmitter system of dogs. The in silico search was followed by the development of PCR-based techniques for the analysis of the putative VNTRs. Highly variable repetitive sequence regions were found in the tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine beta-hydroxylase (DBH) genes. Allele frequency and genotype distribution of these novel polymorphisms together with the exon 3 and exon 1 VNTR of the dopamine D4 receptor gene were determined in a large sample involving four dog breeds (German Shepherd, Belgian Tervueren, Groenandael, and Malinois) and European Grey Wolves. A significant difference of allele and genotype frequencies was demonstrated among the analyzed breeds; therefore, an association analysis was also carried out between the activity-impulsivity phenotype and the described VNTRs. Preliminary findings are presented that polymorphisms of the DRD4, DBH, and DAT genes can be associated with attention deficit among Belgian Tervuerens.

  15. Effects of low dose endosulfan exposure on brain neurotransmitter levels in the African clawed frog Xenopus laevis.

    PubMed

    Preud'homme, Valérie; Milla, Sylvain; Gillardin, Virginie; De Pauw, Edwin; Denoël, Mathieu; Kestemont, Patrick

    2015-02-01

    Understanding the impact of pesticides in amphibians is of growing concern to assess the causes of their decline. Among pesticides, endosulfan belongs to one of the potential sources of danger because of its wide use and known effects, particularly neurotoxic, on a variety of organisms. However, the effect of endosulfan was not yet evaluated on amphibians at levels encompassing simultaneously brain neurotransmitters and behavioural endpoints. In this context, tadpoles of the African clawed frog Xenopus laevis were submitted to four treatments during 27 d: one control, one ethanol control, and two low environmental concentrations of endosulfan (0.1 and 1 μg L(-1)). Endosulfan induced a significant increase of brain serotonin level at both concentrations and a significant increase of brain dopamine and GABA levels at the lower exposure but acetylcholinesterase activity was not modified by the treatment. The gene coding for the GABA transporter 1 was up-regulated in endosulfan contaminated tadpoles while the expression of other genes coding for the neurotransmitter receptors or for the enzymes involved in their metabolic pathways was not significantly modified by endosulfan exposure. Endosulfan also affected foraging, and locomotion in links with the results of the physiological assays, but no effects were seen on growth. These results show that low environmental concentrations of endosulfan can induce adverse responses in X. laevis tadpoles. At a broader perspective, this suggests that more research using and linking multiple markers should be used to understand the complex mode of action of pollutants.

  16. Direct assessment of substrate binding to the Neurotransmitter:Sodium Symporter LeuT by solid state NMR

    PubMed Central

    Erlendsson, Simon; Gotfryd, Kamil; Larsen, Flemming Hofmann; Mortensen, Jonas Sigurd; Geiger, Michel-Andreas; van Rossum, Barth-Jan; Oschkinat, Hartmut; Gether, Ulrik; Teilum, Kaare; Loland, Claus J

    2017-01-01

    The Neurotransmitter:Sodium Symporters (NSSs) represent an important class of proteins mediating sodium-dependent uptake of neurotransmitters from the extracellular space. The substrate binding stoichiometry of the bacterial NSS protein, LeuT, and thus the principal transport mechanism, has been heavily debated. Here we used solid state NMR to specifically characterize the bound leucine ligand and probe the number of binding sites in LeuT. We were able to produce high-quality NMR spectra of substrate bound to microcrystalline LeuT samples and identify one set of sodium-dependent substrate-specific chemical shifts. Furthermore, our data show that the binding site mutants F253A and L400S, which probe the major S1 binding site and the proposed S2 binding site, respectively, retain sodium-dependent substrate binding in the S1 site similar to the wild-type protein. We conclude that under our experimental conditions there is only one detectable leucine molecule bound to LeuT. DOI: http://dx.doi.org/10.7554/eLife.19314.001 PMID:28117663

  17. Direct assessment of substrate binding to the Neurotransmitter:Sodium Symporter LeuT by solid state NMR.

    PubMed

    Erlendsson, Simon; Gotfryd, Kamil; Larsen, Flemming Hofmann; Mortensen, Jonas Sigurd; Geiger, Michel-Andreas; van Rossum, Barth-Jan; Oschkinat, Hartmut; Gether, Ulrik; Teilum, Kaare; Loland, Claus J

    2017-01-24

    The Neurotransmitter:Sodium Symporters (NSSs) represent an important class of proteins mediating sodium-dependent uptake of neurotransmitters from the extracellular space. The substrate binding stoichiometry of the bacterial NSS protein, LeuT, and thus the principal transport mechanism, has been heavily debated. Here we used solid state NMR to specifically characterize the bound leucine ligand and probe the number of binding sites in LeuT. We were able to produce high-quality NMR spectra of substrate bound to microcrystalline LeuT samples and identify one set of sodium-dependent substrate-specific chemical shifts. Furthermore, our data show that the binding site mutants F253A and L400S, which probe the major S1 binding site and the proposed S2 binding site, respectively, retain sodium-dependent substrate binding in the S1 site similar to the wild-type protein. We conclude that under our experimental conditions there is only one detectable leucine molecule bound to LeuT.

  18. Coupled global and local changes direct substrate translocation by neurotransmitter-sodium symporter ortholog LeuT.

    PubMed

    Cheng, Mary Hongying; Bahar, Ivet

    2013-08-06

    Significant advances have been made in recent years in characterizing neurotransmitter:sodium symporter (NSS) family structure and function. Yet, many time-resolved events and intermediates that control the various stages of transport cycle remain to be elucidated. Whether NSSs harbor one or two sites for binding their substrates (neurotransmitters or amino acids), and what the role of the secondary site S2 is, if any, are still unresolved. Using molecular modeling and simulations for LeuT, a bacterial NSS, we present a comprehensive account of substrate-binding and -stabilization events, and subsequently triggered interactions leading to substrate (alanine) release. LeuT instantaneous conformation as it reconfigures from substrate-receiving (outward-facing) to -releasing (inward-facing) state appears to be a determinant of its affinity to bind substrate at site S2. In the outward-facing state, S1 robustly binds alanine and regulates subsequent redistribution of interactions to trigger extracellular gate closure; whereas S2 is only a transient binding site. The substrate-binding affinity at S2 increases in an intermediate close to inward-facing state. LeuT harbors the two substrate-binding sites, and small displacements of second substrate near S2 are observed to induce concerted small translocations in the substrate bound to primary site S1, although complete release requires collective structural rearrangements that fully expose the intracellular vestibule to the cytoplasm.

  19. Contributions to the field of neurotransmitters by Japanese scientists, and reflections on my own research

    PubMed Central

    Otsuka, Masanori

    2007-01-01

    Part I describes important contributions made by some Japanese pioneers in the field of neurotransmitters: (their achievements in parentheses) J. Takamine (isolation and crystallization of adrenaline); K. Shimidzu (early hint for acetylcholine as a neurotransmitter); F. Kanematsu (donation of the Kanematsu Memorial Institute in Sydney); T. Hayashi (discovery of the excitatory action of glutamate and the inhibitory action of GABA); and I. Sano (discovery of a high concentration of dopamine in striatum, its reduction in a patient with Parkinson’s disease and the treatment with DOPA). In Part II, I present some of my reflections on my research on neurotransmitters. The work of my colleagues and myself has made some significant contributions to the establishment of neurotransmitter roles played by GABA and substance P, the first amino acid and the first peptide neurotransmitters, respectively. By the early 1960s, 3 substances, i.e., acetylcholine, noradrenaline, and adrenaline, had been established as neurotransmitters. Now the number of neurotransmitters is believed to be as many as 50 or even more mainly due to the inclusion of several amino acids and a large number of peptide transmitters. PMID:24019584

  20. Contributions to the field of neurotransmitters by Japanese scientists, and reflections on my own research.

    PubMed

    Otsuka, Masanori

    2007-03-01

    PART I DESCRIBES IMPORTANT CONTRIBUTIONS MADE BY SOME JAPANESE PIONEERS IN THE FIELD OF NEUROTRANSMITTERS: (their achievements in parentheses) J. Takamine (isolation and crystallization of adrenaline); K. Shimidzu (early hint for acetylcholine as a neurotransmitter); F. Kanematsu (donation of the Kanematsu Memorial Institute in Sydney); T. Hayashi (discovery of the excitatory action of glutamate and the inhibitory action of GABA); and I. Sano (discovery of a high concentration of dopamine in striatum, its reduction in a patient with Parkinson's disease and the treatment with DOPA). In Part II, I present some of my reflections on my research on neurotransmitters. The work of my colleagues and myself has made some significant contributions to the establishment of neurotransmitter roles played by GABA and substance P, the first amino acid and the first peptide neurotransmitters, respectively. By the early 1960s, 3 substances, i.e., acetylcholine, noradrenaline, and adrenaline, had been established as neurotransmitters. Now the number of neurotransmitters is believed to be as many as 50 or even more mainly due to the inclusion of several amino acids and a large number of peptide transmitters.

  1. On a gas electron multiplier based synthetic diagnostic for soft x-ray tomography on WEST with focus on impurity transport studies

    NASA Astrophysics Data System (ADS)

    Jardin, A.; Mazon, D.; Malard, P.; O'Mullane, M.; Chernyshova, M.; Czarski, T.; Malinowski, K.; Kasprowicz, G.; Wojenski, A.; Pozniak, K.

    2017-08-01

    The tokamak WEST aims at testing ITER divertor high heat flux component technology in long pulse operation. Unfortunately, heavy impurities like tungsten (W) sputtered from the plasma facing components can pollute the plasma core by radiation cooling in the soft x-ray (SXR) range, which is detrimental for the energy confinement and plasma stability. SXR diagnostics give valuable information to monitor impurities and study their transport. The WEST SXR diagnostic is composed of two new cameras based on the Gas Electron Multiplier (GEM) technology. The WEST GEM cameras will be used for impurity transport studies by performing 2D tomographic reconstructions with spectral resolution in tunable energy bands. In this paper, we characterize the GEM spectral response and investigate W density reconstruction thanks to a synthetic diagnostic recently developed and coupled with a tomography algorithm based on the minimum Fisher information (MFI) inversion method. The synthetic diagnostic includes the SXR source from a given plasma scenario, the photoionization, electron cloud transport and avalanche in the detection volume using Magboltz, and tomographic reconstruction of the radiation from the GEM signal. Preliminary studies of the effect of transport on the W ionization equilibrium and on the reconstruction capabilities are also presented.

  2. Water-transporting proteins.

    PubMed

    Zeuthen, Thomas

    2010-04-01

    Transport through lipids and aquaporins is osmotic and entirely driven by the difference in osmotic pressure. Water transport in cotransporters and uniporters is different: Water can be cotransported, energized by coupling to the substrate flux by a mechanism closely associated with protein. In the K(+)/Cl(-) and the Na(+)/K(+)/2Cl(-) cotransporters, water is entirely cotransported, while water transport in glucose uniporters and Na(+)-coupled transporters of nutrients and neurotransmitters takes place by both osmosis and cotransport. The molecular mechanism behind cotransport of water is not clear. It is associated with the substrate movements in aqueous pathways within the protein; a conventional unstirred layer mechanism can be ruled out, due to high rates of diffusion in the cytoplasm. The physiological roles of the various modes of water transport are reviewed in relation to epithelial transport. Epithelial water transport is energized by the movements of ions, but how the coupling takes place is uncertain. All epithelia can transport water uphill against an osmotic gradient, which is hard to explain by simple osmosis. Furthermore, genetic removal of aquaporins has not given support to osmosis as the exclusive mode of transport. Water cotransport can explain the coupling between ion and water transport, a major fraction of transepithelial water transport and uphill water transport. Aquaporins enhance water transport by utilizing osmotic gradients and cause the osmolarity of the transportate to approach isotonicity.

  3. Synaptic Assembly of the Brain in the Absence of Neurotransmitter Secretion

    NASA Astrophysics Data System (ADS)

    Verhage, Matthijs; Maia, Ascanio S.; Plomp, Jaap J.; Brussaard, Arjen B.; Heeroma, Joost H.; Vermeer, Hendrika; Toonen, Ruud F.; Hammer, Robert E.; van den Berg, Timo K.; Missler, Markus; Geuze, Hans J.; Südhof, Thomas C.

    2000-02-01

    Brain function requires precisely orchestrated connectivity between neurons. Establishment of these connections is believed to require signals secreted from outgrowing axons, followed by synapse formation between selected neurons. Deletion of a single protein, Munc18-1, in mice leads to a complete loss of neurotransmitter secretion from synaptic vesicles throughout development. However, this does not prevent normal brain assembly, including formation of layered structures, fiber pathways, and morphologically defined synapses. After assembly is completed, neurons undergo apoptosis, leading to widespread neurodegeneration. Thus, synaptic connectivity does not depend on neurotransmitter secretion, but its maintenance does. Neurotransmitter secretion probably functions to validate already established synaptic connections.

  4. Neurotransmitters and neuromodulators controlling the anterior byssus retractor muscle of Mytilus edulis.

    PubMed

    Muneoka, Y; Fujisawa, Y; Matsuura, M; Ikeda, T

    1991-01-01

    1. The anterior byssus retractor muscle (ABRM) of Mytilus edulis is innervated by at least two kinds of nerves, excitatory and relaxing nerves. The principal neurotransmitters released from these nerves have been shown to be acetylcholine and serotonin, respectively. 2. Some other monoamines, such as dopamine and octopamine, and various peptides, such as FMRFamide-related peptides, Mytilus inhibitory peptides, SCP-related peptides and a catch-relaxing peptide, may also be involved in the regulation of the muscle as neurotransmitters or neuromodulators. 3. The ABRM seems to be typical of invertebrate muscles controlled by multiple neurotransmitters and neuromodulators.

  5. Phorbol Ester Effects on Neurotransmission: Interaction with Neurotransmitters and Calcium in Smooth Muscle

    NASA Astrophysics Data System (ADS)

    Baraban, Jay M.; Gould, Robert J.; Peroutka, Stephen J.; Snyder, Solomon H.

    1985-01-01

    Stimulation of the phosphatidylinositol cycle by neurotransmitters generates diacylglycerol, an activator of protein kinase C, which may regulate some forms of neurotransmission. Phorbol esters, potent inflammatory and tumorpromoting compounds, also activate protein kinase C. We demonstrate potent and selective effects of phorbol esters on smooth muscle, indicating a role for protein kinase C in neurotransmission. In rat vas deferens and dog basilar artery, phorbol esters synergize with calcium to mimic the contractile effects of neurotransmitters that act through the phosphatidylinositol cycle. In guinea pig ileum and rat uterus, phorbol esters block contractions produced by these neurotransmitters.

  6. Phorbol ester effects on neurotransmission: interaction with neurotransmitters and calcium in smooth muscle.

    PubMed Central

    Baraban, J M; Gould, R J; Peroutka, S J; Snyder, S H

    1985-01-01

    Stimulation of the phosphatidylinositol cycle by neurotransmitters generates diacylglycerol, an activator of protein kinase C, which may regulate some forms of neurotransmission. Phorbol esters, potent inflammatory and tumor-promoting compounds, also activate protein kinase C. We demonstrate potent and selective effects of phorbol esters on smooth muscle, indicating a role for protein kinase C in neurotransmission. In rat vas deferens and dog basilar artery, phorbol esters synergize with calcium to mimic the contractile effects of neurotransmitters that act through the phosphatidylinositol cycle. In guinea pig ileum and rat uterus, phorbol esters block contractions produced by these neurotransmitters. PMID:2857490

  7. Citation bias and selective focus on positive findings in the literature on the serotonin transporter gene (5-HTTLPR), life stress and depression.

    PubMed

    de Vries, Y A; Roest, A M; Franzen, M; Munafò, M R; Bastiaansen, J A

    2016-10-01

    Caspi et al.'s 2003 report that 5-HTTLPR genotype moderates the influence of life stress on depression has been highly influential but remains contentious. We examined whether the evidence base for the 5-HTTLPR-stress interaction has been distorted by citation bias and a selective focus on positive findings. A total of 73 primary studies were coded for study outcomes and focus on positive findings in the abstract. Citation rates were compared between studies with positive and negative results, both within this network of primary studies and in Web of Science. In addition, the impact of focus on citation rates was examined. In all, 24 (33%) studies were coded as positive, but these received 48% of within-network and 68% of Web of Science citations. The 38 (52%) negative studies received 42 and 23% of citations, respectively, while the 11 (15%) unclear studies received 10 and 9%. Of the negative studies, the 16 studies without a positive focus (42%) received 47% of within-network citations and 32% of Web of Science citations, while the 13 (34%) studies with a positive focus received 39 and 51%, respectively, and the nine (24%) studies with a partially positive focus received 14 and 17%. Negative studies received fewer citations than positive studies. Furthermore, over half of the negative studies had a (partially) positive focus, and Web of Science citation rates were higher for these studies. Thus, discussion of the 5-HTTLPR-stress interaction is more positive than warranted. This study exemplifies how evidence-base-distorting mechanisms undermine the authenticity of research findings.

  8. The role of serotonin and neurotransmitters during craniofacial development.

    PubMed

    Moiseiwitsch, J R

    2000-01-01

    Several neurotransmitters, in particular serotonin (5-HT), have demonstrated multiple functions during early development and mid-gestational craniofacial morphogenesis. Early studies indicated that 5-HT is present in the oocyte, where it appears to function as a regulator of cell cleavage. Later, it has a significant role during gastrulation, during which there are significant areas of 5-HT uptake in the primitive streak. Subsequently, in association with neurulation, 5-HT uptake is seen in the floor plate of the developing neural tube. During neural crest formation and branchial arch formation, 5-HT has been demonstrated to facilitate cell migration and stimulate cell differentiation. During morphogenesis of the craniofacial structures, 5-HT stimulates dental development and may aid in cusp formation. All of the most commonly prescribed antidepressant drugs inhibit serotonin uptake, yet they do not appear to cause major craniofacial malformations in vivo. Given the wide spectrum of effects that 5-HT has during development, it is difficult to understand why these anti-depressants are not major teratogens. Redundancy within the system may allow receptor and uptake pathways to function normally even with lower than normal levels of circulating serotonin. Serotonin-binding proteins, that are expressed in most craniofacial regions at critical times during craniofacial development, may have a buffering capacity that maintains adequate 5-HT tissue concentrations over a wide range of 5-HT serum concentrations. Dental development appears to be particularly sensitive to even small fluctuations in concentrations of 5-HT. Therefore, it may be that children of patients who have received selective serotonergic re-uptake inhibitors (such as Prozac and Zoloft) or the less selective tricyclic anti-depressant drugs (such as Elavil) would be at a higher risk for developmental dental defects such as anodontia and hypodontia. In this review, the evidence supporting a role for 5-HT

  9. Effects of methylmercury on neurotransmitter release from rat brain synaptosomes.

    PubMed

    Minnema, D J; Cooper, G P; Greenland, R D

    1989-07-01

    Although the effects of methylmercury (MeHg) at the neuromuscular junction have been well characterized, similar studies employing CNS preparations and transmitters have been limited. We found that MeHg (0.5-5.0 microM) produced a concentration-dependent increase in the spontaneous release of [3H]dopamine. gamma-[3H]aminobutyric acid, and [3H]acetylcholine from synaptosomes isolated from rat brain striatum, cortex, and hippocampus, respectively. At these same concentrations MeHg did not attenuate calcium-dependent depolarization-evoked 3H-transmitter release. MeHg did not appear to induce calcium influx into the nerve terminal since the increase in release persists in the absence of extrasynaptosomal calcium. The increase in spontaneous transmitter release induced by MeHg persisted in the presence of low extrasynaptosomal sodium, suggesting that MeHg's effects on release are not mediated by either Na+, K+-ATPase inhibition or selective increases in membrane sodium permeability. MeHg produced only a very small increase in 45Ca efflux from synaptosomes preloaded with 45Ca, whereas these same MeHg concentrations produced large increases in 45Ca efflux from preloaded isolated mitochondria. MeHg did increase the efflux of [3H]deoxyglucose phosphate from synaptosomes. An increase in the efflux of [3H]deoxyglucose phosphate is believed to reflect an increase in neuronal membrane permeability. The quantitative and temporal aspects of the MeHg-induced [3H]-deoxyglucose phosphate efflux were similar to those observed for MeHg-induced neurotransmitter release. These data suggest that the increase in spontaneous transmitter release induced by MeHg is mainly the result of transmitter leakage that occurs subsequent to MeHg-induced increases in synaptosomal membrane permeability. However, these results cannot exclude possible effects of MeHg on intrasynaptosomal calcium homeostasis.

  10. Acute effects of tianeptine on circulating neurotransmitters and cardiovascular parameters.

    PubMed

    Lechin, Fuad; van der Dijs, Bertha; Hernández, Gerardo; Orozco, Beatriz; Rodríguez, Simon; Baez, Scarlet

    2006-03-01

    Tianeptine is a serotonin-uptake enhancer drug whose antidepressant effectiveness is based on its ability to reduce rather than increase serotonin availability at the synaptic cleft. This paradoxical neuropharmacological mechanism has raised doubt among neuropharmacologists and psychiatrists as to the role of tianeptine as a trusty-reliable antidepressant drug. This controversial issue led us to investigate the acute effects of a single, oral dose (12.5 mg) of this drug on circulating neurotransmitters and cardiovascular parameters in 50 healthy subjects. The drug provoked a striking and significant reduction of plasma noradrenaline (NA) and plasma serotonin (f-5-HT) while it increased plasma dopamine (DA) and platelet serotonin (p-5-HT) concentrations within the 4-h study period. No adrenaline (Ad) changes were registered. The NA/Ad ratio and the f-5-HT/p-5-HT ratio showed significant reduction throughout the test. Finally, although diastolic blood pressure (DBP) showed significant decrease, neither systolic blood pressure (SBP) nor heart rate (HR) showed significant change. These findings are consistent with the postulation that tianeptine reduces both neural sympathetic activity and parasympathetic activity without affecting adrenal sympathetic activity, enabling us to discuss the possible mechanisms involved in the antidepressant effects of tianeptine. The well-known fact that major depressed patients always show raised NA plus lower than normal p-5-HT levels, both disorders which are normalized by tianeptine, gives neurochemical support to the clinical improvement triggered by the drug in these patients. Summarizing, the results presented in this study demonstrate that tianeptine triggers significant reduction of circulating noradrenaline and plasma serotonin while increasing circulating dopamine and platelet serotonin. Other possible neuropharmacological effects are also discussed.

  11. Hurdles with using in vitro models to predict human blood-brain barrier drug permeability: a special focus on transporters and metabolizing enzymes.

    PubMed

    Shawahna, Ramzi; Decleves, Xavier; Scherrmann, Jean-Michel

    2013-01-01

    The penetration of drugs into the human brain through the blood-brain barrier (BBB) is a major obstacle limiting the development of successful neuropharmaceuticals. This restricted permeability is due to the delicate intercellular junctions, efflux transporters and metabolizing enzymes present at the BBB. The pharmaceutical industry and academic research relies heavily on permeability studies conducted in animals and in vitro models of the BBB. This text reviews the available animal and in vitro BBB models with special emphasis on the situation in freshly isolated human brain microvessels and the unique tightness between brain endothelial cells, drug transport pathways and metabolic capacity. We first outline the delicate structure of the intercellular junctions and the particular interaction between the brain endothelial cells and other components of the neurovascular unit. We then examine the differences in transporters and metabolizing enzymes between species and in vitro systems and those found in isolated brain microvessels. Finally, we review the possibilities of benchmarking in vitro models of the BBB in terms of gene and protein expression.

  12. Neurotransmitter-based strategies for the treatment of cognitive dysfunction in Down syndrome.

    PubMed

    Das, Devsmita; Phillips, Cristy; Hsieh, Wayne; Sumanth, Krithika; Dang, Van; Salehi, Ahmad

    2014-10-03

    Down syndrome (DS) is a multisystem disorder affecting the cardiovascular, respiratory, gastrointestinal, neurological, hematopoietic, and musculoskeletal systems and is characterized by significant cognitive disability and a possible common pathogenic mechanism with Alzheimer's disease. During the last decade, numerous studies have supported the notion that the triplication of specific genes on human chromosome 21 plays a significant role in cognitive dysfunction in DS. Here we reviewed studies in trisomic mouse models and humans, including children and adults with DS. In order to identify groups of genes that contribute to cognitive disability in DS, multiple mouse models of DS with segmental trisomy have been generated. Over-expression of these particular genes in DS can lead to dysfunction of several neurotransmitter systems. Therapeutic strategies for DS have either focused on normalizing the expression of triplicated genes with important roles in DS or restoring the function of these systems. Indeed, our extensive review of studies on the pathogenesis of DS suggests that one plausible strategy for the treatment of cognitive dysfunction is to target the cholinergic, serotonergic, GABA-ergic, glutamatergic, and norepinephrinergic system. However, a fundamental strategy for treatment of cognitive dysfunction in DS would include reducing to normal levels the expression of specific triplicated genes in affected systems before the onset of neurodegeneration.

  13. Availability of neurotransmitter glutamate is diminished when beta-hydroxybutyrate replaces glucose in cultured neurons.

    PubMed

    Lund, Trine M; Risa, Oystein; Sonnewald, Ursula; Schousboe, Arne; Waagepetersen, Helle S

    2009-07-01

    Ketone bodies serve as alternative energy substrates for the brain in cases of low glucose availability such as during starvation or in patients treated with a ketogenic diet. The ketone bodies are metabolized via a distinct pathway confined to the mitochondria. We have compared metabolism of [2,4-(13)C]beta-hydroxybutyrate to that of [1,6-(13)C]glucose in cultured glutamatergic neurons and investigated the effect of neuronal activity focusing on the aspartate-glutamate homeostasis, an essential component of the excitatory activity in the brain. The amount of (13)C incorporation and cellular content was lower for glutamate and higher for aspartate in the presence of [2,4-(13)C]beta-hydroxybutyrate as opposed to [1,6-(13)C]glucose. Our results suggest that the change in aspartate-glutamate homeostasis is due to a decreased availability of NADH for cytosolic malate dehydrogenase and thus reduced malate-aspartate shuttle activity in neurons using beta-hydroxybutyrate. In the presence of glucose, the glutamate content decreased significantly upon activation of neurotransmitter release, whereas in the presence of only beta-hydroxybutyrate, no decrease in the glutamate content was observed. Thus, the fraction of the glutamate pool available for transmitter release was diminished when metabolizing beta-hydroxybutyrate, which is in line with the hypothesis of formation of transmitter glutamate via an obligatory involvement of the malate-aspartate shuttle.

  14. Early toxic effect of 6-hydroxydopamine on extracellular concentrations of neurotransmitters in the rat striatum: an in vivo microdialysis study.

    PubMed

    Tobón-Velasco, Julio César; Silva-Adaya, Daniela; Carmona-Aparicio, Liliana; García, Esperanza; Galván-Arzate, Sonia; Santamaría, Abel

    2010-12-01

    The early effects of 6-OHDA as a Parkinsonian model in rodents are relevant since pharmacological and toxicological points of view, as they can explain the acute and chronic deleterious events occurring in the striatum. In this study, we focused our attention on the neurochemical and motor dysfunction produced after a pulse infusion of 6-OHDA, paying special attention to the capacity of this molecule to induce neurotransmitter release and behavioural alterations. Extracellular levels of dopamine, serotonin, norepinephrine, glutamate, glutamine, aspartate, glycine and GABA were all assessed in striatal dialysates in freely moving rats immediately after exposed to a single pulse of 6-OHDA in dorsal striatum, and major behavioural markers of motor alterations were simultaneously explored. Enhanced release of dopamine, serotonin and norepinephrine was found immediately after 6-OHDA pulse. Delayed glutamate and glycine release were detected and a biphasic effect on GABA was observed. Mostly serotonin and dopamine outflow, followed by glutamate, correlated with wet dog shakes and other behavioural qualitative alterations. Early dopamine release, accompanied by other neurotransmitters, can generate an excitatory environment affecting the striatal neurons with immediate consequences for behavioural performance. In turn, these changes might be accounting for later features of toxicity described in this model.

  15. Neurotransmitter signaling pathways required for normal development in Xenopus laevis embryos: a pharmacological survey screen

    PubMed Central

    Sullivan, Kelly G.; Levin, Michael

    2016-01-01

    Neurotransmitters are not only involved in brain function but are also important signaling molecules for many diverse cell types. Neurotransmitters are widely conserved, from evolutionarily ancient organisms lacking nervous systems through man. Here, we report results from a loss- and gain-of-function survey, using pharmacologic modulators of several neurotransmitter pathways to examine possible roles in normal embryogenesis. Applying reagents targeting the glutamatergic, adrenergic, and dopaminergic pathways to embryos of Xenopus laevis from gastrulation to organogenesis stages, we observed and quantified numerous malformations including craniofacial defects, hyperpigmentation, muscle mispatterning, and miscoiling of the gut. These data implicate several key neurotransmitters in new embryonic patterning roles, reveal novel earlier stages for processes involved in eye development, suggest new targets for subsequent molecular-genetic investigation, and highlight the necessity for in-depth toxicology studies of psychoactive compounds to which human embryos might be exposed during pregnancy. PMID:27060969

  16. Mimicking Neurotransmitter Release in Chemical Synapses via Hysteresis Engineering in MoS2 Transistors.

    PubMed

    Arnold, Andrew J; Razavieh, Ali; Nasr, Joseph R; Schulman, Daniel S; Eichfeld, Chad M; Das, Saptarshi

    2017-03-28

    Neurotransmitter release in chemical synapses is fundamental to diverse brain functions such as motor action, learning, cognition, emotion, perception, and consciousness. Moreover, improper functioning or abnormal release of neurotransmitter is associated with numerous neurological disorders such as epilepsy, sclerosis, schizophrenia, Alzheimer's disease, and Parkinson's disease. We have utilized hysteresis engineering in a back-gated MoS2 field effect transistor (FET) in order to mimic such neurotransmitter release dynamics in chemical synapses. All three essential features, i.e., quantal, stochastic, and excitatory or inhibitory nature of neurotransmitter release, were accurately captured in our experimental demonstration. We also mimicked an important phenomenon called long-term potentiation (LTP), which forms the basis of human memory. Finally, we demonstrated how to engineer the LTP time by operating the MoS2 FET in different regimes. Our findings could provide a critical component toward the design of next-generation smart and intelligent human-like machines and human-machine interfaces.

  17. Smart Growth and Transportation

    EPA Pesticide Factsheets

    Describes the relationship between smart growth and transportation, focusing smart and sustainable street design, transit-oriented development, parking management, sustainable transportation planning, and related resources.

  18. The effect of polychlorinated biphenyls on the high affinity uptake of the neurotransmitters, dopamine, serotonin, glutamate and GABA, into rat brain synaptosomes.

    PubMed

    Mariussen, E; Fonnum, F

    2001-02-21

    Studies have shown that polychlorinated biphenyls (PCB) may affect cognitive functions both in human and also in experimental animals. We have investigated whether this effect could be caused by an inhibition of the uptake of selected neurotransmitters into rat brain synaptosomes. Ortho-chlorinated biphenyls were found to inhibit transmitter transport into synaptosomes from rat brain. In contrast, several nonortho-chlorinated biphenyls did not inhibit uptake. The uptake of dopamine, glutamate, GABA and serotonin was inhibited by the PCB mixtures, Aroclor 1242 and 1254. Under identical condition, the uptake of dopamine was inhibited more efficient than that of glutamate. The inhibition of neurotransmitter uptake was found to be dependent on the chlorination patterns of the PCB congeners, (i) ortho-chlorinated PCBs with four to five chlorine substituents (with the exception of 2,2',6,6'-TeCB) were the most effective inhibitors; (ii) hexa- or heptachlorinated PCBs were poor inhibitors or partial inhibitors (e.g. 2,2',4,4',5,5'-HCB) of glutamate and GABA uptake. Kinetic studies indicated that Aroclor 1242 inhibited dopamine uptake mainly competitively. The uptake of glutamate and GABA was inhibited in either a mixed competitive or in a non-competitive way, respectively. The neurotoxic consequences of the effect of different PCBs on neurotransmitter uptake on the uptake into synaptosomes are discussed.

  19. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor.

    PubMed

    Bunzow, J R; Sonders, M S; Arttamangkul, S; Harrison, L M; Zhang, G; Quigley, D I; Darland, T; Suchland, K L; Pasumamula, S; Kennedy, J L; Olson, S B; Magenis, R E; Amara, S G; Grandy, D K

    2001-12-01

    The trace amine para-tyramine is structurally and functionally related to the amphetamines and the biogenic amine neurotransmitters. It is currently thought that the biological activities elicited by trace amines such as p-tyramine and the psychostimulant amphetamines are manifestations of their ability to inhibit the clearance of extracellular transmitter and/or stimulate the efflux of transmitter from intracellular stores. Here we report the discovery and pharmacological characterization of a rat G protein-coupled receptor that stimulates the production of cAMP when exposed to the trace amines p-tyramine, beta-phenethylamine, tryptamine, and octopamine. An extensive pharmacological survey revealed that psychostimulant and hallucinogenic amphetamines, numerous ergoline derivatives, adrenergic ligands, and 3-methylated metabolites of the catecholamine neurotransmitters are also good agonists at the rat trace amine receptor 1 (rTAR1). These results suggest that the trace amines and catecholamine metabolites may serve as the endogenous ligands of a novel intercellular signaling system found widely throughout the vertebrate brain and periphery. Furthermore, the discovery that amphetamines, including 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"), are potent rTAR1 agonists suggests that the effects of these widely used drugs may be mediated in part by this receptor as well as their previously characterized targets, the neurotransmitter transporter proteins.

  20. High harmonics focusing undulator

    SciTech Connect

    Varfolomeev, A.A.; Hairetdinov, A.H.; Smirnov, A.V.; Khlebnikov, A.S.

    1995-12-31

    It was shown in our previous work that there exist a possibility to enhance significantly the {open_quote}natural{close_quote} focusing properties of the hybrid undulator. Here we analyze the actual undulator configurations which could provide such field structure. Numerical simulations using 2D code PANDIRA were carried out and the enhanced focusing properties of the undulator were demonstrated. The obtained results provide the solution for the beam transport in a very long (short wavelength) undulator schemes.

  1. Etomidate and propofol inhibit the neurotransmitter release machinery at different sites

    PubMed Central

    Herring, Bruce E; McMillan, Kyle; Pike, Carolyn M; Marks, Jeremy; Fox, Aaron P; Xie, Zheng

    2011-01-01

    The mechanism of general anaesthetic action is only partially understood. Facilitation of inhibitory GABAA receptors plays an important role in the action of most anaesthetics, but is thought to be especially relevant in the case of intravenous anaesthetics, like etomidate and propofol. Recent evidence suggests that anaesthetics also inhibit excitatory synaptic transmission via a presynaptic mechanism(s), but it has been difficult to determine whether these agents act on the neurotransmitter release machinery itself. In the present study we sought to determine whether the intravenous anaesthetics propofol and etomidate inhibit the release machinery. For these studies we used an experimental approach that directly regulated [Ca2+]i at neurotransmitter release sites, thereby bypassing anaesthetic effects on channels and receptors in order to allow anaesthetic effects on the neurotransmitter release machinery to be examined in isolation. The data show that clinically relevant concentrations of propofol and etomidate inhibited the neurotransmitter release machinery in neurosecretory cells and in cultured hippocampal neurons. md130A is a mutant form of syntaxin with a truncated C-terminus. Overexpressing md130A in PC12 cells completely eliminated the reduction in neurotransmitter release produced by propofol, without affecting release itself. In contrast, overexpressing md130A in PC12 cells had little or no effect on the response to etomidate. These results suggest that both propofol and etomidate inhibit neurotransmitter release by a direct interaction with SNAREs and/or SNARE-associated proteins but they do so at different sites. PMID:21173083

  2. Electrochemical sensors and biosensors for determination of catecholamine neurotransmitters: A review.

    PubMed

    Ribeiro, José A; Fernandes, Paula M V; Pereira, Carlos M; Silva, F

    2016-11-01

    This work describes the state of the art of electrochemical devices for the detection of an important class of neurotransmitters: the catecholamines. This class of biogenic amines includes dopamine, noradrenaline (also called norepinephrine) and adrenaline (also called epinephrine). Researchers have focused on the role of catecholamine molecules within the human body because they are involved in many important biological functions and are commonly associated with several diseases, such as Alzheimer's and Parkinson. Furthermore, the release of catecholamines as a consequence of induced stimulus is an important indicator of reward-related behaviors, such as food, drink, sex and drug addiction. Thus, the development of simple, fast and sensitive electroanalytical methodologies for the determination of catecholamines is currently needed in clinical and biomedical fields, as they have the potential to serve as clinically relevant biomarkers for specific disease states or to monitor treatment efficacy. Currently, three main strategies have used by researchers to detect catecholamine molecules, namely: the use electrochemical materials in combination with, for example, HPLC or FIA, the incorporation of new materials/layers on the sensor surfaces (Tables 1-7) and in vivo detection, manly by using FSCV at CFMEs (Section 10). The developed methodologies were able not only to accurately detect catecholamines at relevant concentration levels, but to do so in the presence of co-existing interferences in samples detected (ascorbate, for example). This review examines the progress made in electrochemical sensors for the selective detection of catecholamines in the last 15 years, with special focus on highly innovative features introduced by nanotechnology. As the literature in rather extensive, we try to simplify this work by summarizing and grouping electrochemical sensors according to the manner their substrates were chemically modified. We also discuss the current and future

  3. Cryogenic fluid management (base R/T): Cryogenic fluid systems, Cryogenic Orbital Nitrogen Experiment (CONE), Cryogenic Orbital Hydrogen Experiment (COHE). (Transportation focused technology)

    NASA Technical Reports Server (NTRS)

    Symons, Pat

    1991-01-01

    The topics presented are covered in viewgraph form. The concluded remarks are: (1) advanced cryogenic fluid systems technology is enhancing or enabling to all known transportation scenarios for space exploration; (2) an integrated/coordinated program involving LeRC/MSFC has been formulated to address all known CFM needs - new needs should they develop, can be accommodated within available skills/facilities; (3) all required/experienced personnel and facilities are finally in place - data from initial ground-based experiments is being collected and analyzed - small scale STS experiments are nearing flight - program is beginning to yield significant results; (4) future proposed funding to primarily come from two sources; and (5) cryogenic fluid experimentation is essential to provide required technology and assure implementation in future NASA missions.

  4. Mass spectrometric evaluation of neurotransmitter levels in IMR 32 cell line in response to Ayurvedic medicines.

    PubMed

    Mamidala, Madhu Poornima; Rajesh, N; Rajesh, Vidya

    2016-06-30

    Ayurvedic herbal medicines are administered as part of disease management for many neurodevelopmental disorders like Autism Spectrum Disorder (ASD) and linked comorbid challenges. The biochemistry of the behavioral abnormalities as observed in comorbid conditions is already reported to involve neurotransmitters like gamma-aminobutyric acid (GABA), serotonin (5-HT) and dopamine (DA). The aim of our study is to evaluate the effect of ayurvedic medicines on neurotransmitter levels in IMR 32. Such a study will give some insight into the molecular mechanism of the action of these medicines and help us to understand their contributions in neurotransmitter homeostasis. Solutions of Brahmi, Brahmi vati, Brahmi ghrita and Saraswata ghrita, each at 50 μM, were added to differentiated IMR 32 cells and grown for 24 h. The cell secretion was analysed by ultra-fast liquid chromatography/mass spectrometry (UFLC/MS) in electrospray ionisation (ESI) mode for the neurotransmitters DA, 5-HT and GABA. The mobile phase selected was 0.1% formic acid with 15 μg/mL Na2 -EDTA (A) and 0.1% formic acid in acetonitrile (B) introduced in the ratio of 92:8. All neurotransmitters under study were eluted within 7 min with GABA eluting at 3.82 min, 5-HT at 4.48 min and DA at 5.47 min, respectively. Linearity was excellent with a correlation coefficient (R(2) ) of 0.999; repeatability and accuracy were also within acceptable range. All herbal drugs evaluated increased the neurotransmitter levels and Brahmi vati increased the neurotransmitter levels to a larger extent. Decreased levels of neurotransmitters were observed in behavioral abnormalities which were also observed in children with ASD. Herbal medicines given as part of ayurvedic medicine increased the neurotransmitter levels in IMR 32. Thus, these ayurvedic medicines when prescribed to children with ASD might alleviate the abnormal behavioral symptoms by maintaining neurotransmitter homeostasis. Copyright © 2016 John Wiley & Sons

  5. Transporting evidence-based interventions across cultures: using focus groups with teachers and parents of pre-school children to inform the implementation of the Incredible Years Teacher Training Programme in Jamaica.

    PubMed

    Baker-Henningham, H

    2011-09-01

    Evidence-based programmes to prevent and treat conduct problems in young children are available, but there is limited information on the extent to which they can be effectively transported to developing countries. This study used focus group discussions with parents and teachers of pre-school children to investigate whether an evidence-based programme - the Incredible Years (IY) Teacher Training Programme - could be transported to the Jamaican pre-school setting. Ten focus group discussions were held with 50 pre-school teachers and 47 parents of pre-school children. For each focus group, a semi-structured questioning guide was used to explore parents' and teachers' perceptions of the dimensions and causes of problem behaviour in young children and strategies used to manage child behaviour. All focus group discussions were audiotaped and transcribed, and thematic analysis was used to analyse the data. Parents and teachers shared similar views of what constitutes good behaviour and poor behaviour, and both parents and teachers believed that the major influences on children's behaviour are factors in the home. Many appropriate and useful strategies for managing child behaviour were used including showing children affection, spending time with children, using praise, incentives and rewards and withdrawing privileges and using timeout as consequences for misbehaviour. Some inappropriate strategies were also used, especially corporal punishment, although there was a general consensus within all groups that this is not desirable or effective. Through the focus groups, it was clear that parents and teachers were familiar with many of the strategies and principles introduced through the IY Teacher Training Programme, and the programme was largely compatible with their values and beliefs. However, some topics require additional emphasis thus lengthening the time required for training. It was also evident that there is a strong perceived need for training in child behaviour

  6. Ion focusing

    DOEpatents

    Cooks, Robert Graham; Baird, Zane; Peng, Wen-Ping

    2017-01-17

    The invention generally relates to apparatuses for focusing ions at or above ambient pressure and methods of use thereof. In certain embodiments, the invention provides an apparatus for focusing ions that includes an electrode having a cavity, at least one inlet within the electrode configured to operatively couple with an ionization source, such that discharge generated by the ionization source is injected into the cavity of the electrode, and an outlet. The cavity in the electrode is shaped such that upon application of voltage to the electrode, ions within the cavity are focused and directed to the outlet, which is positioned such that a proximal end of the outlet receives the focused ions and a distal end of the outlet is open to ambient pressure.

  7. Ion focusing

    SciTech Connect

    Cooks, Robert Graham; Baird, Zane; Peng, Wen-Ping

    2015-11-10

    The invention generally relates to apparatuses for focusing ions at or above ambient pressure and methods of use thereof. In certain embodiments, the invention provides an apparatus for focusing ions that includes an electrode having a cavity, at least one inlet within the electrode configured to operatively couple with an ionization source, such that discharge generated by the ionization source is injected into the cavity of the electrode, and an outlet. The cavity in the electrode is shaped such that upon application of voltage to the electrode, ions within the cavity are focused and directed to the outlet, which is positioned such that a proximal end of the outlet receives the focused ions and a distal end of the outlet is open to ambient pressure.

  8. Effects of cognitive-behavioral therapy on Eating Disorders: neurotransmitter secretory response to treatment.

    PubMed

    Brambilla, F; Dalle Grave, R; Calugi, S; Marchesini, G; Baroni, S; Marazziti, D

    2010-06-01

    The effects of cognitive-behavioral therapy (CBT) on central dopamine (DA), noradrenaline (NE) and serotonin (5-HT) secretion were studied in a group of 50 female inpatients, of which 14 suffered from anorexia nervosa restricted type (AN-R), 14 from anorexia nervosa bingeing-purging type (AN-BP), and 22 from bulimia nervosa (BN). The aim of the study was to see whether or not CBT modifies the secretion of central DA (blood homovanillic acid=HVA), NE (blood 3-methoxy-4-hydroxy-phenylglycol=MHPG) and the 5-HT transporter (as evaluated by the platelet paroxetine binding=[(3)H]-Par-binding), if the physical and psychological effects of CBT correlate with changes of the neurotransmitter secretion; and if the biological effects of CBT are linked to specific psychopathological aspect of the disorders. The treatment lasted 20 weeks. Body-mass Index, bingeing and purging, specific AN-BN psychopathological (EDE 12-OD), depression (Beck Inventory), anxiety (STAY Form-Y-1), impulsiveness (Barratt Impulsiveness Scale), self-esteem (Rosenberg Self-Biochemical Scale) and temperament (Temperament and Character Inventory, Cloninger Scale) were assessed at baseline and at the end of the treatment. CBT significantly improved the psychophysical aspects of the diseases. HVA and MHPG concentrations did not change. The [(3)H]-Par-binding parameters, the maximum binding capacity (B(max)) and dissociation constant (K(d)) values did not change in either AN-R or AN-BP patients, while the [(3)H]-Par B(max) (and not the K(d)) increased significantly in BN patients. Correlations emerged between basal and final [(3)H]-Par B(max) values and psychopathological scores, but not between CBT-induced differences between basal and final values. Our data suggest that only in BN CBT may act through changes in 5-HT system function. Copyright 2009 Elsevier Ltd. All rights reserved.

  9. Neurotransmitter regulation of circadian structural changes in the fly's visual system.

    PubMed

    Meinertzhagen, I A; Pyza, E

    1999-04-15

    The visual system of the fly's compound eye undergoes a number of cyclical day/night changes that have a circadian basis. Such responses are seen in the synaptic terminals of the photoreceptors and in their large monopolar-cell interneurons in the first optic neuropile, or lamina. These changes include, in the photoreceptor terminals, rhythms in the numbers of synapses and the vertical migration of screening pigment; and, in the monopolar cells L1 and L2, a rhythm in the transients of the electroretinogram and in the cyclical swelling of L1 and L2 lamina axons, as well as of the epithelial glia that surround these. Some of these changes are seen in both the housefly and the fruit fly, but the time-course of such changes differs between the two species. Many of the changes are influenced by the injection of various transmitter candidates, in a direction that can be reconciled with the possibility of normal endogenous release of two substances, 5HT from the neurites of 5HT-immunoreactive neurons, and pigment dispersing factor peptide from the neurites of PDH cells. Consistent with this interpretation, the immunoreactive varicosities of PDH cells exhibit size changes attributable to their cyclical release of peptide, or to its cyclical synthesis and/or transport from the PDH cell somata. Thus, neurotransmitter substances not only have rapid electrophysiological actions in the optic lobe, but also longer-lasting, presumably indirect, neuromodulatory actions, which are manifest as structural changes among the lamina's neurons and synapses. These actions involve an interplay between aminergic and peptidergic systems, but the exact role and especially the site of action of each has still to be elucidated.

  10. Enkephalin co-expression with classic neurotransmitters in the amygdaloid complex of the rat.

    PubMed

    Poulin, Jean-François; Castonguay-Lebel, Zoé; Laforest, Sylvie; Drolet, Guy

    2008-02-20

    This study aimed at characterizing the neurotransmitter phenotype of enkephalin neurons in the rat amygdaloid complex. We first established the detailed distribution of vesicular glutamate transporters 1 and 2 (VGLUT1 and -2) and glutamate decarboxylase 65 (GAD65) in the amygdala by using in situ hybridization. In the amygdaloid complex, GAD65 is strongly expressed in striatal-like divisions, namely, the anterior amygdaloid area, the central nucleus (CEA), the intercalated nuclei, and the dorsal part of the medial nucleus (MEA). VGLUT1 and -2 expression is mostly segregated to specific divisions of the amygdale, with VGLUT2 being expressed only in the MEA, the anterior cortical nucleus (COAa), and the anterior basomedial nucleus (BMAa), whereas VGLUT1 is expressed in all other divisions of the amygdala. Second, we assessed the co-expression of preproenkephalin (ppENK) with GAD65, VGLUT1, or VGLUT2 by using double fluorescent in situ hybridization. We found that ppENK mRNA co-localized exclusively with GAD65 in all striatal-like structures of the amygdaloid complex with the exception of the MEA, where ENK also co-localized with VGLUT2 mRNA. This co-localization is most apparent in the posteroventral part of the MEA, where 70% of ENKergic cells expressed VGLUT2. In addition, ppENK also co-localized with VGLUT1 because more than 95% of ENK cells in the basolateral amygdala expressed VGLUT1. In contrast, less than 25% of ENKergic cells expressed VGLUT1 in the lateral nucleus of the amygdale, with the majority of ENK cells expressing GAD65 mRNA in this nucleus. These results have broad implications for understanding the functional roles of enkephalinergic neurotransmission in the amygdaloid complex.

  11. Evidence for histamine as a neurotransmitter in the cardiac sympathetic nervous system.

    PubMed

    Li, Mingkai; Hu, Jing; Chen, Zhong; Meng, Jia; Wang, Haifang; Ma, Xue; Luo, Xiaoxing

    2006-07-01

    The colocalization of histamine (HA) and norepinephrine (NE) immunoreactivities was identified within the superior cervical ganglia neurons of the guinea pig. HA and NE immunoreactivity levels were significantly attenuated after chemical sympathectomy with 6-hydroxydopamine (6-OHDA). Coexistence of NE and HA was also visualized in the cardiac sympathetic axon and varicosities labeled with anterograde tracer biotinylated dextran amine. Depolarization of cardiac sympathetic nerve endings (synaptosomes) with 50 mM potassium stimulated endogenous HA release, which was significantly attenuated by 6-OHDA or a vesicular monoamine transporter 2 (VMAT2) inhibitor reserpine pretreatments. Compound 48/80, a mast cell releaser, did not affect cardiac synaptosome HA exocytosis. Furthermore, K+ -evoked HA release was abolished by the N-type Ca2+ -channel blocker omega-conotoxin but was not affected by the L-type Ca2+ -channel blocker lacidipine. Cardiac synaptosome HA exocytosis was augmented by the enhanced synthesis of HA or the inhibition of HA metabolism. HA H3-receptor activation by (R)-alpha-methylhistamine inhibited high K+ -evoked histamine release. The HA H3 receptor antagonist thioperamide enhanced K+ -evoked HA release and blocked the (R)-alpha-methylhistamine effect. The K+ -evoked endogenous NE release was attenuated by preloading the cardiac synaptosomes with L-histidine or quinacrine. These inhibitory effects were reversed by thioperamide or antagonized by alpha-fluoromethylhistidine. Our findings indicate that high K+ -evoked corelease of NE and HA may be inhibited by endogenous HA via activation of presynaptic HA H3-receptors. The H3-receptor may function as an autoreceptor, rather than a heteroreceptor, in the regulation of sympathetic neurotransmission and HA may be a novel sympathetic neurotransmitter.

  12. The solute carrier 6 family of transporters

    PubMed Central

    Bröer, Stefan; Gether, Ulrik

    2012-01-01

    The solute carrier 6 (SLC6) family of the human genome comprises transporters for neurotransmitters, amino acids, osmolytes and energy metabolites. Members of this family play critical roles in neurotransmission, cellular and whole body homeostasis. Malfunction or altered expression of these transporters is associated with a variety of diseases. Pharmacological inhibition of the neurotransmitter transporters in this family is an important strategy in the management of neurological and psychiatric disorders. This review provides an overview of the biochemical and pharmacological properties of the SLC6 family transporters. LINKED ARTICLES BJP published a themed section on Transporters in 2011. To view articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.2011.164.issue-7/issuetoc PMID:22519513

  13. HIGHWAY INFRASTRUCTURE FOCUS AREA NEXT-GENERATION INFRASTRUCTURE MATERIALS VOLUME I - TECHNICAL PROPOSAL & MANAGEMENTENHANCEMENT OF TRANSPORTATION INFRASTRUCTURE WITH IRON-BASED AMORPHOUS-METAL AND CERAMIC COATINGS

    SciTech Connect

    Farmer, J C

    2007-12-04

    The infrastructure for transportation in the United States allows for a high level of mobility and freight activity for the current population of 300 million residents, and several million business establishments. According to a Department of Transportation study, more than 230 million motor vehicles, ships, airplanes, and railroads cars were used on 6.4 million kilometers (4 million miles) of highways, railroads, airports, and waterways in 1998. Pipelines and storage tanks were considered to be part of this deteriorating infrastructure. The annual direct cost of corrosion in the infrastructure category was estimated to be approximately $22.6 billion in 1998. There were 583,000 bridges in the United States in 1998. Of this total, 200,000 bridges were steel, 235,000 were conventional reinforced concrete, 108,000 bridges were constructed using pre-stressed concrete, and the balance was made using other materials of construction. Approximately 15 percent of the bridges accounted for at this point in time were structurally deficient, primarily due to corrosion of steel and steel reinforcement. Iron-based amorphous metals, including SAM2X5 (Fe{sub 49.7}Cr{sub 17.7}Mn{sub 1.9}Mo{sub 7.4}W{sub 1.6}B{sub 15.2}C{sub 3.8}Si{sub 2.4}) and SAM1651 (Fe{sub 48}Mo{sub 14}Cr{sub 15}Y{sub 2}C{sub 15}B{sub 6}) have been developed, and have very good corrosion resistance. These materials have been prepared as a melt-spun ribbons, as well as gas atomized powders and thermal-spray coatings. During electrochemical testing in several environments, including seawater at 90 C, the passive film stabilities of these materials were found to be comparable to that of more expensive high-performance alloys, based on electrochemical measurements of the passive film breakdown potential and general corrosion rates. These materials also performed very well in standard salt fog tests. Chromium (Cr), molybdenum (Mo) and tungsten (W) provided corrosion resistance, and boron (B) enabled glass formation

  14. Study of Chinese pollution with the 3D regional chemistry transport CHIMERE model and remote sensing observations, with a focus on mineral dust impacts

    NASA Astrophysics Data System (ADS)

    Lachatre, Mathieu; Foret, Gilles; Beekmann, Matthias; Cheiney, Audrey; Dufour, Gaëlle; Laurent, Benoit; Cuesta, Juan

    2017-04-01

    Since the end of the 20th century, China has observed important growth in numerous sectors. China's Gross Domestic Product (GDP) has been multiply by 4 during the 2000-2010 decade (National Bureau of Statistics of China), mostly because of the industry's growth. These evolutions have been accompanied by important increases of atmospheric pollutants emissions (Yinmin et al, Atmo Env, 2016). As a consequence and for about 10 years now, Chinese authorities have been working to reduce pollutant levels, because atmospheric pollution is a major health issue for Chinese population especially within cities, for which World Health Organisation's standards for major pollutants (Ozone, PM2.5, PM10) are often exceeded. Particles have multiple issues, as they impact on health and global warming. Their impacts will depend on their sources (primary or secondary pollutants) and natures (Particle size distribution, chemical composition…). Controlling particles loading is a complex task as their sources are various and dispersed on the Chinese territories: mineral dust can be emitted from Chinese deserts in large amount (Laurent et al., GPC, 2006), ammonia can be emitted from agriculture and livestock (Kang et al., ACP, 2016) and lots of urban primary pollutants can be emitted from urbanized areas. It is then necessary to work from a continental to local scales to understand more precisely pollution of urbanized areas. It is then mandatory to discriminate and quantify pollution sources and to estimate the impact of natural pollution and the major contributing sources. We propose here an approach based on a model and satellite observation synergy to estimate what controls Chinese pollution. We use the regional chemistry transport model CHIMERE (Menut et al., GMD, 2013) to simulate atmospheric pollutants concentrations. A large domain (72°E-145°E; 17.5°N-55°N), with a ¼°x¼° resolution is used to make multi-annual simulations. CHIMERE model include most of the pollutants

  15. N-acyl amino acids and N-acyl neurotransmitter conjugates: neuromodulators and probes for new drug targets.

    PubMed

    Connor, Mark; Vaughan, Chris W; Vandenberg, Robert J

    2010-08-01

    The myriad functions of lipids as signalling molecules is one of the most interesting fields in contemporary pharmacology, with a host of compounds recognized as mediators of communication within and between cells. The N-acyl conjugates of amino acids and neurotransmitters (NAANs) have recently come to prominence because of their potential roles in the nervous system, vasculature and the immune system. NAAN are compounds such as glycine, GABA or dopamine conjugated with long chain fatty acids. More than 70 endogenous NAAN have been reported although their physiological role remains uncertain, with various NAAN interacting with a low affinity at G protein coupled receptors (GPCR) and ion channels. Regardless of their potential physiological function, NAAN are of great interest to pharmacologists because of their potential as flexible tools to probe new sites on GPCRs, transporters and ion channels. NAANs are amphipathic molecules, with a wide variety of potential fatty acid and headgroup moieties, a combination which provides a rich source of potential ligands engaging novel binding sites and mechanisms for modulation of membrane proteins such as GPCRs, ion channels and transporters. The unique actions of subsets of NAAN on voltage-gated calcium channels and glycine transporters indicate that the wide variety of NAAN may provide a readily exploitable resource for defining new pharmacological targets. Investigation of the physiological roles and pharmacological potential of these simple lipid conjugates is in its infancy, and we believe that there is much to be learnt from their careful study.

  16. Nod Factor Effects on Root Hair-Specific Transcriptome of Medicago truncatula: Focus on Plasma Membrane Transport Systems and Reactive Oxygen Species Networks

    PubMed Central

    Damiani, Isabelle; Drain, Alice; Guichard, Marjorie; Balzergue, Sandrine; Boscari, Alexandre; Boyer, Jean-Christophe; Brunaud, Véronique; Cottaz, Sylvain; Rancurel, Corinne; Da Rocha, Martine; Fizames, Cécile; Fort, Sébastien; Gaillard, Isabelle; Maillol, Vincent; Danchin, Etienne G. J.; Rouached, Hatem; Samain, Eric; Su, Yan-Hua; Thouin, Julien; Touraine, Bruno; Puppo, Alain; Frachisse, Jean-Marie; Pauly, Nicolas; Sentenac, Hervé

    2016-01-01

    Root hairs are involved in water and nutrient uptake, and thereby in plant autotrophy. In legumes, they also play a crucial role in establishment of rhizobial symbiosis. To obtain a holistic view of Medicago truncatula genes expressed in root hairs and of their regulation during the first hours of the engagement in rhizobial symbiotic interaction, a high throughput RNA sequencing on isolated root hairs from roots challenged or not with lipochitooligosaccharides Nod factors (NF) for 4 or 20 h was carried out. This provided a repertoire of genes displaying expression in root hairs, responding or not to NF, and specific or not to legumes. In analyzing the transcriptome dataset, special attention was paid to pumps, transporters, or channels active at the plasma membrane, to other proteins likely to play a role in nutrient ion uptake, NF electrical and calcium signaling, control of the redox status or the dynamic reprogramming of root hair transcriptome induced by NF treatment, and to the identification of papilionoid legume-specific genes expressed in root hairs. About 10% of the root hair expressed genes were significantly up- or down-regulated by NF treatment, suggesting their involvement in remodeling plant functions to allow establishment of the symbiotic relationship. For instance, NF-induced changes in expression of genes encoding plasma membrane transport systems or disease response proteins indicate that root hairs reduce their involvement in nutrient ion absorption and adapt their immune system in order to engage in the symbiotic interaction. It also appears that the redox status of root hair cells is tuned in response to NF perception. In addition, 1176 genes that could be considered as “papilionoid legume-specific” were identified in the M. truncatula root hair transcriptome, from which 141 were found to possess an ortholog in every of the six legume genomes that we considered, suggesting their involvement in essential functions specific to legumes. This

  17. Nod Factor Effects on Root Hair-Specific Transcriptome of Medicago truncatula: Focus on Plasma Membrane Transport Systems and Reactive Oxygen Species Networks.

    PubMed

    Damiani, Isabelle; Drain, Alice; Guichard, Marjorie; Balzergue, Sandrine; Boscari, Alexandre; Boyer, Jean-Christophe; Brunaud, Véronique; Cottaz, Sylvain; Rancurel, Corinne; Da Rocha, Martine; Fizames, Cécile; Fort, Sébastien; Gaillard, Isabelle; Maillol, Vincent; Danchin, Etienne G J; Rouached, Hatem; Samain, Eric; Su, Yan-Hua; Thouin, Julien; Touraine, Bruno; Puppo, Alain; Frachisse, Jean-Marie; Pauly, Nicolas; Sentenac, Hervé

    2016-01-01

    Root hairs are involved in water and nutrient uptake, and thereby in plant autotrophy. In legumes, they also play a crucial role in establishment of rhizobial symbiosis. To obtain a holistic view of Medicago truncatula genes expressed in root hairs and of their regulation during the first hours of the engagement in rhizobial symbiotic interaction, a high throughput RNA sequencing on isolated root hairs from roots challenged or not with lipochitooligosaccharides Nod factors (NF) for 4 or 20 h was carried out. This provided a repertoire of genes displaying expression in root hairs, responding or not to NF, and specific or not to legumes. In analyzing the transcriptome dataset, special attention was paid to pumps, transporters, or channels active at the plasma membrane, to other proteins likely to play a role in nutrient ion uptake, NF electrical and calcium signaling, control of the redox status or the dynamic reprogramming of root hair transcriptome induced by NF treatment, and to the identification of papilionoid legume-specific genes expressed in root hairs. About 10% of the root hair expressed genes were significantly up- or down-regulated by NF treatment, suggesting their involvement in remodeling plant functions to allow establishment of the symbiotic relationship. For instance, NF-induced changes in expression of genes encoding plasma membrane transport systems or disease response proteins indicate that root hairs reduce their involvement in nutrient ion absorption and adapt their immune system in order to engage in the symbiotic interaction. It also appears that the redox status of root hair cells is tuned in response to NF perception. In addition, 1176 genes that could be considered as "papilionoid legume-specific" were identified in the M. truncatula root hair transcriptome, from which 141 were found to possess an ortholog in every of the six legume genomes that we considered, suggesting their involvement in essential functions specific to legumes. This

  18. Cosmic-ray neutron transport at a forest field site: the sensitivity to various environmental conditions with focus on biomass and canopy interception

    NASA Astrophysics Data System (ADS)

    Andreasen, Mie; Jensen, Karsten H.; Desilets, Darin; Zreda, Marek; Bogena, Heye R.; Looms, Majken C.

    2017-04-01

    Cosmic-ray neutron intensity is inversely correlated to all hydrogen present in the upper decimeters of the subsurface and the first few hectometers of the atmosphere above the ground surface. This correlation forms the base of the cosmic-ray neutron soil moisture estimation method. The method is, however, complicated by the fact that several hydrogen pools other than soil moisture affect the neutron intensity. In order to improve the cosmic-ray neutron soil moisture estimation method and explore the potential for additional applications, knowledge about the environmental effect on cosmic-ray neutron intensity is essential (e.g., the effect of vegetation, litter layer and soil type). In this study the environmental effect is examined by performing a sensitivity analysis using neutron transport modeling. We use a neutron transport model with various representations of the forest and different parameters describing the subsurface to match measured height profiles and time series of thermal and epithermal neutron intensities at a field site in Denmark. Overall, modeled thermal and epithermal neutron intensities are in satisfactory agreement with measurements; however, the choice of forest canopy conceptualization is found to be significant. Modeling results show that the effect of canopy interception, soil chemistry and dry bulk density of litter and mineral soil on neutron intensity is small. On the other hand, the neutron intensity decreases significantly with added litter-layer thickness, especially for epithermal neutron energies. Forest biomass also has a significant influence on the neutron intensity height profiles at the examined field site, altering both the shape of the profiles and the ground-level thermal-to-epithermal neutron ratio. This ratio increases with increasing amounts of biomass, and was confirmed by measurements from three sites representing agricultural, heathland and forest land cover. A much smaller effect of canopy interception on the ground

  19. APP+, a fluorescent analogue of the neurotoxin MPP+, is a marker of catecholamine neurons in brain tissue, but not a fluorescent false neurotransmitter.

    PubMed

    Karpowicz, Richard J; Dunn, Matthew; Sulzer, David; Sames, Dalibor

    2013-05-15

    We have previously introduced fluorescent false neurotransmitters (FFNs) as optical reporters that enable visualization of individual dopaminergic presynaptic terminals and their activity in the brain. In this context, we examined the fluorescent pyridinium dye 4-(4-dimethylamino)phenyl-1-methylpyridinium (APP+), a fluorescent analogue of the dopaminergic neurotoxin MPP+, in acute mouse brain tissue. APP+ is a substrate for the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), and as such represented a candidate for the development of new FFN probes. Here we report that APP+ labels cell bodies of catecholaminergic neurons in the midbrain in a DAT- and NET-dependent manner, as well as fine dopaminergic axonal processes in the dorsal striatum. APP+ destaining from presynaptic terminals in the dorsal striatum was also examined under the conditions inducing depolarization and exocytotic neurotransmitter release. Application of KCl led to a small but significant degree of destaining (approximately 15% compared to control), which stands in contrast to a nearly complete destaining of the new generation FFN agent, FFN102. Electrical stimulation of brain slices at 10 Hz afforded no significant change in the APP+ signal. These results indicate that the majority of the APP+ signal in axonal processes originates from labeled organelles including mitochondria, whereas only a minor component of the APP+ signal represents the releasable synaptic vesicular pool. These results also show that APP+ may serve as a useful probe for identifying catecholaminergic innervations in the brain, although it is a poor candidate for the development of FFNs.

  20. The dose-dependent toxicological effects and potential perturbation on the neurotransmitter secretion in brain following intranasal instillation of copper nanoparticles.

    PubMed

    Zhang, Lili; Bai, Ru; Liu, Ying; Meng, Li; Li, Bai; Wang, Liming; Xu, Ligeng; Le Guyader, Laurent; Chen, Chunying

    2012-08-01

    Increasing production and application of metallic nanomaterials are likely to result in the release of these particles into the environment. These released nanoparticles may enter into the lungs and the central nervous system (CNS) directly through inhalation, which therefore poses a potential risk to human health. Herein, we focus on the systemic toxicity and potential influence on the neurotransmitter secretion of intranasally instilled copper nanoparticles (23.5 nm) at three different doses. Copper nanoparticle-exposed mice exhibit pathological lesions at different degrees in certain tissues and especially in lung tissue as revealed by histopathology and transmission electron microscopy (TEM) observations. Inductively-coupled plasma mass spectrometry (ICP-MS) results show that the liver, lung and olfactory bulb are the main tissues in which the copper concentrations increased significantly after exposure to a higher level of Cu nanoparticles (40 mg/kg of body weight). The secretion levels of various neurotransmitters changed as well in some brain regions, especially in the olfactory bulb. Our results indicate that the intranasally instilled copper nanoparticles not only cause the lesions where the copper accumulates, but also affect the neurotransmitter levels in the brain.

  1. Microstructural analysis and transport properties of MoO and MoC nanostructures prepared by focused electron beam-induced deposition.

    PubMed

    Makise, Kazumasa; Mitsuishi, Kazutaka; Shimojo, Masayuki; Shinozaki, Bunju

    2014-07-18

    By electron-beam-induced deposition, we have succeeded in the direct fabrication of nanowires of molybdenum oxide (MoOx) and molybdenum carbide (MoC) on a SiO2 substrate set in a scanning electron microscope. In order to prepare MoOx specimens of high purity, a precursor gas of molybdenum hexacarbonyl [Mo(CO)6] is used, mixed with oxygen gas. On the other hand, MoC is grown by mixing H2O gas with the precursor gas. The electrical transport properties of the nanowires are investigated by the DC four-terminal method. A highly resistive MoOx nanowire prepared from an as-deposited specimen by annealing in air shows nonlinear current-voltage characteristics and a high photoconductivity. The resistivity ρ of an as-deposited amorphous MoC (a-MoC) nanowire takes its maximum at a temperature T ≈ 10 K and decreases to ≈ 0 with decreasing temperature. This behavior of ρ(T) indicates the possible occurrence of superconductivity in a-MoC nanowires. The characteristic of ρ(T) below the superconducting transition temperature Tc ≈ 4 K can be well explained by the quantum phase-slip model with a coherence length ξ(0) ≈ 8 nm at T = 0.

  2. Microstructural analysis and Transport Properties of MoO and MoC nanostructures prepared by focused electron beam-induced deposition

    PubMed Central

    Makise, Kazumasa; Mitsuishi, Kazutaka; Shimojo, Masayuki; Shinozaki, Bunju

    2014-01-01

    By electron-beam-induced deposition, we have succeeded in the direct fabrication of nanowires of molybdenum oxide (MoOx) and molybdenum carbide (MoC) on a SiO2 substrate set in a scanning electron microscope. In order to prepare MoOx specimens of high purity, a precursor gas of molybdenum hexacarbonyl [Mo(CO)6] is used, mixed with oxygen gas. On the other hand, MoC is grown by mixing H2O gas with the precursor gas. The electrical transport properties of the nanowires are investigated by the DC four-terminal method. A highly resistive MoOx nanowire prepared from an as-deposited specimen by annealing in air shows nonlinear current-voltage characteristics and a high photoconductivity. The resistivity ρ of an as-deposited amorphous MoC (a-MoC) nanowire takes its maximum at a temperature T ≈ 10 K and decreases to ≈ 0 with decreasing temperature. This behavior of ρ(T) indicates the possible occurrence of superconductivity in a-MoC nanowires. The characteristic of ρ(T) below the superconducting transition temperature Tc ≈ 4 K can be well explained by the quantum phase-slip model with a coherence length ξ(0) ≈ 8 nm at T = 0. PMID:25033894

  3. Microstructural analysis and Transport Properties of MoO and MoC nanostructures prepared by focused electron beam-induced deposition

    NASA Astrophysics Data System (ADS)

    Makise, Kazumasa; Mitsuishi, Kazutaka; Shimojo, Masayuki; Shinozaki, Bunju

    2014-07-01

    By electron-beam-induced deposition, we have succeeded in the direct fabrication of nanowires of molybdenum oxide (MoOx) and molybdenum carbide (MoC) on a SiO2 substrate set in a scanning electron microscope. In order to prepare MoOx specimens of high purity, a precursor gas of molybdenum hexacarbonyl [Mo(CO)6] is used, mixed with oxygen gas. On the other hand, MoC is grown by mixing H2O gas with the precursor gas. The electrical transport properties of the nanowires are investigated by the DC four-terminal method. A highly resistive MoOx nanowire prepared from an as-deposited specimen by annealing in air shows nonlinear current-voltage characteristics and a high photoconductivity. The resistivity ρ of an as-deposited amorphous MoC (a-MoC) nanowire takes its maximum at a temperature T ~ 10 K and decreases to ~ 0 with decreasing temperature. This behavior of ρ(T) indicates the possible occurrence of superconductivity in a-MoC nanowires. The characteristic of ρ(T) below the superconducting transition temperature Tc ~ 4 K can be well explained by the quantum phase-slip model with a coherence length ξ(0) ~ 8 nm at T = 0.

  4. Molecular physiology of vesicular glutamate transporters in the digestive system.

    PubMed

    Li, Tao; Ghishan, Fayez-K; Bai, Liqun

    2005-03-28

    Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Packaging and storage of glutamate into glutamatergic neuronal vesicles require ATP-dependent vesicular glutamate uptake systems, which utilize the electrochemical proton gradient as a driving force. Three vesicular glutamate transporters (VGLUT1-3) have been recently identified from neuronal tissue where they play a key role to maintain the vesicular glutamate level. Recently, it has been demonstrated that glutamate signaling is also functional in peripheral neuronal and non-neuronal tissues, and occurs in sites of pituitary, adrenal, pineal glands, bone, GI tract, pancreas, skin, and testis. The glutamate receptors and VGLUTs in digestive system have been found in both neuronal and endocrinal cells. The glutamate signaling in the digestive system may have significant relevance to diabetes and GI tract motility disorders. This review will focus on the most recent update of molecular physiology of digestive VGLUTs.

  5. Pulsed Laser-Assisted Focused Electron-Beam-Induced Etching of Titanium with XeF 2 : Enhanced Reaction Rate and Precursor Transport

    SciTech Connect

    Noh, J. H.; Fowlkes, J. D.; Timilsina, R.; Stanford, M. G.; Lewis, B. B.; Rack, P. D.

    2015-01-28

    We introduce a laser-assisted focused electron-beam-induced etching (LA-FEBIE) process which is a versatile, direct write nanofabrication method that allows nanoscale patterning and editing; we do this in order to enhance the etch rate of electron-beam-induced etching. The results demonstrate that the titanium electron stimulated etch rate via the XeF2 precursor can be enhanced up to a factor of 6 times with an intermittent pulsed laser assist. Moreover, the evolution of the etching process is correlated to in situ stage current measurements and scanning electron micrographs as a function of time. Finally, the increased etch rate is attributed to photothermally enhanced Ti–F reaction and TiF4 desorption and in some regimes enhanced XeF2 surface diffusion to the reaction zone.

  6. Pulsed Laser-Assisted Focused Electron-Beam-Induced Etching of Titanium with XeF 2 : Enhanced Reaction Rate and Precursor Transport

    DOE PAGES

    Noh, J. H.; Fowlkes, J. D.; Timilsina, R.; ...

    2015-01-28

    We introduce a laser-assisted focused electron-beam-induced etching (LA-FEBIE) process which is a versatile, direct write nanofabrication method that allows nanoscale patterning and editing; we do this in order to enhance the etch rate of electron-beam-induced etching. The results demonstrate that the titanium electron stimulated etch rate via the XeF2 precursor can be enhanced up to a factor of 6 times with an intermittent pulsed laser assist. Moreover, the evolution of the etching process is correlated to in situ stage current measurements and scanning electron micrographs as a function of time. Finally, the increased etch rate is attributed to photothermally enhancedmore » Ti–F reaction and TiF4 desorption and in some regimes enhanced XeF2 surface diffusion to the reaction zone.« less

  7. Pulsed laser-assisted focused electron-beam-induced etching of titanium with XeF2: enhanced reaction rate and precursor transport.

    PubMed

    Noh, J H; Fowlkes, J D; Timilsina, R; Stanford, M G; Lewis, B B; Rack, P D

    2015-02-25

    In order to enhance the etch rate of electron-beam-induced etching, we introduce a laser-assisted focused electron-beam-induced etching (LA-FEBIE) process which is a versatile, direct write nanofabrication method that allows nanoscale patterning and editing. The results demonstrate that the titanium electron stimulated etch rate via the XeF2 precursor can be enhanced up to a factor of 6 times with an intermittent pulsed laser assist. The evolution of the etching process is correlated to in situ stage current measurements and scanning electron micrographs as a function of time. The increased etch rate is attributed to photothermally enhanced Ti-F reaction and TiF4 desorption and in some regimes enhanced XeF2 surface diffusion to the reaction zone.

  8. Transport Phenomena.

    ERIC Educational Resources Information Center

    McCready, Mark J.; Leighton, David T.

    1987-01-01

    Discusses the problems created in graduate chemical engineering programs when students enter with a wide diversity of understandings of transport phenomena. Describes a two-semester graduate transport course sequence at the University of Notre Dame which focuses on fluid mechanics and heat and mass transfer. (TW)

  9. Transport Phenomena.

    ERIC Educational Resources Information Center

    McCready, Mark J.; Leighton, David T.

    1987-01-01

    Discusses the problems created in graduate chemical engineering programs when students enter with a wide diversity of understandings of transport phenomena. Describes a two-semester graduate transport course sequence at the University of Notre Dame which focuses on fluid mechanics and heat and mass transfer. (TW)

  10. SLC1 Glutamate Transporters

    PubMed Central

    Grewer, Christof; Gameiro, Armanda; Rauen, Thomas

    2014-01-01

    The plasma membrane transporters for the neurotransmitter glutamate belong to the solute carrier 1 (SLC1) family. They are secondary active transporters, taking up glutamate into the cell against a substantial concentration gradient. The driving force for concentrative uptake is provided by the cotransport of Na+ ions and the countertransport of one K+ in a step independent of the glutamate translocation step. Due to eletrogenicity of transport, the transmembrane potential can also act as a driving force. Glutamate transporters are expressed in many tissues, but are of particular importance in the brain, where they contribute to the termination of excitatory neurotransmission. Glutamate transporters can also run in reverse, resulting in glutamate release from cells. Due to these important physiological functions, glutamate transporter expression and, therefore, the transport rate, are tightly regulated. This review summarizes recent literature on the functional and biophysical properties, structure-function relationships, regulation, physiological significance, and pharmacology of glutamate transporters. Particular emphasis is on the insight from rapid kinetic and electrophysiological studies, transcriptional regulation of transporter expression, and reverse transport and its importance for pathophysiological glutamate release under ischemic conditions. PMID:24240778

  11. Recent progress and challenges in nanotechnology for biomedical applications: an insight into the analysis of neurotransmitters.

    PubMed

    Shankaran, Dhesingh Ravi; Miura, Norio

    2007-01-01

    Nanotechnology offers exciting opportunities and unprecedented compatibilities in manipulating chemical and biological materials at the atomic or molecular scale for the development of novel functional materials with enhanced capabilities. It plays a central role in the recent technological advances in biomedical technology, especially in the areas of disease diagnosis, drug design and drug delivery. In this review, we present the recent trend and challenges in the development of nanomaterials for biomedical applications with a special emphasis on the analysis of neurotransmitters. Neurotransmitters are the chemical messengers which transform information and signals all over the body. They play prime role in functioning of the central nervous system (CNS) and governs most of the metabolic functions including movement, pleasure, pain, mood, emotion, thinking, digestion, sleep, addiction, fear, anxiety and depression. Thus, development of high-performance and user-friendly analytical methods for ultra-sensitive detection of neurotransmitters remain a major challenge in modern biomedical analysis. Nanostructured materials are emerging as a powerful mean for diagnosis of CNS disorders because of their unique optical, size and surface characteristics. This review provides a brief outline on the basic concepts and recent advancements of nanotechnology for biomedical applications, especially in the analysis of neurotransmitters. A brief introduction to the nanomaterials, bionanotechnology and neurotransmitters is also included along with discussions on most of the patents published in these areas.

  12. Pharmacogenomics in psychiatry: the relevance of receptor and transporter polymorphisms.

    PubMed

    Reynolds, Gavin P; McGowan, Olga O; Dalton, Caroline F

    2014-04-01

    The treatment of severe mental illness, and of psychiatric disorders in general, is limited in its efficacy and tolerability. There appear to be substantial interindividual differences in response to psychiatric drug treatments that are generally far greater than the differences between individual drugs; likewise, the occurrence of adverse effects also varies profoundly between individuals. These differences are thought to reflect, at least in part, genetic variability. The action of psychiatric drugs primarily involves effects on synaptic neurotransmission; the genes for neurotransmitter receptors and transporters have provided strong candidates in pharmacogenetic research in psychiatry. This paper reviews some aspects of the pharmacogenetics of neurotransmitter receptors and transporters in the treatment of psychiatric disorders. A focus on serotonin, catecholamines and amino acid transmitter systems reflects the direction of research efforts, while relevant results from some genome-wide association studies are also presented. There are many inconsistencies, particularly between candidate gene and genome-wide association studies. However, some consistency is seen in candidate gene studies supporting established pharmacological mechanisms of antipsychotic and antidepressant response with associations of functional genetic polymorphisms in, respectively, the dopamine D2 receptor and serotonin transporter and receptors. More recently identified effects of genes related to amino acid neurotransmission on the outcome of treatment of schizophrenia, bipolar illness or depression reflect the growing understanding of the roles of glutamate and γ-aminobutyric acid dysfunction in severe mental illness. A complete understanding of psychiatric pharmacogenomics will also need to take into account epigenetic factors, such as DNA methylation, that influence individual responses to drugs.

  13. Pharmacogenomics in psychiatry: the relevance of receptor and transporter polymorphisms

    PubMed Central

    Reynolds, Gavin P; McGowan, Olga O; Dalton, Caroline F

    2014-01-01

    The treatment of severe mental illness, and of psychiatric disorders in general, is limited in its efficacy and tolerability. There appear to be substantial interindividual differences in response to psychiatric drug treatments that are generally far greater than the differences between individual drugs; likewise, the occurrence of adverse effects also varies profoundly between individuals. These differences are thought to reflect, at least in part, genetic variability. The action of psychiatric drugs primarily involves effects on synaptic neurotransmission; the genes for neurotransmitter receptors and transporters have provided strong candidates in pharmacogenetic research in psychiatry. This paper reviews some aspects of the pharmacogenetics of neurotransmitter receptors and transporters in the treatment of psychiatric disorders. A focus on serotonin, catecholamines and amino acid transmitter systems reflects the direction of research efforts, while relevant results from some genome-wide association studies are also presented. There are many inconsistencies, particularly between candidate gene and genome-wide association studies. However, some consistency is seen in candidate gene studies supporting established pharmacological mechanisms of antipsychotic and antidepressant response with associations of functional genetic polymorphisms in, respectively, the dopamine D2 receptor and serotonin transporter and receptors. More recently identified effects of genes related to amino acid neurotransmission on the outcome of treatment of schizophrenia, bipolar illness or depression reflect the growing understanding of the roles of glutamate and γ-aminobutyric acid dysfunction in severe mental illness. A complete understanding of psychiatric pharmacogenomics will also need to take into account epigenetic factors, such as DNA methylation, that influence individual responses to drugs. PMID:24354796

  14. Frontal cortex and hippocampus neurotransmitter receptor complex level parallels spatial memory performance in the radial arm maze.

    PubMed

    Shanmugasundaram, Bharanidharan; Sase, Ajinkya; Miklosi, András G; Sialana, Fernando J; Subramaniyan, Saraswathi; Aher, Yogesh D; Gröger, Marion; Höger, Harald; Bennett, Keiryn L; Lubec, Gert

    2015-08-01

    Several neurotransmitter receptors have been proposed to be involved in memory formation. However, information on receptor complexes (RCs) in the radial arm maze (RAM) is missing. It was therefore the aim of this study to determine major neurotransmitter RCs levels that are modulated by RAM training because receptors are known to work in homo-or heteromeric assemblies. Immediate early gene Arc expression was determined by immunohistochemistry to show if prefrontal cortices (PFC) and hippocampi were activated following RAM training as these regions are known to be mainly implicated in spatial memory. Twelve rats per group, trained and untrained in the twelve arm RAM were used, frontal cortices and hippocampi were taken, RCs in membrane protein were quantified by blue-native PAGE immunoblotting. RCs components were characterised by co-immunoprecipitation followed by mass spectrometrical analysis and by the use of the proximity ligation assay. Arc expression was significantly higher in PFC of trained as compared to untrained rats whereas it was comparable in hippocampi. Frontal cortical levels of RCs containing AMPA receptors GluA1, GluA2, NMDA receptors GluN1 and GluN2A, dopamine receptor D1, acetylcholine nicotinic receptor alpha 7 (nAChR-α7) and hippocampal levels of RCs containing D1, GluN1, GluN2B and nAChR-α7 were increased in the trained group; phosphorylated dopamine transporter levels were decreased in the trained group. D1 and GluN1 receptors were shown to be in the same complex. Taken together, distinct RCs were paralleling performance in the RAM which is relevant for interpretation of previous and design of future work on RCs in memory studies.

  15. Hindbrain lactostasis regulates hypothalamic AMPK activity and metabolic neurotransmitter mRNA and protein responses to hypoglycemia.

    PubMed

    Gujar, Amit D; Ibrahim, Baher A; Tamrakar, Pratistha; Cherian, Ajeesh Koshy; Briski, Karen P

    2014-04-01

    Nerve cell metabolic activity is monitored in multiple brain regions, including the hypothalamus and hindbrain dorsal vagal complex (DVC), but it is unclear if individual metabolosensory loci operate autonomously or interact to coordinate central nervous system (CNS) reactivity to energy imbalance. This research addressed the hypothesis that hypoglycemia-associated DVC lactoprivation stimulates hypothalamic AMPK activity and metabolic neurotransmitter expression. As DVC catecholaminergic neurons express biomarkers for metabolic monitoring, we investigated whether these cells are a source of lactate deficit signaling to the hypothalamus. Caudal fourth ventricle (CV4) infusion of the glucose metabolite l-lactate during insulin-induced hypoglycemia reversed changes in DVC A2 noradrenergic, arcuate neuropeptide Y (NPY) and pro-opiomelanocortin (POMC), and lateral hypothalamic orexin-A (ORX) neuronal AMPK activity, coincident with exacerbation of hypoglycemia. Hindbrain lactate repletion also blunted hypoglycemic upregulation of arcuate NPY mRNA and protein. This treatment did not alter hypoglycemic paraventricular oxytocin (OT) and lateral hypothalamic ORX mRNA profiles, but exacerbated or reversed adjustments in OT and ORX neuropeptide synthesis, respectively. CV4 delivery of the monocarboxylate transporter inhibitor, 4-CIN, increased A2 phosphoAMPK (pAMPK), elevated circulating glucose, and stimulated feeding, responses that were attenuated by 6-hydroxydopamine pretreatment. 4-CIN-infused rats exhibited increased (NPY, ORX neurons) or decreased (POMC neurons) pAMPK concurrent with hyperglycemia. These data show that hindbrain lactoprivic signaling regulates hypothalamic AMPK and key effector neurotransmitter responses to hypoglycemia. Evidence that A2 AMPK activity is lactate-dependent, and that DVC catecholamine cells are critical for lactoprivic control of glucose, feeding, and hypothalamic AMPK, implies A2 derivation of this metabolic regulatory stimulus.

  16. Decomposing the profile of PM in two low polluted German cities--mapping of air mass residence time, focusing on potential long range transport impacts.

    PubMed

    Dimitriou, Konstantinos; Kassomenos, Pavlos

    2014-07-01

    This paper aims to decompose the profile of particulates in Karlsruhe and Potsdam (Germany), focusing on the localization of PM potential transboundary sources. An air mass cluster analysis was implemented, followed by a study of air mass residence time on a grid of a 0.5° × 0.5° resolution. Particulate/gaseous daily air pollution and meteorological data were used to indicate PM local sources. Four Principal Component Analysis (PCA) components were produced: traffic, photochemical, industrial/domestic and particulate. PM2.5/PM10 ratio seasonal trends, indicated production of PMCOARSE (PM10-PM2.5) from secondary sources in Potsdam during warm period (WP). The residing areas of incoming slow moving air masses are potential transboundary PM sources. For Karlsruhe those areas were mainly around the city. An air mass residence time secondary peak was observed over Stuttgart. For Potsdam, areas with increased dwelling time of the arriving air parcels were detected particularly above E/SE Germany.

  17. Optical, physical and chemical properties of aerosols transported to a coastal site in the western Mediterranean: a focus on primary marine aerosols

    NASA Astrophysics Data System (ADS)

    Claeys, Marine; Roberts, Greg; Mallet, Marc; Arndt, Jovanna; Sellegri, Karine; Sciare, Jean; Wenger, John; Sauvage, Bastien

    2017-06-01

    calculated during the PMA period, with maximum values up to -40 W m-2 at the surface. A similar range of values were found for the BBP period to those during the dust period (SW DRF at the surface and TOA of -23 ± 6 and -15 ± 4 W m-2 respectively). The multiple sources of measurements at Ersa allowed the detection of a PMA-dominant period and their characterisation in terms of ageing, origin, transport, optical and physical properties and direct climatic impact.

  18. Transverse field focused system

    DOEpatents

    Anderson, Oscar A.

    1986-01-01

    A transverse field focused (TFF) system for transport or acceleration of an intense sheet beam of negative ions in which a serial arrangement of a plurality of pairs of concentric cylindrical-arc electrodes is provided. Acceleration of the sheet beam can be achieved by progressively increasing the mean electrode voltage of successive electrode pairs. Because the beam is curved by the electrodes, the system can be designed to transport the beam through a maze passage which is baffled to prevent line of sight therethrough. Edge containment of the beam can be achieved by shaping the side edges of the electrodes to produce an electric force vector directed inwardly from the electrode edges.

  19. The structure and function of the dopamine transporter and its role in CNS diseases.

    PubMed

    McHugh, Patrick C; Buckley, David A

    2015-01-01

    In this chapter, we explore the basic science of the dopamine transporter (DAT), an integral component of a system that regulates dopamine homeostasis. Dopamine is a key neurotransmitter for several brain functions including locomotor control and reward systems. The transporter structure, function, mechanism of action, localization, and distribution, in addition to gene regulation, are discussed. Over many years, a wealth of information concerning the DAT has been accrued and has led to increased interest in the role of the DAT in a plethora of central nervous system diseases. These DAT characteristics are explored in relation to a range of neurological and neuropsychiatric diseases, with a particular focus on the genetics of the DAT. In addition, we discuss the pharmacology of the DAT and how this relates to disease and addiction. © 2015 Elsevier Inc. All rights reserved.

  20. Tsunami focusing

    NASA Astrophysics Data System (ADS)

    Spillane, M. C.; Titov, V. V.; Moore, C. W.; Aydin, B.; Kanoglu, U.; Synolakis, C. E.

    2010-12-01

    Tsunamis are long waves generated by impulsive disturbances of the seafloor or coastal topography caused by earthquakes, submarine/subaerial mass failures. They evolve substantially through three dimensional - 2 spatial+1 temporal - spreading as the initial surface deformation propagates. This is referred to as its directivity and focusing. A directivity function was first defined by Ben-Menahem (1961, Bull. Seismol. Soc. Am. 51, 401-435) using the source length and the rupture velocity. Okal (2003, Pure Appl. Geophys. 160, 2189-2221) discussed the details of the analysis of Ben-Menahem (1961) and demonstrated the distinct difference between the directivity patterns of landslide and earthquake generated tsunamis. Marchuk and Titov (1989, Proc. IUGG/IOC International Tsunami Symposium, July 31 - August 3, 1989, Novosibirsk, USSR. p.11-17) described the process of tsunami focusing for a rectangular initial deformation combining positive and negative surface displacements. They showed the existence of a focusing point where abnormal tsunami wave height can be registered. Here, first, we describe and quantify numerically tsunami focusing processes for a combined positive and negative - N-wave type - strip source representing the 17 July 1998 Papua New Guinea and 17 July 2006 Java events. Specifically, considering field observations and tsunami focusing, we propose a source mechanism for the 17 July 2006 Java event. Then, we introduce a new analytical solution for a strip source propagating over a flat bottom using the linear shallow-water wave equation. The analytical solution of Carrier and Yeh (2005, Computer Modeling In Engineering & Sciences, 10(2), 113-121) appears to have two drawbacks. One, the solution involves singular complete elliptic integral of the first kind which results in a self-similar approximate solution for the far-field at large times. Two, only the propagation of Gaussian shaped finite-crest wave profiles can be modeled. Our solution is not only

  1. Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala.

    PubMed

    Du, Jianyang; Reznikov, Leah R; Price, Margaret P; Zha, Xiang-ming; Lu, Yuan; Moninger, Thomas O; Wemmie, John A; Welsh, Michael J

    2014-06-17

    Stimulating presynaptic terminals can increase the proton concentration in synapses. Potential receptors for protons are acid-sensing ion channels (ASICs), Na(+)- and Ca(2+)-permeable channels that are activated by extracellular acidosis. Those observations suggest that protons might be a neurotransmitter. We found that presynaptic stimulation transiently reduced extracellular pH in the amygdala. The protons activated ASICs in lateral amygdala pyramidal neurons, generating excitatory postsynaptic currents. Moreover, both protons and ASICs were required for synaptic plasticity in lateral amygdala neurons. The results identify protons as a neurotransmitter, and they establish ASICs as the postsynaptic receptor. They also indicate that protons and ASICs are a neurotransmitter/receptor pair critical for amygdala-dependent learning and memory.

  2. Temperature affects the development of central neurotransmitter systems of tilapia, Oreochromis mossambicus.

    PubMed

    Wang, L H; Tsai, C L

    2000-05-12

    The effects of temperature on the development of central neurotransmitter systems were investigated with tilapia, Oreochromis mossambicus. Zero-day-old (the hatching day) tilapia were kept at four different temperatures: 20 (lower), 24 (control), and 28 and 32 degrees C (elevated), respectively. On the 5th day, brain serotonin (5-HT), norepinephrine (NE), gamma-aminobutyric acid (GABA), and glutamate (Glu) contents were quantified by a high-performance liquid chromatograph with electrochemical detection. Similar experiments were performed on the 5-, 10-, 15-, 20-, and 25-day-olds. The results showed that aquatic temperature influenced brain 5-HT, NE, Glu, and GABA contents during its respective restricted period. The influence of both lower and elevated temperatures on the neurotransmitter content, either increasing or suppressing, is dependent on its developing stage. The facts provide an evidence that the development of central neurotransmitter systems is influenced by aquatic temperature during its specific effective period.

  3. Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala

    PubMed Central

    Du, Jianyang; Reznikov, Leah R.; Price, Margaret P.; Zha, Xiang-ming; Lu, Yuan; Moninger, Thomas O.; Wemmie, John A.; Welsh, Michael J.

    2014-01-01

    Stimulating presynaptic terminals can increase the proton concentration in synapses. Potential receptors for protons are acid-sensing ion channels (ASICs), Na+- and Ca2+-permeable channels that are activated by extracellular acidosis. Those observations suggest that protons might be a neurotransmitter. We found that presynaptic stimulation transiently reduced extracellular pH in the amygdala. The protons activated ASICs in lateral amygdala pyramidal neurons, generating excitatory postsynaptic currents. Moreover, both protons and ASICs were required for synaptic plasticity in lateral amygdala neurons. The results identify protons as a neurotransmitter, and they establish ASICs as the postsynaptic receptor. They also indicate that protons and ASICs are a neurotransmitter/receptor pair critical for amygdala-dependent learning and memory. PMID:24889629

  4. Convergent Pathways for Steroid Hormone-and Neurotransmitter-Induced Rat Sexual Behavior

    NASA Astrophysics Data System (ADS)

    Mani, S. K.; Allen, J. M. C.; Clark, J. H.; Blaustein, J. D.; O'Malley, B. W.

    1994-08-01

    Estrogen and progesterone modulate gene expression in rodents by activation of intracellular receptors in the hypothalamus, which regulate neuronal networks that control female sexual behavior. However, the neurotransmitter dopamine has been shown to activate certain steroid receptors in a ligand-independent manner. A dopamine receptor stimulant and a D_1 receptor agonist, but not a D_2 receptor agonist, mimicked the effects of progesterone in facilitating sexual behavior in female rats. The facilitatory effect of the neurotransmitter was blocked by progesterone receptor antagonists, a D_1 receptor antagonist, or antisense oligonucleotides to the progesterone receptor. The results suggest that in rodents neurotransmitters may regulate in vivo gene expression and behavior by means of cross-talk with steroid receptors in the brain.

  5. Neurotransmitter Specific, Cellular-Resolution Functional Brain Mapping Using Receptor Coated Nanoparticles: Assessment of the Possibility

    PubMed Central

    Forati, Ebrahim; Sabouni, Abas; Ray, Supriyo; Head, Brian; Schoen, Christian; Sievenpiper, Dan

    2015-01-01

    Receptor coated resonant nanoparticles and quantum dots are proposed to provide a cellular-level resolution image of neural activities inside the brain. The functionalized nanoparticles and quantum dots in this approach will selectively bind to different neurotransmitters in the extra-synaptic regions of neurons. This allows us to detect neural activities in real time by monitoring the nanoparticles and quantum dots optically. Gold nanoparticles (GNPs) with two different geometries (sphere and rod) and quantum dots (QDs) with different sizes were studied along with three different neurotransmitters: dopamine, gamma-Aminobutyric acid (GABA), and glycine. The absorption/emission spectra of GNPs and QDs before and after binding of neurotransmitters and their corresponding receptors are reported. The results using QDs and nanorods with diameter 25nm and aspect rations larger than three were promising for the development of the proposed functional brain mapping approach. PMID:26717196

  6. Neurotransmitters and motor activity: effects on functional recovery after brain injury.

    PubMed

    Goldstein, Larry B

    2006-10-01

    There are complex relationships among behavioral experience, brain morphology, and functional recovery of an animal before and after brain injury. A large series of experimental studies have shown that exogenous manipulation of central neurotransmitter levels can directly affect plastic changes in the brain and can modulate the effects of experience and training. These complex relationships provide a formidable challenge for studies aimed at understanding neurotransmitter effects on the recovery process. Experiments delineating norepinephrine-modulated locomotor recovery after injury to the cerebral cortex illustrate the close relationships among neurotransmitter levels, brain plasticity, and behavioral recovery. Understanding the neurobiological processes underlying recovery, and how they might be manipulated, may lead to novel strategies for improving recovery from stroke-related gait impairment in humans.

  7. Differential stimulation of the retina with subretinally injected exogenous neurotransmitter: A biomimetic alternative to electrical stimulation

    NASA Astrophysics Data System (ADS)

    Rountree, Corey M.; Inayat, Samsoon; Troy, John B.; Saggere, Laxman

    2016-12-01

    Subretinal stimulation of the retina with neurotransmitters, the normal means of conveying visual information, is a potentially better alternative to electrical stimulation widely used in current retinal prostheses for treating blindness from photoreceptor degenerative diseases. Yet, no subretinal electrical or chemical stimulation study has stimulated the OFF and ON pathways differentially through inner retinal activation. Here, we demonstrate the feasibility of differentially stimulating retinal ganglion cells (RGCs) through the inner nuclear layer of the retina with glutamate, a primary neurotransmitter chemical, in a biomimetic way. We show that controlled pulsatile delivery of glutamate into the subsurface of explanted wild-type rat retinas elicits highly localized simultaneous inhibitory and excitatory spike rate responses in OFF and ON RGCs. We also present the spatiotemporal characteristics of RGC responses to subretinally injected glutamate and the therapeutic stimulation parameters. Our findings could pave the way for future development of a neurotransmitter-based subretinal prosthesis offering more naturalistic vision and better visual acuity than electrical prostheses.

  8. Monoamine transporters: insights from molecular dynamics simulations

    PubMed Central

    Grouleff, Julie; Ladefoged, Lucy Kate; Koldsø, Heidi; Schiøtt, Birgit

    2015-01-01

    The human monoamine transporters (MATs) facilitate the reuptake of the neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft. Imbalance in monoaminergic neurotransmission is linked to various diseases including major depression, attention deficit hyperactivity disorder, schizophrenia, and Parkinson’s disease. Inhibition of the MATs is thus an important strategy for treatment of such diseases. The MATs are sodium-coupled transport proteins belonging to the neurotransmitter/Na+ symporter (NSS) family, and the publication of the first high-resolution structure of a NSS family member, the bacterial leucine transporter LeuT, in 2005, proved to be a major stepping stone for understanding this family of transporters. Structural data allows for the use of computational methods to study the MATs, which in turn has led to a number of important discoveries. The process of substrate translocation across the membrane is an intrinsically dynamic process. Molecular dynamics simulations, which can provide atomistic details of molecular motion on ns to ms timescales, are therefore well-suited for studying transport processes. In this review, we outline how molecular dynamics simulations have provided insight into the large scale motions associated with transport of the neurotransmitters, as well as the presence of external and internal gates, the coupling between ion and substrate transport, and differences in the conformational changes induced by substrates and inhibitors. PMID:26528185

  9. Adiabatic Focuser

    SciTech Connect

    Chen, P.; Oide, K.; Sessler, Andrew M.; Yu, S.S.

    1989-08-01

    Theoretical analysis is made of an intense relativistic electron beam. such as would be available from a linear collider, moving through a plasma of increasing density, but density always less than that of the beam (underdense). In this situation. the plasma electrons are expelled from the beam channel and the electrons are subject to an ever-increasing focusing force provided by the channel ions. Analysis is made on the beam radiation energy loss in the classical, the transition, and the quantum regimes. It is shown that the focuser is insensitive to the beam energy spread due to radiation loss. Furthermore, because of the different scaling behaviors in the nonclassical regimes, the radiation limit on lenses (the Oide limit) can be exceeded. The sensitivity of the system to the optic mismatch and the nonlinearity is also analyzed. Examples are given with SLC-type and TLC-type parameters.

  10. Neurotransmitter alteration in a testosterone propionate-induced polycystic ovarian syndrome rat model.

    PubMed

    Chaudhari, Nirja K; Nampoothiri, Laxmipriya P

    2017-02-01

    Polycystic ovarian syndrome (PCOS), one of the leading causes of infertility seen in women, is characterized by anovulation and hyperandrogenism, resulting in ovarian dysfunction. In addition, associations of several metabolic complications like insulin resistance, obesity, dyslipidemia and psychological co-morbidities are well known in PCOS. One of the major factors influencing mood and the emotional state of mind is neurotransmitters. Also, these neurotransmitters are very crucial for GnRH release. Hence, the current study investigates the status of neurotransmitters in PCOS. A PCOS rat model was developed using testosterone. Twenty-one-day-old rats were subcutaneously injected with 10 mg/kg body weight of testosterone propionate (TP) for 35 days. The animals were validated for PCOS characteristics by monitoring estrus cyclicity, serum testosterone and estradiol levels and by histological examination of ovarian sections. Neurotransmitter estimation was carried out using fluorometric and spectrophotometric methods. TP-treated animals demonstrated increased serum testosterone levels with unaltered estradiol content, disturbed estrus cyclicity and many peripheral cysts in the ovary compared to control rats mimicking human PCOS. Norepinephrine (NE), dopamine, serotonin, γ-amino butyric acid (GABA) and epinephrine levels were significantly low in TP-induced PCOS rats compared to control ones, whereas the activity of acetylcholinesterase in the PCOS brain was markedly elevated. Neurotransmitter alteration could be one of the reasons for disturbed gonadotropin-releasing hormone (GnRH) release, consequently directing the ovarian dysfunction in PCOS. Also, decrease in neurotransmitters, mainly NE, serotonin and dopamine (DA) attributes to mood disorders like depression and anxiety in PCOS.

  11. Neurotransmitter signaling through heterotrimeric G proteins: insights from studies in C. elegans

    PubMed Central

    Koelle, Michael R.

    2016-01-01

    Neurotransmitters signal via G protein coupled receptors (GPCRs) to modulate activity of neurons and muscles. C. elegans has ~150 G protein coupled neuropeptide receptor homologs and 28 additional GPCRs for small-molecule neurotransmitters. Genetic studies in C. elegans demonstrate that neurotransmitters diffuse far from their release sites to activate GPCRs on distant cells. Individual receptor types are expressed on limited numbers of cells and thus can provide very specific regulation of an individual neural circuit and behavior. G protein coupled neurotransmitter receptors signal principally via the three types of heterotrimeric G proteins defined by the G alpha subunits Gαo, Gαq, and Gαs. Each of these G alpha proteins is found in all neurons plus some muscles. Gαo and Gαq signaling inhibit and activate neurotransmitter release, respectively. Gαs signaling, like Gαq signaling, promotes neurotransmitter release. Many details of the signaling mechanisms downstream of Gαq and Gαs have been delineated and are consistent with those of their mammalian orthologs. The details of the signaling mechanism downstream of Gαo remain a mystery. Forward genetic screens in C. elegans have identified new molecular components of neural G protein signaling mechanisms, including Regulators of G protein Signaling (RGS proteins) that inhibit signaling, a new Gαq effector (the Trio RhoGEF domain), and the RIC-8 protein that is required for neuronal Gα signaling. A model is presented in which G proteins sum up the variety of neuromodulator signals that impinge on a neuron to calculate its appropriate output level. PMID:26937633

  12. GABA Not Only a Neurotransmitter: Osmotic Regulation by GABAAR Signaling

    PubMed Central

    Cesetti, Tiziana; Ciccolini, Francesca; Li, Yuting

    2012-01-01

    Mature macroglia and almost all neural progenitor types express γ-aminobutyric (GABA) A receptors (GABAARs), whose activation by ambient or synaptic GABA, leads to influx or efflux of chloride (Cl−) depending on its electro-chemical gradient (ECl). Since the flux of Cl− is indissolubly associated to that of osmotically obliged water, GABAARs regulate water movements by modulating ion gradients. In addition, since water movements also occur through specialized water channels and transporters, GABAAR signaling could affect the movement of water by regulating the function of the channels and transporters involved, thereby affecting not only the direction of the water fluxes but also their dynamics. We will here review recent observations indicating that in neural cells GABAAR-mediated osmotic regulation affects the cellular volume thereby activating multiple intracellular signaling mechanisms important for cell proliferation, maturation, and survival. In addition, we will discuss evidence that the osmotic regulation exerted by GABA may contribute to brain water homeostasis in physiological and in pathological conditions causing brain edema, in which the GABAergic transmission is often altered. PMID:22319472

  13. Wide-range, picoampere-sensitivity multichannel VLSI potentiostat for neurotransmitter sensing.

    PubMed

    Murari, Kartikeya; Thakor, Nitish; Stanacevic, Milutin; Cauwenberghs, Gert

    2004-01-01

    Neurotransmitter sensing is critical in studying nervous pathways and neurological disorders. A 16-channel current-measuring VLSI potentiostat with multiple ranges from picoamperes to microamperes is presented for electrochemical detection of electroactive neurotransmitters like dopamine, nitric oxide etc. The analog-to-digital converter design employs a current-mode, first-order single-bit delta-sigma modulator architecture with a two-stage, digitally reconfigurable oversampling ratio for ranging the conversion scale. An integrated prototype is fabricated in CMOS technology, and experimentally characterized. Real-time multi-channel acquisition of dopamine concentration in vitro is performed with a microfabricated sensor array.

  14. Effect of Cassava on motor co-ordination and neurotransmitter level in the albino rat.

    PubMed

    Mathangi, D C; Mohan, V; Namasivayam, A

    1999-01-01

    The root of Cassava, a tropical plant, is consumed in the tropics and has been attributed as the cause for various tropical neuropathies. This study aims to discover the neurotoxic effects of chronic cassava consumption of Indian origin and the effect of malnutrition. The assessment is based on the motor co-ordination and brain neurotransmitters in rats. Cassava consumption reduced the motor co-ordination, but the changes in neurotransmitter levels due to cassava consumption (except for 5HT in corpus striatum) was identical with malnutrition-induced changes, indicating that the toxicity of chronic cassava consumption (of Indian origin) is mainly due to the associated protein calorie malnutrition (PCM).

  15. A practical guide to the synthesis of dinitroindolinyl-caged neurotransmitters

    PubMed Central

    Ellis-Davies, Graham C R

    2014-01-01

    This protocol describes a method for efficient chemical synthesis of dinitroindolinyl derivatives of glutamate and gamma-aminobutyric acid. these caged neurotransmitters are currently the most chemically and photochemically efficient probes for two-photon photolysis in living brain slices. the protocol only requires basic organic synthesis equipment, and no silica gel column chromatography or NMR spectroscopy is needed at any stage. Hplc is used to purify the caged transmitters at the end of the syntheses. thus, the synthesis of dinitroindolinyl-caged neurotransmitters is within the scope of a modestly equipped chemistry laboratory. PMID:21372812

  16. Maritime Intelligent Transport Systems

    NASA Astrophysics Data System (ADS)

    Pietrzykowski, Zbigniew

    The concept of intelligent transport systems, developed since 1980s, includes all modes of transport. Relevant developments in road transport are the most advanced. Recently water transport, particularly maritime transport, has gained more attention in this respect, in connection with building and further developments of maritime intelligent transport systems. The present state and directions of development of telematic systems in maritime transport will be discussed, with a focus on marine navigation.

  17. Regulatory role of intracellular sodium ions in neurotransmitter secretion.

    PubMed

    Melinek, R; Lev-Tov, A; Meiri, H; Erulkar, S D; Rahamimoff, R

    1982-01-01

    Calcium ions are the main inducer of quantal transmitter release of the frog neuromuscular junction; but even in their virtual absence from the extracellular medium, nerve stimulation causes a prolonged augmentation of transmitter release. These facts led to the hypothesis that an accumulation of intracellular sodium can serve as a slow secondary regulator of neurosecretion. Three lines of evidence presented in this article substantiate this hypothesis: firstly, veratridine, which is known to increase sodium fluxes through the voltage-dependent sodium channels, increases transmitter release after nerve stimulation. Secondly, monensin, which was shown to induce sodium transport through nerve membranes, increases evoked transmitter release, tetanic potentiation and posttetanic potentiation. Thirdly, sodium-filled phosphatidylcholine liposomes increase transmitter release. These effects of sodium are probably not due to a direct effect on the transmitter release mechanism, but are caused by sodium-induced calcium translocation from intracellular stores.

  18. Electrophoretic Focusing

    NASA Technical Reports Server (NTRS)

    Snyder, Robert S.

    2001-01-01

    Electrophoretic focusing is a new method of continuous flow electrophoresis that introduces precision flow control to achieve high resolution separations. The electric field is applied perpendicular to an incoming sample lamina and buffer but also perpendicular to the broad faces of the thin rectangular chamber. A uniform fluid cross-flow then enters and exits the separation chamber through the same broad faces which are porous. A balance is achieved by adjusting either the electric field or the cross-flow so the desired sample fraction with its specific migration velocity encounters an opposing flow of the same velocity. Applying an electric field transverse to the incoming sample lamina and opposing this field with a carefully configured buffer flow, a sample constituent can be selected and focused into a narrow stream for subsequent analysis. Monotonically changing either electric field or buffer cross-flow will yield a scan of all constituents of the sample. Stopping the scan increases the collection time for minor constituents to improve their analysis. Using the high voltage gradients and/or cross-flow to rapidly deflect extraneous sample through the porous screens and into either of the side (purge) chambers, the selected sample is focused in the center plane of the separation chamber and collected without contact or interaction with the separation chamber walls. Results will be presented on the separation of a range of materials including dyes, proteins, and monodisperse polystyrene latexes. Sources of sample dispersion inherent in other electrokinetic techniques will be shown to be negligible for a variety of sample concentrations, buffer properties and operating conditions.

  19. Molecular basis of essential amino acid transport from studies of insect nutrient amino acid transporters of the SLC6 family (NAT-SLC6)

    PubMed Central

    Boudko, Dmitri Y.

    2012-01-01

    Two protein families that represent major components of essential amino acid transport in insects have been identified. They are annotated as the SLC6 and SLC7 families of transporters according to phylogenetic proximity to characterized amino acid transporters (HUGO nomenclature). Members of these families have been identified as important apical and basolateral parts of transepithelial essential amino acid absorption in the metazoan alimentary canal. Synergistically, they play critical physiological roles as essential substrate providers to diverse metabolic processes, including generic protein synthesis. This review briefly clarifies the requirements for amino acid transport and a variety of amino acid transport mechanisms, including the aforementioned families. Further it focuses on the large group of Nutrient Amino acid Transporters (NATs), which comprise a recently identified subfamily of the Neurotransmitter Sodium Symporter family (NSS or SLC6). The first insect NAT, cloned from the caterpillar gut, has a broad substrate spectrum similar to mammalian B0 transporters. Several new NAT-SLC6 members have been characterized in an effort to explore mechanisms for the essential amino acid absorption in model dipteran insects. The identification and functional characterization of new B0-like and narrow specificity transporters of essential amino acids in fruit fly and mosquitoes leads to a fundamentally important insight: that NATs evolved and act together as the integrated active core of a transport network that mediates active alimentary absorption and systemic distribution of essential amino acids. This role of NATs is projected from the most primitive prokaryotes to the most complex metazoan organisms, and represents an interesting platform for unraveling the molecular evolution of amino acid transport and modeling amino acid transport disorders. The comparative study of NATs elucidates important adaptive differences between essential amino acid transportomes

  20. Cannabinoids: influence on neurotransmitter uptake in rat brain synaptosomes.

    PubMed

    Banerjee, S P; Snyder, S H; Mechoulam, R

    1975-07-01

    We have examined the effect of Delta1-tetrahydrocannabinol (delat1-THC) and 12 of its derivatives on the uptake of 3H-labeled norepinephrine (NE), dopamine (DA), serotonin (5-HT) gamma-aminobutyric acid (GABA) into synaptosomes in homogenates of various regions of rat brain. Delta1-THC inhibits the accumulation of NE and 5-HT into hypothalamic preparations and DA into the corpus striatum with Ki values of about 12 to 25 muM while GABA uptake into cerebral cortical preparations is inhibited less (Ki = 140 muM). The affinities of delta6-THC, 7-hydroxy-delta1-THC, 7-hydroxy-delta6-THC and cannabidiol for 5-HT, NE and GABA transports are similar to values for delta1-THC, while cannabigerol, cannabinol and delta6-THC-7-oic acid have substantially less affinity. Thus, hydroxylation of C-7 in delta6-THC does not alter inhibitory potency, but its oxidation to an acid and aromatization of ring A greatly reduce affinity. The hydroxyl at C-3(1) of ring C is critical for inhibition of NE, 5-HT and GABA uptake, since its acetylation or methylation abolishes activity. Inhibition of NE, DA, 5-HT and GABA uptake by all cannabinoids examined is noncompetitive. Only about 1% of delta1-THC and delta6-THC and 5% of cannabidiol are fully soluble under our experimental conditions.

  1. Waterborne lead affects circadian variations of brain neurotransmitters in fathead minnows

    SciTech Connect

    Spieler, R.E.; Russo, A.C.; Weber, D.N.

    1995-09-01

    Lead is a potent neurotoxin affecting brain levels of a number of vertebrate neurotransmitters. Reports on these effects are, however, not consistent either among or within species. For example, with lead-intoxicated rats there are reports of decreased acetylcholine (ACh) release and decreased ACh brain levels as well as reports of increased levels or no change in levels. Also, with rats there are reports of increased levels, decreased levels, or no change in brain catecholamines, with lead producing similar changes in both norephinephrine (NE) and dopamine (DA) in some cases and differences in response between the two in others. Although most early reports dealt with whole brain levels, reports on neurotransmitter levels in specific brain regions can be equally conflicting. Similar sorts of discrepancies exist among studies with fishes. Much of the variation among studies on lead effects on neurotransmitters is, no doubt, due to differences among the studies in variables such as: species, age, dosage and duration, route of administration. However, lead can apparently affect circadian locomotor rhythms of both rats and fishes. Therefore, another possible cause for the variation among studies is that there is an interaction among dosage, sampling time and endogenous rhythms. A lead-produced phase shift or disruption in endogenous neurotransmitter rhythms could in turn elicit a host of varying results and interpretations depending on the circadian time of sampling. We elected to examine this possibility in the fathead minnow, Pimephales promelas, a freshwater species widely used for toxicity studies. 15 refs., 3 figs.

  2. [Analysis of correlation between occupational stress and serum monoamine neurotransmitters in nurses].

    PubMed

    Zhan, Yongguo; Tian, Honger; Zhang, Qingdong; Zhu, Xinyun; Cao, Lili; Su, Jingguo; Xu, Tian; Zhu, Huabin; Liu, Ling

    2014-02-01

    To investigate the impact of occupational stress on serum monoamine neurotransmitters in nurses. A total of 131 nurses were included as study subjects by stratified cluster sampling. The occupational health information collection system (based on the Internet of things) was used to measure occupational stress. Serum levels of monoamine neurotransmitters were also measured. Epinephrine (E) was negatively correlated with superior support (P < 0.05) and colleague support (P < 0.05). Negative correlation was also found between dopamine (DA) and job prospect (P < 0.05). Level of 5-hydroxytryptamine was negatively correlated with promotion opportunities (P < 0.05). Norepinephrine (NE), E, and DA were all negatively correlated with work satisfaction (P < 0.05) and positively correlated with daily stress (P < 0.01). NE and E were negatively correlated with sufficient confidence (P < 0.05) and positively correlated with physical complaints (P < 0.01). There was a negative correlation between NE and psychological satisfaction (P < 0.05). Occupational stress in nurses is correlated with serum monoamine neurotransmitters, and it may affect serum levels of monoamine neurotransmitters to a certain extent.

  3. Ectopic vesicular neurotransmitter release along sensory axons mediates neurovascular coupling via glial calcium signaling.

    PubMed

    Thyssen, Anne; Hirnet, Daniela; Wolburg, Hartwig; Schmalzing, Günther; Deitmer, Joachim W; Lohr, Christian

    2010-08-24

    Neurotransmitter release generally is considered to occur at active zones of synapses, and ectopic release of neurotransmitters has been demonstrated in a few instances. However, the mechanism of ectopic neurotransmitter release is poorly understood. We took advantage of the intimate morphological and functional proximity of olfactory receptor axons and specialized glial cells, olfactory ensheathing cells (OECs), to study ectopic neurotransmitter release. Axonal stimulation evoked purinergic and glutamatergic Ca(2+) responses in OECs, indicating ATP and glutamate release. In axons expressing synapto-pHluorin, stimulation evoked an increase in synapto-pHluorin fluorescence, indicative of vesicle fusion. Transmitter release was dependent on Ca(2+) and could be inhibited by bafilomycin A1 and botulinum toxin A. Ca(2+) transients in OECs evoked by ATP, axonal stimulation, and laser photolysis of NP-EGTA resulted in constriction of adjacent blood vessels. Our results indicate that ATP and glutamate are released ectopically by vesicles along axons and mediate neurovascular coupling via glial Ca(2+) signaling.

  4. Rapid structural alterations of the active zone lead to sustained changes in neurotransmitter release.

    PubMed

    Matz, Jacob; Gilyan, Andrew; Kolar, Annette; McCarvill, Terrence; Krueger, Stefan R

    2010-05-11

    The likelihood with which an action potential elicits neurotransmitter release, the release probability (p(r)), is an important component of synaptic strength. Regulatory mechanisms controlling several steps of synaptic vesicle (SV) exocytosis may affect p(r), yet their relative importance in determining p(r) and eliciting temporal changes in neurotransmitter release at individual synapses is largely unknown. We have investigated whether the size of the active zone cytomatrix is a major determinant of p(r) and whether changes in its size lead to corresponding alterations in neurotransmitter release. We have used a fluorescent sensor of SV exocytosis, synaptophysin-pHluorin, to measure p(r) at individual synapses with high accuracy and employed a fluorescently labeled cytomatrix protein, Bassoon, to quantify the amount of active zone cytomatrix present at these synapses. We find that, for synapses made by a visually identified presynaptic neuron, p(r) is indeed strongly correlated with the amount of active zone cytomatrix present at the presynaptic specialization. Intriguingly, active zone cytomatrices are frequently subject to synapse-specific changes in size on a time scale of minutes. These spontaneous alterations in active zone size are associated with corresponding changes in neurotransmitter release. Our results suggest that the size of the active zone cytomatrix has a large influence on the reliability of synaptic transmission. Furthermore, they implicate mechanisms leading to rapid structural alterations at active zones in synapse-specific forms of plasticity.

  5. Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) for intraoperative neurochemical monitoring.

    PubMed

    Kimble, Christopher J; Johnson, David M; Winter, Bruce A; Whitlock, Sidney V; Kressin, Kenneth R; Horne, April E; Robinson, Justin C; Bledsoe, Jonathan M; Tye, Susannah J; Chang, Su-Youne; Agnesi, Filippo; Griessenauer, Christoph J; Covey, Daniel; Shon, Young-Min; Bennet, Kevin E; Garris, Paul A; Lee, Kendall H

    2009-01-01

    The Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) measures extracellular neurotransmitter concentration in vivo and displays the data graphically in nearly real time. WINCS implements two electroanalytical methods, fast-scan cyclic voltammetry (FSCV) and fixed-potential amperometry (FPA), to measure neurotransmitter concentrations at an electrochemical sensor, typically a carbon-fiber microelectrode. WINCS comprises a battery-powered patient module and a custom software application (WINCSware) running on a nearby personal computer. The patient module impresses upon the electrochemical sensor either a constant potential (for FPA) or a time-varying waveform (for FSCV). A transimpedance amplifier converts the resulting current to a signal that is digitized and transmitted to the base station via a Bluetooth radio link. WINCSware controls the operational parameters for FPA or FSCV, and records the transmitted data stream. Filtered data is displayed in various formats, including a background-subtracted plot of sequential FSCV scans - a representation that enables users to distinguish the signatures of various analytes with considerable specificity. Dopamine, glutamate, adenosine and serotonin were selected as analytes for test trials. Proof-of-principle tests included in vitro flow-injection measurements and in vivo measurements in rat and pig. Further testing demonstrated basic functionality in a 3-Tesla MRI unit. WINCS was designed in compliance with consensus standards for medical electrical device safety, and it is anticipated that its capability for real-time intraoperative monitoring of neurotransmitter release at an implanted sensor will prove useful for advancing functional neurosurgery.

  6. Effect of Curare on Responses to Different Putative Neurotransmitters in Aplysia.

    DTIC Science & Technology

    1976-06-01

    The effects of curare on responses resulting from ionophoretic application of several putative neurotransmitters onto Aplysia neurons were studied...In Aplysia nervous tissue, curare appears to be a specfic blocking agent for a class of receptor-activated Na and Cl responses.

  7. Measuring In Vivo Changes in Extracellular Neurotransmitters During Naturally Rewarding Behaviors in Female Syrian Hamsters.

    PubMed

    Moore, Kelsey M; Himmler, Brett T; Teplitzky, Benjamin A; Johnson, Matthew D; Meisel, Robert L

    2017-09-12

    The ability to measure neurotransmitter release on a rapid time scale allows patterns of neurotransmission to be linked to specific behaviors or manipulations; a powerful tool in elucidating underlying mechanisms and circuitry. While the technique of microdialysis has been used for decades to measure nearly any analyte of interest in the brain, this technique is limited in temporal resolution. Alternatively, fast scan cyclic voltammetry is both temporally precise and extremely sensitive; however, because this technically difficult method relies on the electroactivity of the analyte of interest, the possibility to detect nonelectroactive substances (e.g., the neurotransmitter glutamate) is eliminated. This paper details the use of a turn-key system that combines fixed-potential amperometry and enzymatic biosensing to measure both electroactive and nonelectroactive neurotransmitters with temporal precision. The pairing of these two powerful techniques allows for the measurement of both tonic and phasic neurotransmission with relative ease, and permits recording of multiple neurotransmitters simultaneously. The aim of this manuscript is to demonstrate the process of measuring dopamine and glutamate neurotransmission in vivo using a naturally rewarding behavior (i.e., sexual behavior) in female hamsters, with the ultimate goal of displaying the technical feasibility of this assay for examining other behaviors and experimental paradigms.

  8. Review of recent advances in analytical techniques for the determination of neurotransmitters

    PubMed Central

    Perry, Maura; Li, Qiang; Kennedy, Robert T.

    2009-01-01

    Methods and advances for monitoring neurotransmitters in vivo or for tissue analysis of neurotransmitters over the last five years are reviewed. The review is organized primarily by neurotransmitter type. Transmitter and related compounds may be monitored by either in vivo sampling coupled to analytical methods or implanted sensors. Sampling is primarily performed using microdialysis, but low-flow push-pull perfusion may offer advantages of spatial resolution while minimizing the tissue disruption associated with higher flow rates. Analytical techniques coupled to these sampling methods include liquid chromatography, capillary electrophoresis, enzyme assays, sensors, and mass spectrometry. Methods for the detection of amino acid, monoamine, neuropeptide, acetylcholine, nucleoside, and soluable gas neurotransmitters have been developed and improved upon. Advances in the speed and sensitivity of these methods have enabled improvements in temporal resolution and increased the number of compounds detectable. Similar advances have enabled improved detection at tissue samples, with a substantial emphasis on single cell and other small samples. Sensors provide excellent temporal and spatial resolution for in vivo monitoring. Advances in application to catecholamines, indoleamines, and amino acids have been prominent. Improvements in stability, sensitivity, and selectivity of the sensors have been of paramount interest. PMID:19800472

  9. Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: comorbidity between depression and neurodegenerative disorders.

    PubMed

    Anisman, Hymie; Merali, Zul; Hayley, Shawn

    2008-05-01

    Given the array of biological changes induced by stressors, it is not surprising that these experiences may provoke a variety of illnesses. Among others things, stressors promote functional changes of neuropeptide and classical neurotransmitter systems. The peptidergic changes, for instance, include alterations of corticotropin releasing hormone, arginine vasopressin, and bombesin-like peptides at specific brain sites. Similarly some of the neurotransmitter systems influenced by stressors include GABAergic and monoamine functioning. Variations of these processes may limit neurogenesis (and dysregulation of growth factors such as BDNF) and influence cellular viability (through NFkappaB and MAP kinase pathways). As well, stressors activate the inflammatory immune system, notably the release of signaling molecules (cytokines), which may provoke many of the same neuropeptide (and other neurotransmitter) changes. By virtue of their actions on neuronal functioning, inflammatory processes may influence stress-related illness, such as depression, and may be a common denominator for the comorbidity that exists between depression and neurological conditions, including Parkinson's and Alzheimer's diseases, as well as cardiovascular-related pathology. The present report provides an overview of biological endophenotypes associated with stressors that are thought to be related to major depressive disorder and related comorbid conditions. The view is taken that synergy between stressors and inflammatory factors may promote pathological outcomes through their actions on neuropeptides and several neurotransmitters. As well, stressful events may result in the sensitization of neurochemical and cytokine processes, so that later re-exposure to these stimuli may promote rapid and exaggerated responses that favor illness recurrence.

  10. Mechanism of the association between Na+ binding and conformations at the intracellular gate in neurotransmitter:sodium symporters

    SciTech Connect

    Stolzenberg, Sebastian; Quick, Matthias; Zhao, Chunfeng; Gotfryd, Kamil; Khelashvili, George; Gether, Ulrik; Loland, Claus J.; Javitch, Jonathan A.; Noskov, Sergei; Weinstein, Harel; Shi, Lei

    2015-04-13

    Neurotransmitter:sodium symporters (NSSs) terminate neurotransmission by Na+-dependent reuptake of released neurotransmitters. Previous studies suggested that Na+-binding reconfigures dynamically coupled structural elements in an allosteric interaction network (AIN) responsible for function-related conformational changes, but the intramolecular pathway of this mechanism has remained uncharted. Here we describe a new approach for the modeling and analysis of intramolecular dynamics in the bacterial NSS homolog LeuT. From microsecond-scale molecular dynamics simulations and cognate experimental verifications in both LeuT and human dopamine transporter (hDAT), we apply the novel method to identify the composition and the dynamic properties of their conserved AIN. In LeuT, two different perturbations disrupting Na+ binding and transport (i.e. replacing Na+ with Li+ or the Y268A mutation at the intracellular gate) affect the AIN in strikingly similar ways. In contrast, other mutations that affect the intracellular gate (i.e. R5A and D369A) do not significantly impair Na+ cooperativity and transport. Our analysis shows these perturbations to have much lesser effects on the AIN, underscoring the sensitivity of this novel method to the mechanistic nature of the perturbation. Notably, this set of observations holds as well for hDAT, where the aligned Y335A, R60A, and D436A mutations also produce different impacts on Na+ dependence. Furthermore, the detailed AIN generated from our method is shown to connect Na+ binding with global conformational changes that are critical for the transport mechanism. Lastly, that the AIN between the Na+ binding sites and the intracellular gate in bacterial LeuT resembles that in eukaryotic hDAT highlights the conservation of allosteric pathways underlying NSS function.

  11. The dependence of neuronal encoding efficiency on Hebbian plasticity and homeostatic regulation of neurotransmitter release

    PubMed Central

    Faghihi, Faramarz; Moustafa, Ahmed A.

    2015-01-01

    Synapses act as information filters by different molecular mechanisms including retrograde messenger that affect neuronal spiking activity. One of the well-known effects of retrograde messenger in presynaptic neurons is a change of the probability of neurotransmitter release. Hebbian learning describe a strengthening of a synapse between a presynaptic input onto a postsynaptic neuron when both pre- and postsynaptic neurons are coactive. In this work, a theory of homeostatic regulation of neurotransmitter release by retrograde messenger and Hebbian plasticity in neuronal encoding is presented. Encoding efficiency was measured for different synaptic conditions. In order to gain high encoding efficiency, the spiking pattern of a neuron should be dependent on the intensity of the input and show low levels of noise. In this work, we represent spiking trains as zeros and ones (corresponding to non-spike or spike in a time bin, respectively) as words with length equal to three. Then the frequency of each word (here eight words) is measured using spiking trains. These frequencies are used to measure neuronal efficiency in different conditions and for different parameter values. Results show that neurons that have synapses acting as band-pass filters show the highest efficiency to encode their input when both Hebbian mechanism and homeostatic regulation of neurotransmitter release exist in synapses. Specifically, the integration of homeostatic regulation of feedback inhibition with Hebbian mechanism and homeostatic regulation of neurotransmitter release in the synapses leads to even higher efficiency when high stimulus intensity is presented to the neurons. However, neurons with synapses acting as high-pass filters show no remarkable increase in encoding efficiency for all simulated synaptic plasticity mechanisms. This study demonstrates the importance of cooperation of Hebbian mechanism with regulation of neurotransmitter release induced by rapid diffused retrograde

  12. Nicotine stimulates pancreatic cancer xenografts by systemic increase in stress neurotransmitters and suppression of the inhibitory neurotransmitter gamma-aminobutyric acid.

    PubMed

    Al-Wadei, Hussein A N; Plummer, Howard K; Schuller, Hildegard M

    2009-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality in Western countries. We have shown previously that four representative human PDAC cell lines were regulated by beta-adrenoreceptors via cyclic adenosine 3',5'-monophosphate (cAMP)-dependent signaling. In the current study, we have tested the hypothesis that nicotine stimulates the growth of PDAC xenografts in nude mice by increasing the systemic levels of the stress neurotransmitters adrenaline and noradrenaline, which are the physiological agonists for beta-adrenoreceptors and that inhibition by gamma-aminobutyric acid (GABA) of the adenylyl cyclase-dependent pathway downstream of adrenoreceptors blocks this effect. The size of xenografts from PDAC cell line Panc-1 was determined 30 days after inoculation of the cancer cells. Stress neurotransmitters in serum as well as cAMP in the cellular fraction of blood and in tumor tissue were assessed by immunoassays. Levels of GABA, its synthesizing enzymes GAD65 and GAD67 and beta-adrenergic signaling proteins in the tumor tissue were determined by western blotting. Nicotine significantly increased the systemic levels of adrenaline, noradrenaline and cAMP while increasing xenograft size and protein levels of cAMP, cyclic AMP response element-binding protein and p-extracellular signal-regulated kinase 1/2 in the tumor tissue. Nicotine additionally reduced the protein levels of both GAD isozymes and GABA in tumor tissue. Treatment with GABA abolished these responses to nicotine and blocked the development of xenografts in mice not exposed to nicotine. These findings suggest that the development and progression of PDAC is subject to significant modulation by stimulatory stress neurotransmitters and inhibitory GABA and that treatment with GABA may be useful for marker-guided cancer intervention of PDAC.

  13. Self-esteem in remitted patients with mood disorders is not associated with the dopamine receptor D4 and the serotonin transporter genes.

    PubMed

    Serretti, A; Macciardi, F; Di Bella, D; Catalano, M; Smeraldi, E

    1998-08-17

    Disturbances of the dopaminergic and serotoninergic neurotransmitter systems have been implicated in the pathogenesis of depressive symptoms. Associations have been reported between markers of the two neurotransmitter systems and the presence of illness or severity of depressive episodes, but no attention has been focused on the periods of remission. The present report focuses on a possible association of self-esteem in remitted mood disorder patients with the functional polymorphism located in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the dopamine receptor D4 (DRD4). Inpatients (N=162) affected by bipolar (n=103) and unipolar (n=59) disorder (DSM III-R) were assessed by the Self-Esteem Scale (SES, Rosenberg, 1965) and were typed for DRD4 and 5-HTTLPR (n=58 subjects) variants at the third exon using polymerase chain reaction (PCR) techniques. Neither DRD4 nor 5-HTTLPR variants were associated with SES scores, and consideration of possible stratification effects such as sex and psychiatric diagnosis did not reveal any association either. The serotonin transporter and dopamine receptor D4 genes do not, therefore, influence self-esteem in remitted mood disorder subjects.

  14. Effect of canagliflozin and metformin on cortical neurotransmitters in a diabetic rat model.

    PubMed

    Arafa, Nadia M S; Marie, Mohamed-Assem S; AlAzimi, Sara Abdullah Mubarak

    2016-10-25

    The rapid economic development in the Arabian Gulf has resulted in lifestyle changes that have increased the prevalence of obesity and type 2 diabetes, with the greatest increases observed in Kuwait. Dyslipidemia and diabetes are risk factors for disruptions in cortical neurotransmitter homeostasis. This study investigated the effect of the antidiabetic medications canagliflozin (CAN) and metformin (MET) on the levels of cortical neurotransmitters in a diabetic rat model. The rats were assigned to the control (C) group, the diabetic group that did not receive treatment (D) or the diabetic group treated with either CAN (10 mg/kg) or MET (100 mg/kg) for 2 or 4 weeks. Blood and urine glucose levels and cortical acetylcholinesterase (AChE) activity were assayed, and amino acid and monoamine levels were measured using HPLC. The diabetic group exhibited a significant increase in AChE activity and a decrease in monoamine and amino acid neurotransmitter levels. In the CAN group, AChE was significantly lower than that in the D and D + MET groups after 2 weeks of treatment. In addition, a significant increase in some cortical monoamines and amino acids was observed in the D + MET and D + CAN groups compared with the D group. Histopathological analysis revealed the presence of severe focal hemorrhage, neuronal degeneration, and cerebral blood vessel congestion, with gliosis in the cerebrum of rats in the D group. The CAN-treated group exhibited severe cerebral blood vessel congestion after 2 weeks of treatment and focal gliosis in the cerebrum after 4 weeks of treatment. Focal gliosis in the cerebrum of rats in the MET-treated group was observed after 2 and 4 weeks of treatment. We conclude that the effect of CAN and MET on neurotransmitters is potentially mediated by their antihyperglycemic and antihyperlipidemic effects. In addition, the effects of CAN on neurotransmitters might be associated with its receptor activity, and the effect of MET on neurotransmitters

  15. Laurate Biosensors Image Brain Neurotransmitters In Vivo: Can an Antihypertensive Medication Alter Psychostimulant Behavior?

    PubMed Central

    Broderick, Patricia A.; Ho, Helen; Wat, Karyn; Murthy, Vivek

    2008-01-01

    Neuromolecular Imaging (NMI) with novel biosensors enables the selective detection of neurotransmitters in vivo within seconds, on line and in real time. Biosensors remain in place for continuing studies over a period of months. This biotechnological advance is based on conventional electrochemistry; the biosensors detect neurotransmitters by electron transfer. Simply stated, biosensors adsorb electrons from each neurotransmitter at specific oxidation potentials; the current derived from electron transfer is proportional to neurotransmitter concentration. Selective electron transfer properties of these biosensors permit the imaging of neurotransmitters, metabolites and precursors. The novel BRODERICK PROBE® biosensors we have developed, differ in formulation and detection capabilities from biosensors/electrodes used in conventional electrochemistry/voltammetry. In these studies, NMI, specifically, the BRODERICK PROBE® laurate biosensor images neurotransmitter signals within mesolimbic neuronal terminals, nucleus accumbens (NAc); dopamine (DA), serotonin (5-HT), homovanillic acid (HVA) and L-tryptophan (L-TP) are selectively imaged. Simultaneously, we use infrared photobeams to monitor open-field movement behaviors on line with NMI in the same animal subjects. The goals are to investigate integrated neurochemical and behavioral effects of cocaine and caffeine alone and co-administered and further, to use ketanserin to decipher receptor profiles for these psychostimulants, alone and co-administered. The rationale for selecting this medication is: ketanserin (a) is an antihypertensive and cocaine and caffeine produce hypertension and (b) acts at 5-HT2A/2C receptors, prevalent in NAc and implicated in hypertension and cocaine addiction. Key findings are: (a) the moderate dose of caffeine simultaneously potentiates cocaine's neurochemical and behavioral responses. (b) ketanserin simultaneously inhibits cocaine-increased DA and 5-HT release in NAc and open

  16. Kv3.3 immunoreactivity in the vestibular nuclear complex of the rat with focus on the medial vestibular nucleus: targeting of Kv3.3 neurones by terminals positive for vesicular glutamate transporter 1.

    PubMed

    Brooke, Ruth Elizabeth; Corns, Laura; Edwards, Ian James; Deuchars, Jim

    2010-07-23

    Kv3 voltage-gated K(+) channels are important in shaping neuronal excitability and are abundant in the CNS, with each Kv3 gene exhibiting a unique expression pattern. Mice lacking the gene encoding for the Kv3.3 subunit exhibit motor deficits. Furthermore, mutations in this gene have been linked to the human disease spinocerebellar ataxia 13, associated with cerebellar and extra-cerebellar symptoms such as imbalance and nystagmus. Kv subunit localisation is important in defining their functional roles and thus, we investigated the distribution of Kv3.3-immunoreactivity in the vestibular nuclear complex of rats with particular focus on the medial vestibular nucleus (MVN). Kv3.3-immunoreactivity was widespread in the vestibular nuclei and was detected in somata, dendrites and synaptic terminals. Kv3.3-immunoreactivity was observed in distinct neuronal populations and dual labelling with the neuronal marker NeuN revealed 28.5+/-1.9% of NeuN labelled MVN neurones were Kv3.3-positive. Kv3.3-immunoreactivity co-localised presynaptically with the synaptic vesicle marker SV2, parvalbumin, the vesicular glutamate transporter VGluT2 and the glycine transporter GlyT2. VGluT1 terminals were scarce within the MVN (2.5+/-1.1 per 50 microm(2)) and co-localisation was not observed. However, 85.4+/-9.4% of VGluT1 terminals targeted and enclosed Kv3.3-immunoreactive somata. Presynaptic Kv3.3 co-localisation with the GABAergic marker GAD67 was also not observed. Cytoplasmic GlyT2 labelling was observed in a subset of Kv3.3-positive neurones. Electron microscopy confirmed a pre- and post-synaptic distribution of the Kv3.3 protein. This study provides evidence supporting a role for Kv3.3 subunits in vestibular processing by regulating neuronal excitability pre- and post-synaptically.

  17. Focused crossed Andreev reflection

    NASA Astrophysics Data System (ADS)

    Haugen, H.; Brataas, A.; Waintal, X.; Bauer, G. E. W.

    2011-03-01

    We consider non-local transport mediated by Andreev reflection in a two-dimensional electron gas (2DEG) connected to one superconducting and two normal metal terminals. A robust scheme is presented for observing crossed Andreev reflection (CAR) between the normal metal terminals based on electron focusing by weak perpendicular magnetic fields. At slightly elevated temperatures the CAR signature can be easily distinguished from a background of quantum interference fluctuations. The CAR-induced entanglement between electrons can be switched on and off over large distances by the magnetic field.

  18. Role of N-Arachidonoyl-Serotonin (AA-5-HT) in Sleep-Wake Cycle Architecture, Sleep Homeostasis, and Neurotransmitters Regulation.

    PubMed

    Murillo-Rodríguez, Eric; Di Marzo, Vincenzo; Machado, Sergio; Rocha, Nuno B; Veras, André B; Neto, Geraldo A M; Budde, Henning; Arias-Carrión, Oscar; Arankowsky-Sandoval, Gloria

    2017-01-01

    The endocannabinoid system comprises several molecular entities such as endogenous ligands [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)], receptors (CB1 and CB2), enzymes such as [fatty acid amide hydrolase (FAHH) and monoacylglycerol lipase (MAGL)], as well as the anandamide membrane transporter. Although the role of this complex neurobiological system in the sleep-wake cycle modulation has been studied, the contribution of the blocker of FAAH/transient receptor potential cation channel subfamily V member 1 (TRPV1), N-arachidonoyl-serotonin (AA-5-HT) in sleep has not been investigated. Thus, in the present study, varying doses of AA-5-HT (5, 10, or 20 mg/Kg, i.p.) injected at the beginning of the lights-on period of rats, caused no statistical changes in sleep patterns. However, similar pharmacological treatment given to animals at the beginning of the dark period decreased wakefulness (W) and increased slow wave sleep (SWS) as well as rapid eye movement sleep (REMS). Power spectra analysis of states of vigilance showed that injection of AA-5-HT during the lights-off period diminished alpha spectrum across alertness in a dose-dependent fashion. In opposition, delta power spectra was enhanced as well as theta spectrum, during SWS and REMS, respectively. Moreover, the highest dose of AA-5-HT decreased wake-related contents of neurotransmitters such as dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT) whereas the levels of adenosine (AD) were enhanced. In addition, the sleep-inducing properties of AA-5-HT were confirmed since this compound blocked the increase in W caused by stimulants such as cannabidiol (CBD) or modafinil (MOD) during the lights-on period. Additionally, administration of AA-5-HT also prevented the enhancement in contents of DA, NE, EP, 5-HT and AD after CBD of MOD injection. Lastly, the role of AA-5-HT in sleep homeostasis was tested in animals that received either CBD or MOD after total sleep deprivation (TSD). The

  19. Role of N-Arachidonoyl-Serotonin (AA-5-HT) in Sleep-Wake Cycle Architecture, Sleep Homeostasis, and Neurotransmitters Regulation

    PubMed Central

    Murillo-Rodríguez, Eric; Di Marzo, Vincenzo; Machado, Sergio; Rocha, Nuno B.; Veras, André B.; Neto, Geraldo A. M.; Budde, Henning; Arias-Carrión, Oscar; Arankowsky-Sandoval, Gloria

    2017-01-01

    The endocannabinoid system comprises several molecular entities such as endogenous ligands [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)], receptors (CB1 and CB2), enzymes such as [fatty acid amide hydrolase (FAHH) and monoacylglycerol lipase (MAGL)], as well as the anandamide membrane transporter. Although the role of this complex neurobiological system in the sleep–wake cycle modulation has been studied, the contribution of the blocker of FAAH/transient receptor potential cation channel subfamily V member 1 (TRPV1), N-arachidonoyl-serotonin (AA-5-HT) in sleep has not been investigated. Thus, in the present study, varying doses of AA-5-HT (5, 10, or 20 mg/Kg, i.p.) injected at the beginning of the lights-on period of rats, caused no statistical changes in sleep patterns. However, similar pharmacological treatment given to animals at the beginning of the dark period decreased wakefulness (W) and increased slow wave sleep (SWS) as well as rapid eye movement sleep (REMS). Power spectra analysis of states of vigilance showed that injection of AA-5-HT during the lights-off period diminished alpha spectrum across alertness in a dose-dependent fashion. In opposition, delta power spectra was enhanced as well as theta spectrum, during SWS and REMS, respectively. Moreover, the highest dose of AA-5-HT decreased wake-related contents of neurotransmitters such as dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT) whereas the levels of adenosine (AD) were enhanced. In addition, the sleep-inducing properties of AA-5-HT were confirmed since this compound blocked the increase in W caused by stimulants such as cannabidiol (CBD) or modafinil (MOD) during the lights-on period. Additionally, administration of AA-5-HT also prevented the enhancement in contents of DA, NE, EP, 5-HT and AD after CBD of MOD injection. Lastly, the role of AA-5-HT in sleep homeostasis was tested in animals that received either CBD or MOD after total sleep deprivation (TSD). The

  20. SLC Transporters as Therapeutic Targets: Emerging Opportunities

    PubMed Central

    Lin, Lawrence; Yee, Sook Wah; Kim, Richard B.; Giacomini, Kathleen M.

    2015-01-01

    Solute carrier (SLC) transporters — a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes — have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets. PMID:26111766

  1. Miniaturized and Wireless Optical Neurotransmitter Sensor for Real-Time Monitoring of Dopamine in the Brain

    PubMed Central

    Kim, Min H.; Yoon, Hargsoon; Choi, Sang H.; Zhao, Fei; Kim, Jongsung; Song, Kyo D.; Lee, Uhn

    2016-01-01

    Real-time monitoring of extracellular neurotransmitter concentration offers great benefits for diagnosis and treatment of neurological disorders and diseases. This paper presents the study design and results of a miniaturized and wireless optical neurotransmitter sensor (MWONS) for real-time monitoring of brain dopamine concentration. MWONS is based on fluorescent sensing principles and comprises a microspectrometer unit, a microcontroller for data acquisition, and a Bluetooth wireless network for real-time monitoring. MWONS has a custom-designed application software that controls the operation parameters for excitation light sources, data acquisition, and signal processing. MWONS successfully demonstrated a measurement capability with a limit of detection down to a 100 nanomole dopamine concentration, and high selectivity to ascorbic acid (90:1) and uric acid (36:1). PMID:27834927

  2. Analysis of neurotransmitter tissue content of Drosophila melanogaster in different life stages.

    PubMed

    Denno, Madelaine E; Privman, Eve; Venton, B Jill

    2015-01-21

    Drosophila melanogaster is a widely used model organism for studying neurological diseases with similar neurotransmission to mammals. While both larva and adult Drosophila have central nervous systems, not much is known about how neurotransmitter tissue content changes through development. In this study, we quantified tyramine, serotonin, octopamine, and dopamine in larval, pupal, and adult fly brains using capillary electrophoresis coupled to fast-scan cyclic voltammetry. Tyramine and octopamine content varied between life stages, with almost no octopamine being present in the pupa, while tyramine levels in the pupa were very high. Adult females had significantly higher dopamine content than males, but no other neurotransmitters were dependent on sex in the adult. Understanding the tissue content of different life stages will be beneficial for future work comparing the effects of diseases on tissue content throughout development.

  3. Quantification of Amino Acid Neurotransmitters in Cerebrospinal Fluid of Patients with Neurocysticercosis

    PubMed Central

    Camargo, José Augusto; Bertolucci, Paulo Henrique Ferreira

    2015-01-01

    Background : Neurocysticercosis is a parasitic disease that affects the central nervous system. Its main clinical manifestations are epileptic seizures. The objective of this study was to investigate the correlation between neurotransmitter concentrations in cerebrospinal fluid (CSF) and the different evolutive forms of neurocysticercosis with or without seizures. Methods : Neurotransmitter concentrations (Aspartate, Glutamate, GABA, Glutamine, Glycine, Taurine) were determined in CSF samples from 42 patients with neurocysticercosis divided into patients with the active cystic form (n = 24, 12 with and 12 without seizures) and patients with calcified form (n = 18, 12 with and 6 without seizures), and a control group consisting of 59 healthy subjects. Results : Alterations in amino acid concentration were observed in all patients with neurocysticercosis. Conclusion : We conclude that disturbances in amino acid metabolism accompany the presentation of neurocysticercosis. Replacement of the terms inactive cyst by reactive inactive cyst and calcification by reactive calcification is suggested. PMID:26157521

  4. Control of neurotransmitter release by an internal gel matrix in synaptic vesicles.

    PubMed

    Reigada, David; Díez-Pérez, Ismael; Gorostiza, Pau; Verdaguer, Albert; Gómez de Aranda, Inmaculada; Pineda, Oriol; Vilarrasa, Jaume; Marsal, Jordi; Blasi, Joan; Aleu, Jordi; Solsona, Carles

    2003-03-18

    Neurotransmitters are stored in synaptic vesicles, where they have been assumed to be in free solution. Here we report that in Torpedo synaptic vesicles, only 5% of the total acetylcholine (ACh) or ATP content is free, and that the rest is adsorbed to an intravesicular proteoglycan matrix. This matrix, which controls ACh and ATP release by an ion-exchange mechanism, behaves like a smart gel. That is, it releases neurotransmitter and changes its volume when challenged with small ionic concentration change. Immunodetection analysis revealed that the synaptic vesicle proteoglycan SV2 is the core of the intravesicular matrix and is responsible for immobilization and release of ACh and ATP. We suggest that in the early steps of vesicle fusion, this internal matrix regulates the availability of free diffusible ACh and ATP, and thus serves to modulate the quantity of transmitter released.

  5. Microfluidic in-channel multi-electrode platform for neurotransmitter sensing

    NASA Astrophysics Data System (ADS)

    Kara, A.; Mathault, J.; Reitz, A.; Boisvert, M.; Tessier, F.; Greener, J.; Miled, A.

    2016-03-01

    In this project we present a microfluidic platform with in-channel micro-electrodes for in situ screening of bio/chemical samples through a lab-on-chip system. We used a novel method to incorporate electrochemical sensors array (16x20) connected to a PCB, which opens the way for imaging applications. A 200 μm height microfluidic channel was bonded to electrochemical sensors. The micro-channel contains 3 inlets used to introduce phosphate buffer saline (PBS), ferrocynide and neurotransmitters. The flow rate was controlled through automated micro-pumps. A multiplexer was used to scan electrodes and perform individual cyclic voltammograms by a custom potentiostat. The behavior of the system was linear in terms of variation of current versus concentration. It was used to detect the neurotransmitters serotonin, dopamine and glutamate.

  6. New Trends and Perspectives in the Evolution of Neurotransmitters in Microbial, Plant, and Animal Cells.

    PubMed

    Roshchina, Victoria V

    2016-01-01

    The evolutionary perspective on the universal roles of compounds known as neurotransmitters may help in the analysis of relations between all organisms in biocenosis-from microorganisms to plant and animals. This phenomenon, significant for chemosignaling and cellular endocrinology, has been important in human health and the ability to cause disease or immunity, because the "living environment" influences every organism in a biocenosis relationship (microorganism-microorganism, microorganism-plant, microorganism-animal, plant-animal, plant-plant and animal-animal). Non-nervous functions of neurotransmitters (rather "biomediators" on a cellular level) are considered in this review and ample consideration is given to similarities and differences that unite, as well as distinguish, taxonomical kingdoms.

  7. Carbon nanotube yarn electrodes for enhanced detection of neurotransmitter dynamics in live brain tissue.

    PubMed

    Schmidt, Andreas C; Wang, Xin; Zhu, Yuntian; Sombers, Leslie A

    2013-09-24

    This work demonstrates the potential of nanoscale carbon electrode materials for improved detection of electroactive neurotransmitter dynamics in the brain. Individual multiwalled carbon nanotubes were synthesized via chemical vapor deposition, spun into yarns, and used in the fabrication of disk microelectrodes that were subsequently characterized using scanning electron and atomic force microscopies. The carbon nanotube yarn electrodes were coupled with fast-scan cyclic voltammetry and used to discriminately detect rapid neurotransmitter fluctuations in acute brain slices. The results demonstrate that the distinct structural and electronic properties of the nanotubes result in improved selectivity, sensitivity, and spatial resolution, as well as faster apparent electron transfer kinetics when compared to the conventional carbon-fiber microelectrodes typically used in vivo.

  8. FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels.

    PubMed

    Deng, Pan-Yue; Rotman, Ziv; Blundon, Jay A; Cho, Yongcheol; Cui, Jianmin; Cavalli, Valeria; Zakharenko, Stanislav S; Klyachko, Vitaly A

    2013-02-20

    Loss of FMRP causes fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx, and elevated neurotransmitter release. The AP broadening defects caused by FMRP loss have a cell-autonomous presynaptic origin and can be acutely rescued in postnatal neurons. These presynaptic actions of FMRP are translation independent and are mediated selectively by BK channels via interaction of FMRP with BK channel's regulatory β4 subunits. Information-theoretical analysis demonstrates that loss of these FMRP functions causes marked dysregulation of synaptic information transmission. FMRP-dependent AP broadening is not limited to the hippocampus, but also occurs in cortical pyramidal neurons. Our results thus suggest major translation-independent presynaptic functions of FMRP that may have important implications for understanding FXS neuropathology.

  9. Duck cerebellum participates in regulation of food intake via the neurotransmitters serotonin and neuropeptide Y.

    PubMed

    Liu, Hua Z; Li, Xin Y; Tong, Jing J; Qiu, Zheng Y; Zhan, Han C; Sha, Jun N; Peng, Ke M

    2008-10-01

    Two important neurotransmitters, serotonin (5-hydroxytryptamine, 5-HT) and neuropeptide Y (NPY), have been confirmed to be involved in food intake regulation. To clarify whether the cerebellum participates in modulation of food intake through these two neurotransmitters, we investigated the distribution and expression levels of 5-HT and NPY in cerebellum of the duck. Our results showed that 5-HT and NPY were distributed only at the Purkinje cell layer of the duck cerebellum. Moreover, the expression level of 5-HT in fasted (4 h) and tryptophan (100-200 mg/kg)-treated ducks was significantly higher than that in control animals (P<0.01), whereas the expression of NPY was significantly decreased (P<0.01). Therefore, our results indicated that inhibitory regulation of food intake respectively increased and decreased cerebellar 5-HT and NPY in the duck.

  10. Calcium-sensing beyond neurotransmitters: functions of synaptotagmins in neuroendocrine and endocrine secretion.

    PubMed

    Gustavsson, Natalia; Han, Weiping

    2009-08-01

    Neurotransmitters, neuropeptides and hormones are released through the regulated exocytosis of SVs (synaptic vesicles) and LDCVs (large dense-core vesicles), a process that is controlled by calcium. Synaptotagmins are a family of type 1 membrane proteins that share a common domain structure. Most synaptotagmins are located in brain and endocrine cells, and some of these synaptotagmins bind to phospholipids and calcium at levels that trigger regulated exocytosis of SVs and LDCVs. This led to the proposed synaptotagmin-calcium-sensor paradigm, that is, members of the synaptotagmin family function as calcium sensors for the regulated exocytosis of neurotransmitters, neuropeptides and hormones. Here, we provide an overview of the synaptotagmin family, and review the recent mouse genetic studies aimed at understanding the functions of synaptotagmins in neurotransmission and endocrine-hormone secretion. Also, we discuss potential roles of synaptotagmins in non-traditional endocrine systems.

  11. Synaptotagmin-12, a synaptic vesicle phosphoprotein that modulates spontaneous neurotransmitter release

    PubMed Central

    Maximov, Anton; Shin, Ok-Ho; Liu, Xinran; Südhof, Thomas C.

    2007-01-01

    Central synapses exhibit spontaneous neurotransmitter release that is selectively regulated by cAMP-dependent protein kinase A (PKA). We now show that synaptic vesicles contain synaptotagmin-12, a synaptotagmin isoform that differs from classical synaptotagmins in that it does not bind Ca2+. In synaptic vesicles, synaptotagmin-12 forms a complex with synaptotagmin-1 that prevents synaptotagmin-1 from interacting with SNARE complexes. We demonstrate that synaptotagmin-12 is phosphorylated by cAMP-dependent PKA on serine97, and show that expression of synaptotagmin-12 in neurons increases spontaneous neurotransmitter release by approximately threefold, but has no effect on evoked release. Replacing serine97 by alanine abolishes synaptotagmin-12 phosphorylation and blocks its effect on spontaneous release. Our data suggest that spontaneous synaptic-vesicle exocytosis is selectively modulated by a Ca2+-independent synaptotagmin isoform, synaptotagmin-12, which is controlled by cAMP-dependent phosphorylation. PMID:17190793

  12. Synaptotagmin-12, a synaptic vesicle phosphoprotein that modulates spontaneous neurotransmitter release.

    PubMed

    Maximov, Anton; Shin, Ok-Ho; Liu, Xinran; Südhof, Thomas C

    2007-01-01

    Central synapses exhibit spontaneous neurotransmitter release that is selectively regulated by cAMP-dependent protein kinase A (PKA). We now show that synaptic vesicles contain synaptotagmin-12, a synaptotagmin isoform that differs from classical synaptotagmins in that it does not bind Ca(2+). In synaptic vesicles, synaptotagmin-12 forms a complex with synaptotagmin-1 that prevents synaptotagmin-1 from interacting with SNARE complexes. We demonstrate that synaptotagmin-12 is phosphorylated by cAMP-dependent PKA on serine(97), and show that expression of synaptotagmin-12 in neurons increases spontaneous neurotransmitter release by approximately threefold, but has no effect on evoked release. Replacing serine(97) by alanine abolishes synaptotagmin-12 phosphorylation and blocks its effect on spontaneous release. Our data suggest that spontaneous synaptic-vesicle exocytosis is selectively modulated by a Ca(2+)-independent synaptotagmin isoform, synaptotagmin-12, which is controlled by cAMP-dependent phosphorylation.

  13. [Detection of neurotransmitter interactions with PET and SPECT by pharmacological challenge paradigms].

    PubMed

    Schlösser, R

    2000-01-01

    Functional brain imaging with positron emission tomography (PET) and single photon emission computerized tomography (SPECT) enables the in vivo study of specific neurochemical processes in the context of normal regulatory mechanisms and pathophysiological alterations of the brain. By combining these methods with pharmacological challenge-paradigms, the study of functional interactions of different neurotransmitter systems is possible. This review will present data from animal and healthy volunteer studies as well as first data from investigations in different patient populations with regard to this research direction. Especially, interactions of different neurotransmitter systems with the dopaminergic and the cholinergic system will be discussed. The database acquired so far confirms existing models of neuronal feedback-circuits, and the first clinical results are consistent with the hypothesis of an increased dopaminergic responsivity in schizophrenic patients. These results open up new perspectives for a further evaluation of treatment response predictors from drug-challenge studies and for the development of new drug treatments for neuropsychiatric disorders.

  14. Probe-pin device for optical neurotransmitter sensing in the brain

    NASA Astrophysics Data System (ADS)

    Kim, Min Hyuck; Song, Kyo D.; Yoon, Hargsoon; Park, Yeonjoon; Choi, Sang H.; Lee, Dae-Sung; Shin, Kyu-Sik; Hwang, Hak-In; Lee, Uhn

    2015-04-01

    Development of an optical neurotransmitter sensing device using nano-plasmonic probes and a micro-spectrometer for real time monitoring of neural signals in the brain is underway. Clinical application of this device technology is to provide autonomous closed-loop feedback control to a deep brain stimulation (DBS) system and enhance the accuracy and efficacy of DBS treatment. By far, we have developed an implantable probe-pin device based on localized field enhancement of surface plasmonic resonance on a nanostructured sensing domain which can amplify neurochemical signals from evoked neural activity in the brain. In this paper, we will introduce the details of design and sensing performance of a proto-typed microspectrometer and nanostructured probing devices for real time measurement of neurotransmitter concentrations.

  15. Noninvasive fractal biomarker of clock neurotransmitter disturbance in humans with dementia

    PubMed Central

    Hu, Kun; Harper, David G.; Shea, Steven A.; Stopa, Edward G.; Scheer, Frank A. J. L.

    2013-01-01

    Human motor activity has a robust, intrinsic fractal structure with similar patterns from minutes to hours. The fractal activity patterns appear to be physiologically important because the patterns persist under different environmental conditions but are significantly altered/reduced with aging and Alzheimer's disease (AD). Here, we report that dementia patients, known to have disrupted circadian rhythmicity, also have disrupted fractal activity patterns and that the disruption is more pronounced in patients with more amyloid plaques (a marker of AD severity). Moreover, the degree of fractal activity disruption is strongly associated with vasopressinergic and neurotensinergic neurons (two major circadian neurotransmitters) in postmortem suprachiasmatic nucleus (SCN), and can better predict changes of the two neurotransmitters than traditional circadian measures. These findings suggest that the SCN impacts human activity regulation at multiple time scales and that disrupted fractal activity may serve as a non-invasive biomarker of SCN neurodegeneration in dementia. PMID:23863985

  16. Phosphorylation of Complexin by PKA Regulates Activity-dependent Spontaneous Neurotransmitter Release and Structural Synaptic Plasticity

    PubMed Central

    Cho, Richard W.; Buhl, Lauren K.; Volfson, Dina; Tran, Adrienne; Li, Feng; Akbergenova, Yulia; Littleton, J. Troy

    2016-01-01

    Summary Synaptic plasticity is a fundamental feature of the nervous system that allows adaptation to changing behavioral environments. Most studies of synaptic plasticity have examined the regulated trafficking of postsynaptic glutamate receptors that generates alterations in synaptic transmission. Whether and how changes in the presynaptic release machinery contribute to neuronal plasticity is less clear. The SNARE complex mediates neurotransmitter release in response to presynaptic Ca++ entry. Here we show that the SNARE fusion clamp Complexin undergoes activity-dependent phosphorylation that alters the basic properties of neurotransmission in Drosophila. Retrograde signaling following stimulation activates PKA-dependent phosphorylation of the Complexin C-terminus that selectively and transiently enhances spontaneous release. Enhanced spontaneous release is required for activity-dependent synaptic growth. These data indicate that SNARE-dependent fusion mechanisms can be regulated in an activity-dependent manner and highlight the key role of spontaneous neurotransmitter release as a mediator of functional and structural plasticity. PMID:26590346

  17. Neuron-glia signaling in developing retina mediated by neurotransmitter spillover.

    PubMed

    Rosa, Juliana M; Bos, Rémi; Sack, Georgeann S; Fortuny, Cécile; Agarwal, Amit; Bergles, Dwight E; Flannery, John G; Feller, Marla B

    2015-08-14

    Neuron-glia interactions play a critical role in the maturation of neural circuits; however, little is known about the pathways that mediate their communication in the developing CNS. We investigated neuron-glia signaling in the developing retina, where we demonstrate that retinal waves reliably induce calcium transients in Müller glial cells (MCs). During cholinergic waves, MC calcium transients were blocked by muscarinic acetylcholine receptor antagonists, whereas during glutamatergic waves, MC calcium transients were inhibited by ionotropic glutamate receptor antagonists, indicating that the responsiveness of MCs changes to match the neurotransmitter used to support retinal waves. Using an optical glutamate sensor we show that the decline in MC calcium transients is caused by a reduction in the amount of glutamate reaching MCs. Together, these studies indicate that neurons and MCs exhibit correlated activity during a critical period of retinal maturation that is enabled by neurotransmitter spillover from retinal synapses.

  18. Computational approaches for the study of serotonin and its membrane transporter SERT: implications for drug design in neurological sciences.

    PubMed

    Pratuangdejkul, J; Schneider, B; Launay, J-M; Kellermann, O; Manivet, P

    2008-01-01

    Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter of the central nervous and peripheral systems (CNS), plays a critical role in a wide variety of physiological and behavioral processes. In the serotonergic system, deregulation of the tightly controlled extracellular concentration of 5-HT appears to be at the origin of a host of metabolic and psychiatric disorders. A key step that regulates 5-HT external level is the re-uptake of 5-HT into cells by the 5-HT transporter (SERT), which is besides the target of numerous drugs interacting with the serotonergic system. Therapeutic strategies have mainly focused on the development of compounds that block the activity of SERT, for instance reuptake inhibitors (e.g. tricyclics, "selective" serotonin reuptake inhibitors) and in the past, specific substrate-type releasers (e.g. amphetamine and cocaine derivatives). Today, generation of new drugs targetting SERT with enhanced selectivity and reduced toxicity is one of the most challenging tasks in drug design. In this context, studies aiming at characterizing the physicochemical properties of 5-HT as well as the biological active conformation of SERT are a prerequisite to the design of new leads. However, the absence of a high-resolution 3D-structure for SERT has hampered the design of new transporter inhibitors. Using computational approaches, numerous efforts were made to shed light on the structure of 5-HT and its transporter. In this review, we compared several in silico methods dedicated to the modeling of 5-HT and SERT with an emphasis on i) quantum chemistry for study of 5-HT conformation and ii) ligand-based (QSAR and pharmacophore models) and transporter-based (homology models) approaches for studying SERT molecule. In addition, we discuss some methodological aspects of the computational work in connection with the construction of putative but reliable 3D structural models of SERT that may help to predict the mechanisms of neurotransmitter transport.

  19. Aspects of astrocyte energy metabolism, amino acid neurotransmitter homoeostasis and metabolic compartmentation

    PubMed Central

    Kreft, Marko; Bak, Lasse K; Waagepetersen, Helle S; Schousboe, Arne

    2012-01-01

    Astrocytes are key players in brain function; they are intimately involved in neuronal signalling processes and their metabolism is tightly coupled to that of neurons. In the present review, we will be concerned with a discussion of aspects of astrocyte metabolism, including energy-generating pathways and amino acid homoeostasis. A discussion of the impact that uptake of neurotransmitter glutamate may have on these pathways is included along with a section on metabolic compartmentation. PMID:22435484

  20. Aspects of astrocyte energy metabolism, amino acid neurotransmitter homoeostasis and metabolic compartmentation.

    PubMed

    Kreft, Marko; Bak, Lasse K; Waagepetersen, Helle S; Schousboe, Arne

    2012-04-27

    Astrocytes are key players in brain function; they are intimately involved in neuronal signalling processes and their metabolism is tightly coupled to that of neurons. In the present review, we will be concerned with a discussion of aspects of astrocyte metabolism, including energy-generating pathways and amino acid homoeostasis. A discussion of the impact that uptake of neurotransmitter glutamate may have on these pathways is included along with a section on metabolic compartmentation.

  1. Regulation of nonsmall-cell lung cancer stem cell like cells by neurotransmitters and opioid peptides.

    PubMed

    Banerjee, Jheelam; Papu John, Arokya M S; Schuller, Hildegard M

    2015-12-15

    Nonsmall-cell lung cancer (NSCLC) is the leading type of lung cancer and has a poor prognosis. We have shown that chronic stress promoted NSCLC xenografts in mice via stress neurotransmitter-activated cAMP signaling downstream of beta-adrenergic receptors and incidental beta-blocker therapy was reported to improve clinical outcomes in NSCLC patients. These findings suggest that psychological stress promotes NSCLC whereas pharmacologically or psychologically induced decreases in cAMP may inhibit NSCLC. Cancer stem cells are thought to drive the development, progression and resistance to therapy of NSCLC. However, their potential regulation by stress neurotransmitters has not been investigated. In the current study, epinephrine increased the number of cancer stem cell like cells (CSCs) from three NSCLC cell lines in spheroid formation assays while enhancing intracellular cAMP and the stem cell markers sonic hedgehog (SHH), aldehyde dehydrogenase-1 (ALDH-1) and Gli1, effects reversed by GABA or dynorphin B via Gαi -mediated inhibition of cAMP formation. The growth of NSCLC xenografts in a mouse model of stress reduction was significantly reduced as compared with mice maintained under standard conditions. Stress reduction reduced serum levels of corticosterone, norepinephrine and epinephrine while the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and opioid peptides increased. Stress reduction significantly reduced cAMP, VEGF, p-ERK, p-AKT, p-CREB, p-SRc, SHH, ALDH-1 and Gli1 in xenograft tissues whereas cleaved caspase-3 and p53 were induced. We conclude that stress neurotransmitters activate CSCs in NSCLC via multiple cAMP-mediated pathways and that pharmacologically or psychologically induced decreases in cAMP signaling may improve clinical outcomes in NSCLC patients.

  2. Sensing small neurotransmitter-enzyme interaction with nanoporous gated ion-sensitive field effect transistors.

    PubMed

    Kisner, Alexandre; Stockmann, Regina; Jansen, Michael; Yegin, Ugur; Offenhäusser, Andreas; Kubota, Lauro Tatsuo; Mourzina, Yulia

    2012-01-15

    Ion-sensitive field effect transistors with gates having a high density of nanopores were fabricated and employed to sense the neurotransmitter dopamine with high selectivity and detectability at micromolar range. The nanoporous structure of the gates was produced by applying a relatively simple anodizing process, which yielded a porous alumina layer with pores exhibiting a mean diameter ranging from 20 to 35 nm. Gate-source voltages of the transistors demonstrated a pH-dependence that was linear over a wide range and could be understood as changes in surface charges during protonation and deprotonation. The large surface area provided by the pores allowed the physical immobilization of tyrosinase, which is an enzyme that oxidizes dopamine, on the gates of the transistors, and thus, changes the acid-base behavior on their surfaces. Concentration-dependent dopamine interacting with immobilized tyrosinase showed a linear dependence into a physiological range of interest for dopamine concentration in the changes of gate-source voltages. In comparison with previous approaches, a response time relatively fast for detecting dopamine was obtained. Additionally, selectivity assays for other neurotransmitters that are abundantly found in the brain were examined. These results demonstrate that the nanoporous structure of ion-sensitive field effect transistors can easily be used to immobilize specific enzyme that can readily and selectively detect small neurotransmitter molecule based on its acid-base interaction with the receptor. Therefore, it could serve as a technology platform for molecular studies of neurotransmitter-enzyme binding and drugs screening. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. The role of peripheral nerve fibers and their neurotransmitters in cartilage and bone physiology and pathophysiology.

    PubMed

    Grässel, Susanne G

    2014-01-01

    The peripheral nervous system is critically involved in bone metabolism, osteogenesis, and bone remodeling. Nerve fibers of sympathetic and sensory origin innervate synovial tissue and subchondral bone of diathrodial joints. They modulate vascularization and matrix differentiation during endochondral ossification in embryonic limb development, indicating a distinct role in skeletal growth and limb regeneration processes. In pathophysiological situations, the innervation pattern of sympathetic and sensory nerve fibers is altered in adult joint tissues and bone. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters. Osteoblasts, osteoclasts, mesenchymal stem cells, synovial fibroblasts, and different types of chondrocytes produce distinct subtypes of adrenoceptors, receptors for vasointestinal peptide, for substance P and calcitonin gene-related peptide. Many of these cells even synthesize neuropeptides such as substance P and calcitonin gene-related peptide and are positive for tyrosine-hydroxylase, the rate-limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters modulate osteo-chondrogenic differentiation of mesenchymal progenitor cells during endochondral ossification in limb development. In adults, sensory and sympathetic neurotransmitters are critical for bone regeneration after fracture and are involved in the pathology of inflammatory diseases as rheumatoid arthritis which manifests mainly in joints. Possibly, they might also play a role in pathogenesis of degenerative joint disorders, such as osteoarthritis. All together, accumulating data imply that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for proper limb formation during embryonic skeletal growth. In adults, they modulate bone regeneration, bone remodeling, and articular cartilage homeostasis in addition to their classic neurological actions.

  4. [Single and combining effects of Calculus Bovis and zolpidem on inhibitive neurotransmitter of rat striatum corpora].

    PubMed

    Liu, Ping; He, Xinrong; Guo, Mei

    2010-04-01

    To investigate the correlation effects between single or combined administration of Calculus Bovis or zolpidem and changes of inhibitive neurotransmitter in rat striatum corpora. Sampling from rat striatum corpora was carried out through microdialysis. The content of two inhibitive neurotransmitters in rat corpus striatum- glycine (Gly) and gama aminobutyric acid (GABA), was determined by HPLC, which involved pre-column derivation with orthophthaladehyde, reversed-phase gradient elution and fluorescence detection. GABA content of rat striatum corpora in Calculus Bovis group was significantly increased compared with saline group (P < 0.01). GABA content of zolpidem group and Calculus Boris plus zolpidem group were increased largely compared with saline group as well (P < 0.05). GABA content of Calculus Bovis group was higher than combination group (P < 0.05). GABA content of zolpidem group was not significantly different from combination group. Gly content of Calculus Bovis or zolpidem group was markedly increased compared with saline group or combination group (P < 0.05). Contents of two inhibitive neurotransmitters in rat striatum corpora were all significantly increased in Calculus Bovis group, zolpidem group and combination group. The magnitude of increase was lower in combination group than in Calculus Bovis group and Zolpidem group, suggesting that Calculus Bovis promoted encephalon inhibition is more powerful than zolpidem. The increase in two inhibitive neurotransmitters did not show reinforcing effect in combination group, suggesting that Calculus Bovis and zolpidem may compete the same receptors. Therefore, combination of Calculus Bovis containing drugs and zolpidem has no clinical significance. Calculus Bovis shouldn't as an aperture-opening drugs be used for resuscitation therapy.

  5. OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies

    PubMed Central

    Roth, Megan; Obaidat, Amanda; Hagenbuch, Bruno

    2012-01-01

    The human organic anion and cation transporters are classified within two SLC superfamilies. Superfamily SLCO (formerly SLC21A) consists of organic anion transporting polypeptides (OATPs), while the organic anion transporters (OATs) and the organic cation transporters (OCTs) are classified in the SLC22A superfamily. Individual members of each superfamily are expressed in essentially every epithelium throughout the body, where they play a significant role in drug absorption, distribution and elimination. Substrates of OATPs are mainly large hydrophobic organic anions, while OATs transport smaller and more hydrophilic organic anions and OCTs transport organic cations. In addition to endogenous substrates, such as steroids, hormones and neurotransmitters, numerous drugs and other xenobiotics are transported by these proteins, including statins, antivirals, antibiotics and anticancer drugs. Expression of OATPs, OATs and OCTs can be regulated at the protein or transcriptional level and appears to vary within each family by both protein and tissue type. All three superfamilies consist of 12 transmembrane domain proteins that have intracellular termini. Although no crystal structures have yet been determined, combinations of homology modelling and mutation experiments have been used to explore the mechanism of substrate recognition and transport. Several polymorphisms identified in members of these superfamilies have been shown to affect pharmacokinetics of their drug substrates, confirming the importance of these drug transporters for efficient pharmacological therapy. This review, unlike other reviews that focus on a single transporter family, briefly summarizes the current knowledge of all the functionally characterized human organic anion and cation drug uptake transporters of the SLCO and the SLC22A superfamilies. LINKED ARTICLES BJP recently published a themed section on Transporters. To view the papers in this section visit http://dx.doi.org/10.1111/bph.2011

  6. Fife organizes synaptic vesicles and calcium channels for high-probability neurotransmitter release

    PubMed Central

    Rao, Monica; Ukken, Fiona

    2017-01-01

    The strength of synaptic connections varies significantly and is a key determinant of communication within neural circuits. Mechanistic insight into presynaptic factors that establish and modulate neurotransmitter release properties is crucial to understanding synapse strength, circuit function, and neural plasticity. We previously identified Drosophila Piccolo-RIM-related Fife, which regulates neurotransmission and motor behavior through an unknown mechanism. Here, we demonstrate that Fife localizes and interacts with RIM at the active zone cytomatrix to promote neurotransmitter release. Loss of Fife results in the severe disruption of active zone cytomatrix architecture and molecular organization. Through electron tomographic and electrophysiological studies, we find a decrease in the accumulation of release-ready synaptic vesicles and their release probability caused by impaired coupling to Ca2+ channels. Finally, we find that Fife is essential for the homeostatic modulation of neurotransmission. We propose that Fife organizes active zones to create synaptic vesicle release sites within nanometer distance of Ca2+ channel clusters for reliable and modifiable neurotransmitter release. PMID:27998991

  7. Modulation of monoamine neurotransmitters in fighting fish Betta splendens exposed to waterborne phytoestrogens.

    PubMed

    Clotfelter, Ethan D; McNitt, Meredith M; Carpenter, Russ E; Summers, Cliff H

    2010-12-01

    Endogenous estrogens are known to affect the activity of monoamine neurotransmitters in vertebrate animals, but the effects of exogenous estrogens on neurotransmitters are relatively poorly understood. We exposed sexually mature male fighting fish Betta splendens to environmentally relevant and pharmacological doses of three phytoestrogens that are potential endocrine disruptors in wild fish populations: genistein, equol, and β-sitosterol. We also exposed fish to two doses of the endogenous estrogen 17β-estradiol, which we selected as a positive control because phytoestrogens are putative estrogen mimics. Our results were variable, but the effects were generally modest. Genistein increased dopamine levels in the forebrains of B. splendens at both environmentally relevant and pharmacological doses. The environmentally relevant dose of equol increased dopamine levels in B. splendens forebrains, and the pharmacological dose decreased norepinephrine (forebrain), dopamine (hindbrain), and serotonin (forebrain) levels. The environmentally relevant dose of β-sitosterol decreased norepinephrine and dopamine in the forebrain and hindbrain, respectively. Our results suggest that sources of environmental phytoestrogens, such as runoff or effluent from agricultural fields, wood pulp mills, and sewage treatment plants, have the potential to modulate neurotransmitter activity in free-living fishes in a way that could interfere with normal behavioral processes.

  8. Sympathetic Neurotransmitters Modulate Osteoclastogenesis and Osteoclast Activity in the Context of Collagen-Induced Arthritis

    PubMed Central

    Muschter, Dominique; Schäfer, Nicole; Stangl, Hubert; Straub, Rainer H.; Grässel, Susanne

    2015-01-01

    Excessive synovial osteoclastogenesis is a hallmark of rheumatoid arthritis (RA). Concomitantly, local synovial changes comprise neuronal components of the peripheral sympathetic nervous system. Here, we wanted to analyze if collagen-induced arthritis (CIA) alters bone marrow-derived macrophage (BMM) osteoclastogenesis and osteoclast activity, and how sympathetic neurotransmitters participate in this process. Therefore, BMMs from Dark Agouti rats at different CIA stages were differentiated into osteoclasts in vitro and osteoclast number, cathepsin K activity, matrix resorption and apoptosis were analyzed in the presence of acetylcholine (ACh), noradrenaline (NA) vasoactive intestinal peptide (VIP) and assay-dependent, adenylyl cyclase activator NKH477. We observed modulation of neurotransmitter receptor mRNA expression in CIA osteoclasts without affecting protein level. CIA stage-dependently altered marker gene expression associated with osteoclast differentiation and activity without affecting osteoclast number or activity. Neurotransmitter stimulation modulated osteoclast differentiation, apoptosis and activity. VIP, NA and adenylyl cyclase activator NKH477 inhibited cathepsin K activity and osteoclastogenesis (NKH477, 10-6M NA) whereas ACh mostly acted pro-osteoclastogenic. We conclude that CIA alone does not affect metabolism of in vitro generated osteoclasts whereas stimulation with NA, VIP plus specific activation of adenylyl cyclase induced anti-resorptive effects probably mediated via cAMP signaling. Contrary, we suggest pro-osteoclastogenic and pro-resorptive properties of ACh mediated via muscarinic receptors. PMID:26431344

  9. Differential stimulation of the retina with subretinally injected exogenous neurotransmitter: A biomimetic alternative to electrical stimulation

    PubMed Central

    Rountree, Corey M.; Inayat, Samsoon; Troy, John B.; Saggere, Laxman

    2016-01-01

    Subretinal stimulation of the retina with neurotransmitters, the normal means of conveying visual information, is a potentially better alternative to electrical stimulation widely used in current retinal prostheses for treating blindness from photoreceptor degenerative diseases. Yet, no subretinal electrical or chemical stimulation study has stimulated the OFF and ON pathways differentially through inner retinal activation. Here, we demonstrate the feasibility of differentially stimulating retinal ganglion cells (RGCs) through the inner nuclear layer of the retina with glutamate, a primary neurotransmitter chemical, in a biomimetic way. We show that controlled pulsatile delivery of glutamate into the subsurface of explanted wild-type rat retinas elicits highly localized simultaneous inhibitory and excitatory spike rate responses in OFF and ON RGCs. We also present the spatiotemporal characteristics of RGC responses to subretinally injected glutamate and the therapeutic stimulation parameters. Our findings could pave the way for future development of a neurotransmitter-based subretinal prosthesis offering more naturalistic vision and better visual acuity than electrical prostheses. PMID:27929043

  10. A neuronal Sec1 homolog regulates neurotransmitter release at the squid giant synapse.

    PubMed

    Dresbach, T; Burns, M E; O'Connor, V; DeBello, W M; Betz, H; Augustine, G J

    1998-04-15

    Sec1-related proteins are essential for membrane fusion at distinct stages of the constitutive and regulated secretory pathways in eukaryotic cells. Studies of neuronal isoforms of the Sec1 protein family have yielded evidence for both positive and negative regulatory functions of these proteins in neurotransmitter release. Here, we have identified a squid neuronal homolog (s-Sec1) of Sec1 proteins and examined its function in neurotransmitter release at the squid giant synapse. Microinjection of s-Sec1 into the presynaptic terminal of the giant synapse inhibited evoked neurotransmitter release, but this effect was prevented by coinjecting the cytoplasmic domain of squid syntaxin (s-syntaxin), one of the binding partners of s-Sec1. A 24 amino acid peptide fragment of s-Sec1, which inhibited the binding of s-Sec1 to s-syntaxin in vitro, completely blocked release, suggesting an essential function of the s-Sec1/s-syntaxin interaction in transmitter release. Electron microscopy showed that injection of s-Sec1 did not change the spatial distribution of synaptic vesicles at presynaptic release sites ("active zones"), whereas the inhibitory peptide increased the number of docked vesicles. These distinct morphological effects lead us to conclude that Sec1 proteins function at different stages of synaptic vesicle exocytosis, and that an interaction of s-Sec1 with syntaxin-at a stage blocked by the peptide-is necessary for docked vesicles to fuse.

  11. Neurotransmitter measurement with a fiber optic probe using pulsed ultraviolet resonance Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Schulze, H. Georg; Greek, L. Shane; Blades, Michael W.; Bree, Alan V.; Gorzalka, Boris B.; Turner, Robin F. B.

    1997-05-01

    Many techniques have been developed to investigate the chemistry associated with brain activity. These techniques generally fall into two categories: fast techniques with species restricted sensitivity and slow techniques with generally unrestricted species sensitivity. Therefore, a need exists for a fast non-invasive technique sensitive to a wide array of biologically relevant compounds in order to measure chemical brain events in real time. The work presented here describes the progress made toward the development of a novel neurotransmitter probe. A fiber-optic linked Raman and tunable ultraviolet resonance Raman system was assembled with custom designed optical fiber probes. Probes of several different geometries were constructed and their working curves obtained in aqueous mixtures of methyl orange and potassium nitrate to determine the best probe configuration given particular sample characteristics. Using this system, the ultraviolet resonance Raman spectra of some neurotransmitters were measured with a fiber-optic probe and are reported here for the first time. The probe has also been used to measure neurotransmitter secretions obtained from depolarized rat pheochromocytoma cells.

  12. Individual differences in visual motion perception and neurotransmitter concentrations in the human brain.

    PubMed

    Takeuchi, Tatsuto; Yoshimoto, Sanae; Shimada, Yasuhiro; Kochiyama, Takanori; Kondo, Hirohito M

    2017-02-19

    Recent studies have shown that interindividual variability can be a rich source of information regarding the mechanism of human visual perception. In this study, we examined the mechanisms underlying interindividual variability in the perception of visual motion, one of the fundamental components of visual scene analysis, by measuring neurotransmitter concentrations using magnetic resonance spectroscopy. First, by psychophysically examining two types of motion phenomena-motion assimilation and contrast-we found that, following the presentation of the same stimulus, some participants perceived motion assimilation, while others perceived motion contrast. Furthermore, we found that the concentration of the excitatory neurotransmitter glutamate-glutamine (Glx) in the dorsolateral prefrontal cortex (Brodmann area 46) was positively correlated with the participant's tendency to motion assimilation over motion contrast; however, this effect was not observed in the visual areas. The concentration of the inhibitory neurotransmitter γ-aminobutyric acid had only a weak effect compared with that of Glx. We conclude that excitatory process in the suprasensory area is important for an individual's tendency to determine antagonistically perceived visual motion phenomena.This article is part of the themed issue 'Auditory and visual scene analysis'.

  13. The molecular basis of memory. Part 3: tagging with “emotive” neurotransmitters

    PubMed Central

    Marx, Gerard; Gilon, Chaim

    2014-01-01

    Many neurons of all animals that exhibit memory (snails, worms, flies, vertebrae) present arborized shapes with many varicosities and boutons. These neurons, release neurotransmitters and contain ionotropic receptors that produce and sense electrical signals (ephaptic transmission). The extended shapes maximize neural contact with the surrounding neutrix [defined as: neural extracellular matrix (nECM) + diffusible (neurometals and neurotransmitters)] as well as with other neurons. We propose a tripartite mechanism of animal memory based on the dynamic interactions of splayed neurons with the “neutrix.” Their interactions form cognitive units of information (cuinfo), metal-centered complexes within the nECM around the neuron. Emotive content is provided by NTs, which embody molecular links between physiologic (body) responses and psychic feelings. We propose that neurotransmitters form mixed complexes with cuinfo used for tagging emotive memory. Thus, NTs provide encoding option not available to a Turing, binary-based, device. The neurons employ combinatorially diverse options, with >10 NMs and >90 NTs for encoding (“flavoring”) cuinfo with emotive tags. The neural network efficiently encodes, decodes and consolidates related (entangled) sets of cuinfo into a coherent pattern, the basis for emotionally imbued memory, critical for determining a behavioral choice aimed at survival. The tripartite mechanism with tagging of NTs permits of a causal connection between physiology and psychology. PMID:24778616

  14. Altered levels of brain neurotransmitter from new born rabbits with intrauterine restriction.

    PubMed

    Hernández-Andrade, E; Cortés-Camberos, A J; Díaz, N F; Flores-Herrera, H; García-López, G; González-Jiménez, M; Santamaría, A; Molina-Hernández, A

    2015-01-01

    Fetal intrauterine growth restriction generates chronic hypoxia due to placental insufficiency. Despite the hemodynamic process of blood flow, redistributions are taking place in key organs such as the fetal brain during intrauterine growth restriction, in order to maintain oxygen and nutrients supply. The risk of short- and long-term neurological effects are still present in hypoxic offspring. Most studies previously reported the effect of hypoxia on the levels of a single neurotransmitter, making it difficult to have a better understanding of the relationship among neurotransmitter levels and the defects reported in products that suffer intrauterine growth restriction, such as motor development, coordination and execution of movement, and the learning-memory process. The aim of this study was to evaluate the levels of gamma-aminobutyric acid, glutamate, dopamine and serotonin in three structures of the brain related to the above-mentioned function such as the cerebral cortex, the striatum, and the hippocampus in the chronic hypoxic newborn rabbit model. Our results showed a significant increase in glutamate and dopamine levels in all studied brain structures and a significant decrease in gamma-aminobutyric acid levels but only in the striatum, suggesting that the imbalance on the levels of several neurotransmitters could be involved in new born brain damage due to perinatal hypoxia.

  15. Sex and intrauterine growth restriction modify brain neurotransmitters profile of newborn piglets.

    PubMed

    Vázquez-Gómez, M; Valent, D; García-Contreras, C; Arroyo, L; Óvilo, C; Isabel, B; Bassols, A; González-Bulnes, A

    2016-12-01

    The current study aimed to determine, using a swine model of intrauterine growth restriction (IUGR), whether short- and long-term neurological deficiencies and interactive dysfunctions of Low Birth-Weight (LBW) offspring might be related to altered pattern of neurotransmitters. Hence, we compared the quantities of different neurotransmitters (catecholamines and indoleamines), which were determined by HPLC, at brain structures related to the limbic system (hippocampus and amygdala) in 14 LBW and 10 Normal Body-Weight (NBW) newborn piglets. The results showed, firstly, significant effects of sex on the NBW newborns, with females having higher dopamine (DA) concentrations than males. The IUGR processes affected DA metabolism, with LBW piglets having lower concentrations of noradrenaline at the hippocampus and higher concentrations of the DA metabolites, homovanillic acid (HVA), at both the hippocampus and the amygdala than NBW neonates. The effects of IUGR were modulated by sex; there were no significant differences between LBW and NBW females, but LBW males had higher HVA concentration at the amygdala and higher concentration of 5-hydroxyindoleacetic acid, the serotonin metabolite, at the hippocampus than NBW males. In conclusion, the present study shows that IUGR is mainly related to changes, modulated by sex, in the concentrations of catecholamine neurotransmitters, which are related to adaptation to physical activity and to essential cognitive functions such as learning, memory, reward-motivated behavior and stress.

  16. Protein-protein interactions and protein modules in the control of neurotransmitter release.

    PubMed Central

    Benfenati, F; Onofri, F; Giovedí, S

    1999-01-01

    Information transfer among neurons is operated by neurotransmitters stored in synaptic vesicles and released to the extracellular space by an efficient process of regulated exocytosis. Synaptic vesicles are organized into two distinct functional pools, a large reserve pool in which vesicles are restrained by the actin-based cytoskeleton, and a quantitatively smaller releasable pool in which vesicles approach the presynaptic membrane and eventually fuse with it on stimulation. Both synaptic vesicle trafficking and neurotransmitter release depend on a precise sequence of events that include release from the reserve pool, targeting to the active zone, docking, priming, fusion and endocytotic retrieval of synaptic vesicles. These steps are mediated by a series of specific interactions among cytoskeletal, synaptic vesicle, presynaptic membrane and cytosolic proteins that, by acting in concert, promote the spatial and temporal regulation of the exocytotic machinery. The majority of these interactions are mediated by specific protein modules and domains that are found in many proteins and are involved in numerous intracellular processes. In this paper, the possible physiological role of these multiple protein-protein interactions is analysed, with ensuing updating and clarification of the present molecular model of the process of neurotransmitter release. PMID:10212473

  17. Organic electronics for precise delivery of neurotransmitters to modulate mammalian sensory function

    NASA Astrophysics Data System (ADS)

    Simon, Daniel T.; Kurup, Sindhulakshmi; Larsson, Karin C.; Hori, Ryusuke; Tybrandt, Klas; Goiny, Michel; Jager, Edwin W. H.; Berggren, Magnus; Canlon, Barbara; Richter-Dahlfors, Agneta

    2009-09-01

    Significant advances have been made in the understanding of the pathophysiology, molecular targets and therapies for the treatment of a variety of nervous-system disorders. Particular therapies involve electrical sensing and stimulation of neural activity, and significant effort has therefore been devoted to the refinement of neural electrodes. However, direct electrical interfacing suffers from some inherent problems, such as the inability to discriminate amongst cell types. Thus, there is a need for novel devices to specifically interface nerve cells. Here, we demonstrate an organic electronic device capable of precisely delivering neurotransmitters in vitro and in vivo. In converting electronic addressing into delivery of neurotransmitters, the device mimics the nerve synapse. Using the peripheral auditory system, we show that out of a diverse population of cells, the device can selectively stimulate nerve cells responding to a specific neurotransmitter. This is achieved by precise electronic control of electrophoretic migration through a polymer film. This mechanism provides several sought-after features for regulation of cell signalling: exact dosage determination through electrochemical relationships, minimally disruptive delivery due to lack of fluid flow, and on-off switching. This technology has great potential as a therapeutic platform and could help accelerate the development of therapeutic strategies for nervous-system disorders.

  18. [Neurophysiological and neurotransmitter mechanisms of behavior inhibition in normal and pathological conditions].

    PubMed

    Shul'gina, G I

    2010-01-01

    The data concerning neurophysiological and neurotransmitter mechanisms of two principal kinds of inhibition of behavior is carried out: the inborn genetically determined inhibition and that developed in the course of training. On the basis of the experiments performed by the author and the literature on general neurophysiology the conclusion is made that development of inhibition of behavior during training (i.e. internal inhibition, including "latent inhibition") is determined by the relative strengthening of inhibitory hyperpolarization processes either locally (in a conditioned stimulus analyzer) or globally in the brain cortex and other brain structures during intensification of the inhibitory state (profound inhibition of a reflex and sleep). The main neurotransmitter in development of internal inhibition is gamma-aminobutyric acid. Inhibition of behavior without preliminary training arises either during the action of superstrong stimuli, (exceeding the maximum value inhibition) or during interaction of two and more active systems. A stronger one of these two systems suppresses another one (external inhibition, dominant inhibition, "freezing", "prepulse inhibition", etc.). These kinds of inhibition develop on the background of EEG activation, which suggests participation in their realization of reticular structures and corresponding neurotransmitters (acetylcholine, noradrenalin, dopamine and serotonin). Behavior pathology causes a break of the balanced interaction between the excitation and inhibition in the central nervous system. This affects both genetically determined forms of behavior inhibition and the learned internal inhibition.

  19. Simultaneous analysis of multiple neurotransmitters by hydrophilic interaction liquid chromatography coupled to tandem mass spectrometry.

    PubMed

    Tufi, Sara; Lamoree, Marja; de Boer, Jacob; Leonards, Pim

    2015-05-22

    Neurotransmitters are endogenous metabolites that allow the signal transmission across neuronal synapses. Their biological role is crucial for many physiological functions and their levels can be changed by several diseases. Because of their high polarity, hydrophilic interaction liquid chromatography (HILIC) is a promising tool for neurotransmitter analysis. Due to the large number of HILIC stationary phases available, an evaluation of the column performances and retention behaviors has been performed on five different commercial HILIC packing materials (silica, amino, amide and two zwitterionic stationary phases). Several parameters like the linear correlation between retention and the distribution coefficient (logD), the separation factor k and the column resolution Rs have been investigated and the column performances have been visualized with a heat map and hierarchical clustering analysis. An optimized and validated HILIC-MS/MS method based on the ZIC-cHILIC column is proposed for the simultaneous detection and quantification of twenty compounds consisting of neurotransmitters, precursors and metabolites: 3-methoxytyramine (3-MT), 5-hydroxyindoleacetic acid (5-HIAA), 5-hydroxy-L-tripthophan, acetylcholine, choline, L-3,4-dihydroxyphenylalanine (L-DOPA), dopamine, epinephrine, γ-aminobutyric acid (GABA), glutamate, glutamine, histamine, histidine, L-tryptophan, L-tyrosine, norepinephrine, normetanephrine, phenylalanine, serotonin and tyramine. The method was applied to neuronal metabolite profiling of the central nervous system of the freshwater snail Lymnaea stagnalis. This method is suitable to explore neuronal metabolism and its alteration in different biological matrices.

  20. Organic anion transporter (Slc22a) family members as mediators of toxicity

    SciTech Connect

    Sweet, Douglas H. . E-mail: sweetd@musc.edu

    2005-05-01

    Exposure of the body to toxic organic anions is unavoidable and occurs from both intentional and unintentional sources. Many hormones, neurotransmitters, and waste products of cellular metabolism, or their metabolites, are organic anions. The same is true for a wide variety of medications, herbicides, pesticides, plant and animal toxins, and industrial chemicals and solvents. Rapid and efficient elimination of these substances is often the body's best defense for limiting both systemic exposure and the duration of their pharmacological or toxicological effects. For organic anions, active transepithelial transport across the renal proximal tubule followed by elimination via the urine is a major pathway in this detoxification process. Accordingly, a large number of organic anion transport proteins belonging to several different gene families have been identified and found to be expressed in the proximal nephron. The function of these transporters, in combination with the high volume of renal blood flow, predisposes the kidney to increased toxic susceptibility. Understanding how the kidney mediates the transport of organic anions is integral to achieving desired therapeutic outcomes in response to drug interactions and chemical exposures, to understanding the progression of some disease states, and to predicting the influence of genetic variation upon these processes. This review will focus on the organic anion transporter (OAT) family and discuss the known members, their mechanisms of action, subcellular localization, and current evidence implicating their function as a determinant of the toxicity of certain endogenous and xenobiotic agents.

  1. Pickup Ion Acceleration at the Solar Wind Termination Shock Based on a Focused Transport Approach Including a q-Gaussian Turbulence Model of Variations in the Spiral Magnetic Field Angle

    NASA Astrophysics Data System (ADS)

    Ye, J.; le Roux, J. A.; Arthur, A. D.

    2015-12-01

    Voyager spacecraft observations indicate that interstellar pickup ions are accelerated to ~1 MeV locally at the solar wind termination shock. We present modeling results of the diffusive shock acceleration (DSA) of locally born interstellar pickup ions at the solar wind termination shock by solving the standard focused transport equation numerically. Local time variations in the Parker spiral magnetic field angle are modeled using a q-Gaussian statistical description. The main results are: (1) The injection and DSA of pickup ions depends on the shape and width of the q-Gaussian distribution of the Parker spiral magnetic field angle. (2) Likewise, the accelerated pickup ion pitch-angle distribution also depends on the q-Gaussian distribution of the magnetic field angle. (3) The simulated accelerated pickup ion spectrum is much quieter far downstream than just behind the termination shock as observations show. (4) Magnetic reflection of accelerated pickup ions by the cross-shock magnetic field gradient results in the sporadic formation of highly anisotropic, energy-dependent intensity spikes in the accelerated pickup proton distribution at the termination shock.

  2. Individual synaptic vesicles from the electroplaque of Torpedo californica, a classic cholinergic synapse, also contain transporters for glutamate and ATP

    PubMed Central

    Li, Huinan; Harlow, Mark L.

    2014-01-01

    Abstract The type of neurotransmitter secreted by a neuron is a product of the vesicular transporters present on its synaptic vesicle membranes and the available transmitters in the local cytosolic environment where the synaptic vesicles reside. Synaptic vesicles isolated from electroplaques of the marine ray, Torpedo californica, have served as model vesicles for cholinergic neurotransmission. Many lines of evidence support the idea that in addition to acetylcholine, additional neurotransmitters and/or neuromodulators are also released from cholinergic synapses. We identified the types of vesicular neurotransmitter transporters present at the electroplaque using immunoblot and immunofluoresence techniques with antibodies against the vesicle acetylcholine transporter (VAChT), the vesicular glutamate transporters (VGLUT1, 2, and 3), and the vesicular nucleotide transporter (VNUT). We found that VAChT, VNUT, VGLUT 1 and 2, but not 3 were present by immunoblot, and confirmed that the antibodies were specific to proteins of the axons and terminals of the electroplaque. We used a single‐vesicle imaging technique to determine whether these neurotransmitter transporters were present on the same or different populations of synaptic vesicles. We found that greater than 85% of vesicles that labeled for VAChT colabeled with VGLUT1 or VGLUT2, and approximately 70% colabeled with VNUT. Based upon confidence intervals, at least 52% of cholinergic vesicles isolated are likely to contain all four transporters. The presence of multiple types of neurotransmitter transporters – and potentially neurotransmitters – in individual synaptic vesicles raises fundamental questions about the role of cotransmitter release and neurotransmitter synergy at cholinergic synapses. PMID:24744885

  3. Environment- and activity-dependent dopamine neurotransmitter plasticity in the adult substantia nigra.

    PubMed

    Aumann, Tim D

    2016-04-01

    The ability of neurons to change the amount or type of neurotransmitter they use, or 'neurotransmitter plasticity', is an emerging new form of adult brain plasticity. For example, it has recently been shown that neurons in the adult rat hypothalamus up- or down-regulate dopamine (DA) neurotransmission in response to the amount of light the animal receives (photoperiod), and that this in turn affects anxiety- and depressive-like behaviors (Dulcis et al., 2013). In this Chapter I consolidate recent evidence from my laboratory suggesting neurons in the adult mouse substantia nigra pars compacta (SNc) also undergo DA neurotransmitter plasticity in response to persistent changes in their electrical activity, including that driven by the mouse's environment or behavior. Specifically, we have shown that the amounts of tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) gene promoter activity, TH mRNA and TH protein in SNc neurons increases or decreases after ∼20h of altered electrical activity. Also, infusion of ion-channel agonists or antagonists into the midbrain for 2 weeks results in ∼10% (∼500 neurons) more or fewer TH immunoreactive (TH+) SNc neurons, with no change in the total number of SNc neurons (TH+ and TH-). Targeting ion-channels mediating cell-autonomous pacemaker activity in, or synaptic input and afferent pathways to, SNc neurons are equally effective in this regard. In addition, exposing mice to different environments (sex pairing or environment enrichment) for 1-2 weeks induces ∼10% more or fewer TH+ SNc (and ventral tegmental area or VTA) neurons and this is abolished by concurrent blockade of synaptic transmission in midbrain. Although further research is required to establish SNc (and VTA) DA neurotransmitter plasticity, and to determine whether it alters brain function and behavior, it is an exciting prospect because: (1) It may play important roles in movement, motor learning, reward, motivation, memory and cognition; and (2

  4. Mild closed head traumatic brain injury-induced changes in monoamine neurotransmitters in the trigeminal subnuclei of a rat model: mechanisms underlying orofacial allodynias and headache

    PubMed Central

    Mustafa, Golam; Hou, Jiamei; Nelson, Rachel; Tsuda, Shigeharu; Jahan, Mansura; Mohammad, Naweed S.; Watts, Joseph V.; Thompson, Floyd J.; Bose, Prodip

    2017-01-01

    Our recent findings have demonstrated that rodent models of closed head traumatic brain injury exhibit comprehensive evidence of progressive and enduring orofacial allodynias, a hypersensitive pain response induced by non-painful stimulation. These allodynias, tested using thermal hyperalgesia, correlated with changes in several known pain signaling receptors and molecules along the trigeminal pain pathway, especially in the trigeminal nucleus caudalis. This study focused to extend our previous work to investigate the changes in monoamine neurotransmitter immunoreactivity changes in spinal trigeminal nucleus oralis, pars interpolaris and nucleus tractus solitaries following mild to moderate closed head traumatic brain injury, which are related to tactile allodynia, touch-pressure sensitivity, and visceral pain. Our results exhibited significant alterations in the excitatory monoamine, serotonin, in spinal trigeminal nucleus oralis and pars interpolaris which usually modulate tactile and mechanical sensitivity in addition to the thermal sensitivity. Moreover, we also detected a robust alteration in the expression of serotonin, and inhibitory molecule norepinephrine in the nucleus tractus solitaries, which might indicate the possibility of an alteration in visceral pain, and existence of other morbidities related to solitary nucleus dysfunction in this rodent model of mild to moderate closed head traumatic brain injury. Collectively, widespread changes in monoamine neurotransmitter may be related to orofacial allodynhias and headache after traumatic brain injury. PMID:28761433

  5. GABA transporters as targets for new drugs.

    PubMed

    Sałat, Kinga; Kulig, Katarzyna

    2011-02-01

    GABA, the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tone that counterbalances neuronal excitation. The identification and subsequent development of GABA-transport inhibitors has shown the important role that GABA transporters play in the control of the CNS. To date, four GABA transporters have been cloned (GAT1-4). Compounds that inhibit GABA uptake are targets for epilepsy treatment. Currently, they are also being investigated for other possible indications such as the treatment of psychosis, general anxiety and sleep disorders, drug addiction, acute and chronic pain. These and other issues are discussed in this article.

  6. Pharmacology of Glutamate Transport in the CNS: Substrates and Inhibitors of Excitatory Amino Acid Transporters (EAATs) and the Glutamate/Cystine Exchanger System x c -

    NASA Astrophysics Data System (ADS)

    Bridges, Richard J.; Patel, Sarjubhai A.

    As the primary excitatory neurotransmitter in the mammalian CNS, l-glutamate participates not only in standard fast synaptic communication, but also contributes to higher order signal processing, as well as neuropathology. Given this variety of functional roles, interest has been growing as to how the extracellular concentrations of l-glutamate surrounding neurons are regulated by cellular transporter proteins. This review focuses on two prominent systems, each of which appears capable of influencing both the signaling and pathological actions of l-glutamate within the CNS: the sodium-dependent excitatory amino acid transporters (EAATs) and the glutamate/cystine exchanger, system x c - (Sx c -). While the family of EAAT subtypes limit access to glutamate receptors by rapidly and efficiently sequestering l-glutamate in neurons and glia, Sxc - provides a route for the export of glutamate from cells into the extracellular environment. The primary intent of this work is to provide an overview of the inhibitors and substrates that have been developed to delineate the pharmacological specificity of these transport systems, as well as be exploited as probes with which to selectively investigate function. Particular attention is paid to the development of small molecule templates that mimic the structural properties of the endogenous substrates, l-glutamate, l-aspartate and l-cystine and how strategic control of functional group position and/or the introduction of lipophilic R-groups can impact multiple aspects of the transport process, including: subtype selectivity, inhibitory potency, and substrate activity.

  7. The Role of TM5 in Na2 Release and the Conformational Transition of Neurotransmitter:Sodium Symporters toward the Inward-Open State.

    PubMed

    Stolzenberg, Sebastian; Li, Zheng; Quick, Matthias; Malinauskaite, Lina; Nissen, Poul; Weinstein, Harel; Javitch, Jonathan A; Shi, Lei

    2017-03-20

    Neurotransmitter:sodium symporters (NSS) terminate neurotransmission by the reuptake of released neurotransmitters. This active accumulation of substrate against its concentration gradient is driven by the transmembrane Na+ gradient and requires that the transporter traverses several conformational states. LeuT, a prokaryotic NSS homolog, has been crystallized in outward-open, outward-occluded and inward-open states. Two crystal structures of another prokaryotic NSS homolog, the multi-hydrophobic amino acid transporter (MhsT) from Bacillus halodurans have been resolved in novel inward-occluded states, with the extracellular vestibule closed and the intracellular portion of TM5 (TM5i) in either an unwound or a helical conformation. We have investigated the potential involvement of TM5i in binding and unbinding of Na2, i.e. the Na(+) bound in the Na2 site, by carrying out comparative molecular dynamics simulations of the models derived from the two MhsT structures. We find that the helical TM5i conformation is associated with a higher propensity for Na2 release, which leads to the repositioning of the N terminus (NT) and transition to an inward-open state. By using comparative interaction network analysis, we also identify allosteric pathways connecting TM5i and the Na2 binding site to the extracellular and intracellular regions. Based on our combined computational and mutagenesis studies of MhsT and LeuT, we propose that TM5i plays a key role in Na2 binding and release associated with the conformational transition toward the inward-open state, a role that is likely to be shared across the NSS family.

  8. An Update of the Classical and Novel Methods Used for Measuring Fast Neurotransmitters During Normal and Brain Altered Function

    PubMed Central

    Cifuentes Castro, Victor Hugo; López Valenzuela, Carmen Lucía; Salazar Sánchez, Juan Carlos; Peña, Kenia Pardo; López Pérez, Silvia J.; Ibarra, Jorge Ortega; Villagrán, Alberto Morales

    2014-01-01

    To understand better the cerebral functions, several methods have been developed to study the brain activity, they could be related with morphological, electrophysiological, molecular and neurochemical techniques. Monitoring neurotransmitter concentration is a key role to know better how the brain works during normal or pathological conditions, as well as for studying the changes in neurotransmitter concentration with the use of several drugs that could affect or reestablish the normal brain activity. Immediate response of the brain to environmental conditions is related with the release of the fast acting neurotransmission by glutamate (Glu), γ-aminobutyric acid (GABA) and acetylcholine (ACh) through the opening of ligand-operated ion channels. Neurotransmitter release is mainly determined by the classical microdialysis technique, this is generally coupled to high performance liquid chromatography (HPLC). Detection of neurotransmitters can be done by fluorescence, optical density, electrochemistry or other detection systems more sophisticated. Although the microdialysis method is the golden technique to monitor the brain neurotransmitters, it has a poor temporal resolution. Recently, with the use of biosensor the drawback of temporal resolution has been improved considerably, however other inconveniences have merged, such as stability, reproducibility and the lack of reliable biosensors mainly for GABA. The aim of this review is to show the important advances in the different ways to measure neurotransmitter concentrations; both with the use of classic techniques as well as with the novel methods and alternant approaches to improve the temporal resolution. PMID:25977677

  9. Coupled ion Binding and Structural Transitions Along the Transport Cycle of Glutamate Transporters

    SciTech Connect

    Verdon, Gregory; Oh, SeCheol; Serio, Ryan N.; Boudker, Olga

    2014-05-19

    Membrane transporters that clear the neurotransmitter glutamate from synapses are driven by symport of sodium ions and counter-transport of a potassium ion. Previous crystal structures of a homologous archaeal sodium and aspartate symporter showed that a dedicated transport domain carries the substrate and ions across the membrane. We report new crystal structures of this homologue in ligand-free and ions-only bound outward- and inward-facing conformations. We then show that after ligand release, the apo transport domain adopts a compact and occluded conformation that can traverse the membrane, completing the transport cycle. Sodium binding primes the transport domain to accept its substrate and triggers extracellular gate opening, which prevents inward domain translocation until substrate binding takes place. Moreover, we describe a new cation-binding site ideally suited to bind a counter-transported ion. We suggest that potassium binding at this site stabilizes the translocation-competent conformation of the unloaded transport domain in mammalian homologues.

  10. Cloning of the cocaine-sensitive bovine dopamine transporter

    SciTech Connect

    Usdin, T.B.; Chen, C.; Brownstein, M.J.; Hoffman, B.J. ); Mezey, E. )

    1991-12-15

    A cDNA encoding the dopamine transporter from bovine brain substantia nigra was identified on the basis of its structural homology to other, recently cloned, neurotransmitter transporters. The sequence of the 693-amino acid protein is quite similar to those of the rat {gamma}-aminobutyric acid, human norepinephrine, and rat serotonin transporters. Dopamine transporter mRNA was detected by in situ hybridization in the substantia nigra but not in the locus coeruleus, raphe, caudate, or other brain areas. ({sup 3}H)Dopamine accumulation in tissue culture cells transfected with the cDNA was inhibited by amphetamine, cocaine, and specific inhibitors of dopamine transports, including GBR12909.

  11. Selective amino acid substitutions convert the creatine transporter to a gamma-aminobutyric acid transporter.

    PubMed

    Dodd, Joanna R; Christie, David L

    2007-05-25

    The creatine transporter (CRT) is a member of a large family of sodium-dependent neurotransmitter and amino acid transporters. The CRT is closely related to the gamma-aminobutyric acid (GABA) transporter, GAT-1, yet GABA is not an effective substrate for the CRT. The high resolution structure of a prokaryotic homologue, LeuT has revealed precise details of the substrate binding site for leucine (Yamashita, A., Singh, S. K., Kawate, T., Jin, Y., and Gouaux, E. (2005) Nature 437, 215-223). We have now designed mutations based on sequence comparisons of the CRT with GABA transporters and the LeuT structural template in an attempt to alter the substrate specificity of the CRT. Combinations of two or three amino acid substitutions at four selected positions resulted in the loss of creatine transport activity and gain of a specific GABA transport function. GABA transport by the "gain of function" mutants was sensitive to nipecotic acid, a competitive inhibitor of GABA transporters. Our results show LeuT to be a good structural model to identify amino acid residues involved in the substrate and inhibitor selectivity of eukaryotic sodium-dependent neurotransmitter and amino acid transporters. However, modification of the binding site alone appears to be insufficient for efficient substrate translocation. Additional residues must mediate the conformational changes required for the diffusion of substrate from the binding site to the cytoplasm.

  12. SELF ADMINISTRATION OF OXYCODONE BY ADOLESCENT AND ADULT MICE AFFECTS STRIATAL NEUROTRANSMITTER RECEPTOR GENE EXPRESSION

    PubMed Central

    Mayer-Blackwell, B.; Schlussman, S. D.; Butelman, E. R.; Ho, A.; Ott, J.; Kreek, M. J.; Zhang, Y.

    2014-01-01

    Illicit use of prescription opioid analgesics (e.g., oxycodone) in adolescence is a pressing public health issue. Our goal was to determine whether oxycodone self administration differentially affects striatal neurotransmitter receptor gene expression in the dorsal striatum of adolescent compared to adult C57BL/6J mice. Groups of adolescent mice (4 weeks old, n= 12) and of adult mice (11 weeks old, n= 11) underwent surgery during which a catheter was implanted into their jugular veins. After recovering from surgery, mice self administered oxycodone (0.25 mg/kg/infusion) 2 h/day for 14 consecutive days or served as yoked saline controls. Mice were sacrificed within 1 h after the last self-administration session and the dorsal striatum was isolated for mRNA analysis. Gene expression was analyzed with real time PCR using a commercially available neurotransmitter receptor PCR array containing 84 genes. We found that adolescent mice self administered less oxycodone than adult mice over the 14 days. Monoamine oxidase A (Maoa) and neuropeptide Y receptor 5 mRNA levels were lower in adolescent mice than in adult mice without oxycodone exposure. Oxycodone self administration increased Maoa mRNA levels compared to controls in both age groups. There was a positive correlation of the amount of oxycodone self administered in the last session or across 14 sessions with Maoa mRNA levels. Gastrin-releasing peptide receptor mRNA showed a significant Drug × Age interaction, with point-wise significance. More genes in the dorsal striatum of adolescents (19) changed in response to oxycodone self administration compared to controls than in adult (4) mice. Overall, this study demonstrates that repeated oxycodone self administration alters neurotransmitter receptors gene expression in the dorsal striatum of adolescent and adult mice. PMID:24220688

  13. Chemical stimulation of rat retinal neurons: feasibility of an epiretinal neurotransmitter-based prosthesis

    NASA Astrophysics Data System (ADS)

    Inayat, Samsoon; Rountree, Corey M.; Troy, John B.; Saggere, Laxman

    2015-02-01

    Objective. No cure currently exists for photoreceptor degenerative diseases, which cause partial or total blindness in millions of people worldwide. Electrical retinal prostheses have been developed by several groups with the goal of restoring vision lost to these diseases, but electrical stimulation has limitations. It excites both somas and axons, activating retinal pathways nonphysiologically, and limits spatial resolution because of current spread. Chemical stimulation of retinal ganglion cells (RGCs) using the neurotransmitter glutamate has been suggested as an alternative to electrical stimulation with some significant advantages. However, sufficient scientific data to support developing a chemical-based retinal prosthesis is lacking. The goal of this study was to investigate the feasibility of a neurotransmitter-based retinal prosthesis and determine therapeutic stimulation parameters. Approach. We injected controlled amounts of glutamate into rat retinas from the epiretinal side ex vivo via micropipettes using a pressure injection system and recorded RGC responses with a multielectrode array. Responsive units were identified using a spike rate threshold of 3 Hz. Main results. We recorded both somal and axonal units and demonstrated successful glutamatergic stimulation across different RGC subtypes. Analyses show that exogenous glutamate acts on RGC synapses similar to endogenous glutamate and, unlike electrical prostheses, stimulates only RGC somata. The spatial spread of glutamate stimulation was ˜ 290 μm from the injection site, comparable to current electrical prostheses. Further, the glutamate injections produced spatially differential responses in OFF, ON, and ON-OFF RGC subtypes, suggesting that differential stimulation of the OFF and ON systems may be possible. A temporal resolution of 3.2 Hz was obtained, which is a rate suitable for spatial vision. Significance. We provide strong support for the feasibility of an epiretinal neurotransmitter

  14. Self administration of oxycodone by adolescent and adult mice affects striatal neurotransmitter receptor gene expression.

    PubMed

    Mayer-Blackwell, B; Schlussman, S D; Butelman, E R; Ho, A; Ott, J; Kreek, M J; Zhang, Y

    2014-01-31

    Illicit use of prescription opioid analgesics (e.g., oxycodone) in adolescence is a pressing public health issue. Our goal was to determine whether oxycodone self administration differentially affects striatal neurotransmitter receptor gene expression in the dorsal striatum of adolescent compared to adult C57BL/6J mice. Groups of adolescent mice (4 weeks old, n=12) and of adult mice (11 weeks old, n=11) underwent surgery during which a catheter was implanted into their jugular veins. After recovering from surgery, mice self administered oxycodone (0.25 mg/kg/infusion) 2 h/day for 14 consecutive days or served as yoked saline controls. Mice were sacrificed within 1h after the last self-administration session and the dorsal striatum was isolated for mRNA analysis. Gene expression was analyzed with real time PCR using a commercially available neurotransmitter receptor PCR array containing 84 genes. We found that adolescent mice self administered less oxycodone than adult mice over the 14 days. Monoamine oxidase A (Maoa) and neuropeptide Y receptor 5 mRNA levels were lower in adolescent mice than in adult mice without oxycodone exposure. Oxycodone self administration increased Maoa mRNA levels compared to controls in both age groups. There was a positive correlation of the amount of oxycodone self administered in the last session or across 14 sessions with Maoa mRNA levels. Gastrin-releasing peptide receptor mRNA showed a significant Drug × Age interaction, with point-wise significance. More genes in the dorsal striatum of adolescents (19) changed in response to oxycodone self administration compared to controls than in adult (4) mice. Overall, this study demonstrates that repeated oxycodone self administration alters neurotransmitter receptors gene expression in the dorsal striatum of adolescent and adult mice.

  15. Effects of colistin on amino acid neurotransmitters and blood-brain barrier in the mouse brain.

    PubMed

    Wang, Jian; Yi, Meishuang; Chen, Xueping; Muhammad, Ishfaq; Liu, Fangping; Li, Rui; Li, Jian; Li, Jichang

    2016-01-01

    Neurotoxicity is one of the major potential side effects of colistin therapy. However, the mechanistic aspects of colistin-induced neurotoxicity remain largely unknown. The objective of this study was to examine the effects of colistin on the blood-brain barrier (BBB) and amino acid neurotransmitters in the cerebral cortex of mouse. Mice were divided into four groups (n=5) and were administrated intravenously with 15mg/kg/day of colistin sulfate for 1, 3 and 7days successively while the control group was administrated intravenously with saline solution. The permeability and ultrastructure of the BBB were detected using the Evans blue (EB) dye and transmission electron microscopy (TEM), and the expression of Claudin-5 were determined by real-time PCR examination and western blotting. The brain uptake of colistin was measured by high-performance liquid chromatography (HPLC). The effects of colistin on amino acid neurotransmitters and their receptors were also examined by HPLC and real-time PCR. The results of EB extravasation, TEM and expression of Claudin-5 showed that colistin treatment did not affect the BBB integrity. In addition, multiple doses of colistin could induce accumulation of this compound in the brain parenchyma although there was poor brain uptake of colistin. Moreover, colistin exposure significantly increased the contents of glutamate (Glu) and gamma aminobutyric acid (GABA), and enhanced the mRNA expression levels of gamma aminobutyric acid type A receptor (GABAAR), gamma aminobutyric acid type B receptor (GABABR), N-methyl-d-aspartate 1 receptor (NR1), N-methyl-d-aspartate 2A receptor (NR2A) and N-methyl-d-aspartate 2B receptor (NR2B) in the cerebral cortex. Our data demonstrate that colistin is able to accumulate in the mouse brain and elevate the levels of amino acid neurotransmitters. These findings may be associated with colistin-induced neurotoxicity.

  16. Differential effects of ethanol on regional glutamatergic and GABAergic neurotransmitter pathways in mouse brain.

    PubMed

    Tiwari, Vivek; Veeraiah, Pandichelvam; Subramaniam, Vaidyanathan; Patel, Anant Bahadur

    2014-03-01

    This study investigates the effects of ethanol on neuronal and astroglial metabolism using (1)H-[(13)C]-NMR spectroscopy in conjunction with infusion of [1,6-(13)C2]/[1-(13)C]glucose or [2-(13)C]acetate, respectively. A three-compartment metabolic model was fitted to the (13)C turnover of GluC3 , GluC4, GABAC 2, GABAC 3, AspC3 , and GlnC4 from [1,6-(13)C2 ]glucose to determine the rates of tricarboxylic acid (TCA) and neurotransmitter cycle associated with glutamatergic and GABAergic neurons. The ratio of neurotransmitter cycle to TCA cycle fluxes for glutamatergic and GABAegic neurons was obtained from the steady-state [2-(13)C]acetate experiment and used as constraints during the metabolic model fitting. (1)H MRS measurement suggests that depletion of ethanol from cerebral cortex follows zero order kinetics with rate 0.18 ± 0.04 μmol/g/min. Acute exposure of ethanol reduces the level of glutamate and aspartate in cortical region. GlnC4 labeling was found to be unchanged from a 15 min infusion of [2-(13)C]acetate suggesting that acute ethanol exposure does not affect astroglial metabolism in naive mice. Rates of TCA and neurotransmitter cycle associated with glutamatergic and GABAergic neurons were found to be significantly reduced in cortical and subcortical regions. Acute exposure of ethanol perturbs the level of neurometabolites and decreases the excitatory and inhibitory activity differentially across the regions of brain. Depletion of ethanol and its effect on brain functions were measured using (1)H and (1)H-[(13)C]-NMR spectroscopy in conjunction with infusion of (13)C-labeled substrates. Ethanol depletion from brain follows zero order kinetics. Ethanol perturbs level of glutamate, and the excitatory and inhibitory activity in mice brain.

  17. High dose sapropterin dihydrochloride therapy improves monoamine neurotransmitter turnover in murine phenylketonuria (PKU).

    PubMed

    Winn, Shelley R; Scherer, Tanja; Thöny, Beat; Harding, Cary O

    2016-01-01

    Central nervous system (CNS) deficiencies of the monoamine neurotransmitters, dopamine and serotonin, have been implicated in the pathophysiology of neuropsychiatric dysfunction in phenylketonuria (PKU). Increased brain phenylalanine concentration likely competitively inhibits the activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), the rate limiting steps in dopamine and serotonin synthesis respectively. Tetrahydrobiopterin (BH4) is a required cofactor for TH and TPH activity. Our hypothesis was that treatment of hyperphenylalaninemic Pah(enu2/enu2) mice, a model of human PKU, with sapropterin dihydrochloride, a synthetic form of BH4, would stimulate TH and TPH activities leading to improved dopamine and serotonin synthesis despite persistently elevated brain phenylalanine. Sapropterin (20, 40, or 100mg/kg body weight in 1% ascorbic acid) was administered