Neurotransmitter release mechanisms studied in Caenorhabditis elegans.

PubMed

Barclay, Jeff W; Morgan, Alan; Burgoyne, Robert D

2012-01-01

The process of regulated exocytosis has received considerable interest as a key component of synaptic transmission. Fusion of presynaptic vesicles and the subsequent release of their neurotransmitter contents is driven by a series of interactions between evolutionarily conserved proteins. Key insights into the molecular mechanisms of vesicle fusion have come from research using genetic model systems such as the nematode worm Caenorhabditis elegans. We review here the current knowledge regarding regulated exocytosis at the C. elegans synapse and future research directions involving this model organism. Copyright © 2012 Elsevier Ltd. All rights reserved.

The 'sniffer-patch' technique for detection of neurotransmitter release.

PubMed

Allen, T G

1997-05-01

A wide variety of techniques have been employed for the detection and measurement of neurotransmitter release from biological preparations. Whilst many of these methods offer impressive levels of sensitivity, few are able to combine sensitivity with the necessary temporal and spatial resolution required to study quantal release from single cells. One detection method that is seeing a revival of interest and has the potential to fill this niche is the so-called 'sniffer-patch' technique. In this article, specific examples of the practical aspects of using this technique are discussed along with the procedures involved in calibrating these biosensors to extend their applications to provide quantitative, in addition to simple qualitative, measurements of quantal transmitter release.

Planar Diamond-Based Multiarrays to Monitor Neurotransmitter Release and Action Potential Firing: New Perspectives in Cellular Neuroscience.

PubMed

Carabelli, Valentina; Marcantoni, Andrea; Picollo, Federico; Battiato, Alfio; Bernardi, Ettore; Pasquarelli, Alberto; Olivero, Paolo; Carbone, Emilio

2017-02-15

High biocompatibility, outstanding electrochemical responsiveness, inertness, and transparency make diamond-based multiarrays (DBMs) first-rate biosensors for in vitro detection of electrochemical and electrical signals from excitable cells together, with potential for in vivo applications as neural interfaces and prostheses. Here, we will review the electrochemical and physical properties of various DBMs and how these devices have been employed for recording released neurotransmitter molecules and all-or-none action potentials from living cells. Specifically, we will overview how DBMs can resolve localized exocytotic events from subcellular compartments using high-density microelectrode arrays (MEAs), or monitoring oxidizable neurotransmitter release from populations of cells in culture and tissue slices using low-density MEAs. Interfacing DBMs with excitable cells is currently leading to the promising opportunity of recording electrical signals as well as creating neuronal interfaces through the same device. Given the recent increasingly growing development of newly available DBMs of various geometries to monitor electrical activity and neurotransmitter release in a variety of excitable and neuronal tissues, the discussion will be limited to planar DBMs.

High probability neurotransmitter release sites represent an energy efficient design

PubMed Central

Lu, Zhongmin; Chouhan, Amit K.; Borycz, Jolanta A.; Lu, Zhiyuan; Rossano, Adam J; Brain, Keith L.; Zhou, You; Meinertzhagen, Ian A.; Macleod, Gregory T.

2016-01-01

Nerve terminals contain multiple sites specialized for the release of neurotransmitters. Release usually occurs with low probability, a design thought to confer many advantages. High probability release sites are not uncommon but their advantages are not well understood. Here we test the hypothesis that high probability release sites represent an energy efficient design. We examined release site probabilities and energy efficiency at the terminals of two glutamatergic motor neurons synapsing on the same muscle fiber in Drosophila larvae. Through electrophysiological and ultrastructural measurements we calculated release site probabilities to differ considerably between terminals (0.33 vs. 0.11). We estimated the energy required to release and recycle glutamate from the same measurements. The energy required to remove calcium and sodium ions subsequent to nerve excitation was estimated through microfluorimetric and morphological measurements. We calculated energy efficiency as the number of glutamate molecules released per ATP molecule hydrolyzed, and high probability release site terminals were found to be more efficient (0.13 vs. 0.06). Our analytical model indicates that energy efficiency is optimal (~0.15) at high release site probabilities (~0.76). As limitations in energy supply constrain neural function, high probability release sites might ameliorate such constraints by demanding less energy. Energy efficiency can be viewed as one aspect of nerve terminal function, in balance with others, because high efficiency terminals depress significantly during episodic bursts of activity. PMID:27593375

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

PubMed Central

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

2015-01-01

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, non-synaptic 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 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 non-synaptic 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, non-synaptic sources were found to be the most important followed by transporter concentration and diffusion coefficient. PMID:22460547

SNT-1 functions as the Ca2+ sensor for tonic and evoked neurotransmitter release in C. elegans.

PubMed

Li, Lei; Liu, Haowen; Wang, Wei; Chandra, Mintu; Collins, Brett M; Hu, Zhitao

2018-05-14

Synaptotagmin-1 (Syt1) binds Ca 2+ through its tandem C2 domains (C2A and C2B) and triggers Ca 2+ -dependent neurotransmitter release. Here we show that snt-1 , the homolog of mammalian Syt1, functions as the Ca 2+ sensor for both tonic and evoked neurotransmitter release at the C. elegans neuromuscular junction. Mutations that disrupt Ca 2+ binding in double C2 domains of SNT-1 significantly impaired tonic release, whereas disrupting Ca 2+ binding in a single C2 domain had no effect, indicating that the Ca 2+ binding of the two C2 domains is functionally redundant for tonic release. Stimulus-evoked release was significantly reduced in snt-1 mutants, with prolonged release latency as well as faster rise and decay kinetics. Unlike tonic release, evoked release was triggered by Ca 2+ binding solely to the C2B domain. Moreover, we showed that SNT-1 plays an essential role in the priming process in different subpopulations of synaptic vesicles with tight or loose coupling to Ca 2+ entry. SIGNIFICANCE STATEMENT We showed that SNT-1 in C. elegans regulates evoked neurotransmitter release through Ca 2+ binding to its C2B domain, a similar way to Syt1 in the mouse CNS and the fly NMJ. However, the largely decreased tonic release in snt-1 mutants argues SNT-1 has a clamping function. Indeed, Ca 2+ -binding mutations in the C2 domains in SNT-1 significantly reduced the frequency of the miniature excitatory postsynaptic current (mEPSC), indicating that SNT-1 also acts as a Ca 2+ sensor for tonic release. Therefore, revealing the differential mechanisms between invertebrates and vertebrates will provide significant insights into our understanding how synaptic vesicle fusion is regulated. Copyright © 2018 the authors.

The Nitric Oxide Donor SNAP-Induced Amino Acid Neurotransmitter Release in Cortical Neurons. Effects of Blockers of Voltage-Dependent Sodium and Calcium Channels

PubMed Central

Merino, José Joaquín; Arce, Carmen; Naddaf, Ahmad; Bellver-Landete, Victor; Oset-Gasque, Maria Jesús; González, María Pilar

2014-01-01

Background The discovery that nitric oxide (NO) functions as a signalling molecule in the nervous system has radically changed the concept of neuronal communication. NO induces the release of amino acid neurotransmitters but the underlying mechanisms remain to be elucidated. Findings The aim of this work was to study the effect of NO on amino acid neurotransmitter release (Asp, Glu, Gly and GABA) in cortical neurons as well as the mechanism underlying the release of these neurotransmitters. Cortical neurons were stimulated with SNAP, a NO donor, and the release of different amino acid neurotransmitters was measured by HPLC. The involvement of voltage dependent Na+ and Ca2+ channels as well as cGMP in its mechanism of action was evaluated. Conclusions Our results indicate that NO induces release of aspartate, glutamate, glycine and GABA in cortical neurons and that this release is inhibited by ODQ, an inhibitor of soluble guanylate cyclase. Thus, the NO effect on amino acid neurotransmission could be mediated by cGMP formation in cortical neurons. Our data also demonstrate that the Na+ and Ca2+ voltage- dependent calcium channels are involved in the NO effects on cortical neurons. PMID:24598811

The nitric oxide donor SNAP-induced amino acid neurotransmitter release in cortical neurons. Effects of blockers of voltage-dependent sodium and calcium channels.

PubMed

Merino, José Joaquín; Arce, Carmen; Naddaf, Ahmad; Bellver-Landete, Victor; Oset-Gasque, Maria Jesús; González, María Pilar

2014-01-01

The discovery that nitric oxide (NO) functions as a signalling molecule in the nervous system has radically changed the concept of neuronal communication. NO induces the release of amino acid neurotransmitters but the underlying mechanisms remain to be elucidated. The aim of this work was to study the effect of NO on amino acid neurotransmitter release (Asp, Glu, Gly and GABA) in cortical neurons as well as the mechanism underlying the release of these neurotransmitters. Cortical neurons were stimulated with SNAP, a NO donor, and the release of different amino acid neurotransmitters was measured by HPLC. The involvement of voltage dependent Na+ and Ca2+ channels as well as cGMP in its mechanism of action was evaluated. Our results indicate that NO induces release of aspartate, glutamate, glycine and GABA in cortical neurons and that this release is inhibited by ODQ, an inhibitor of soluble guanylate cyclase. Thus, the NO effect on amino acid neurotransmission could be mediated by cGMP formation in cortical neurons. Our data also demonstrate that the Na+ and Ca2+ voltage- dependent calcium channels are involved in the NO effects on cortical neurons.

Can Nanofluidic Chemical Release Enable Fast, High Resolution Neurotransmitter-Based Neurostimulation?

PubMed

Jones, Peter D; Stelzle, Martin

2016-01-01

Artificial chemical stimulation could provide improvements over electrical neurostimulation. Physiological neurotransmission between neurons relies on the nanoscale release and propagation of specific chemical signals to spatially-localized receptors. Current knowledge of nanoscale fluid dynamics and nanofluidic technology allows us to envision artificial mechanisms to achieve fast, high resolution neurotransmitter release. Substantial technological development is required to reach this goal. Nanofluidic technology-rather than microfluidic-will be necessary; this should come as no surprise given the nanofluidic nature of neurotransmission. This perspective reviews the state of the art of high resolution electrical neuroprostheses and their anticipated limitations. Chemical release rates from nanopores are compared to rates achieved at synapses and with iontophoresis. A review of microfluidic technology justifies the analysis that microfluidic control of chemical release would be insufficient. Novel nanofluidic mechanisms are discussed, and we propose that hydrophobic gating may allow control of chemical release suitable for mimicking neurotransmission. The limited understanding of hydrophobic gating in artificial nanopores and the challenges of fabrication and large-scale integration of nanofluidic components are emphasized. Development of suitable nanofluidic technology will require dedicated, long-term efforts over many years.

Mechanical Regulation in Cell Division and in Neurotransmitter Release

NASA Astrophysics Data System (ADS)

Thiyagarajan, Sathish

During their lifecycle, cells must produce forces which play important roles in several subcellular processes. Force-producing components are organized into macromolecular assemblies of proteins that are often dynamic, and are constructed or disassembled in response to various signals. The forces themselves may directly be involved in subcellular mechanics, or they may influence mechanosensing proteins either within or outside these structures. These proteins play different roles: they may ensure the stability of the force-producing structure, or they may send signals to a coupled process. The generation and sensing of subcellular forces is an active research topic, and this thesis focusses on the roles of these forces in two key areas: cell division and neurotransmitter release. The first part of the thesis deals with the effect of force on cell wall growth regulation during division in the fission yeast Schizosaccharomyces pombe, a cigar-shaped, unicellular organism. During cytokinesis, the last stage of cell division in which the cell physically divides into two, a tense cytokinetic ring anchored to the cellular membrane assembles and constricts, accompanied by the inward centripetal growth of new cell wall, called septum, in the wake of the inward-moving membrane. The contour of the septum hole maintains its circularity as it reduces in size--an indication of regulated growth. To characterize the cell wall growth process, we performed image analysis on contours of the leading edge of the septum obtained via fluorescence microscopy in the labs of our collaborators. We quantified the deviations from circularity using the edge roughness. The roughness was spatially correlated, suggestive of regulated growth. We hypothesized that the cell wall growers are mechanosensitive and respond to the force exerted by the ring. A mathematical model based on this hypothesis then showed that this leads to corrections of roughness in a curvature-dependent fashion. Thus, one of

Multiple functions of neuronal plasma membrane neurotransmitter transporters.

PubMed

Raiteri, Luca; Raiteri, Maurizio

2015-11-01

Removal from receptors of neurotransmitters just released into synapses is one of the major steps in neurotransmission. Transporters situated on the plasma membrane of nerve endings and glial cells perform the process of neurotransmitter (re)uptake. Because the density of transporters in the membranes can fluctuate, transporters can determine the transmitter concentrations at receptors, thus modulating indirectly the excitability of neighboring neurons. Evidence is accumulating that neurotransmitter transporters can exhibit multiple functions. Being bidirectional, neurotransmitter transporters can mediate transmitter release by working in reverse, most often under pathological conditions that cause ionic gradient dysregulations. Some transporters reverse to release transmitters, like dopamine or serotonin, when activated by 'indirectly acting' substrates, like the amphetamines. Some transporters exhibit as one major function the ability to capture transmitters into nerve terminals that perform insufficient synthesis. Transporter activation can generate conductances that regulate directly neuronal excitability. Synaptic and non-synaptic transporters play different roles. Cytosolic Na(+) elevations accompanying transport can interact with plasmalemmal or/and mitochondrial Na(+)/Ca(2+) exchangers thus generating calcium signals. Finally, neurotransmitter transporters can behave as receptors mediating releasing stimuli able to cause transmitter efflux through multiple mechanisms. Neurotransmitter transporters are therefore likely to play hitherto unknown roles in multiple therapeutic treatments. Copyright © 2015 Elsevier Ltd. All rights reserved.

UNC-13L, UNC-13S, and Tomosyn form a protein code for fast and slow neurotransmitter release in Caenorhabditis elegans

PubMed Central

Hu, Zhitao; Tong, Xia-Jing; Kaplan, Joshua M

2013-01-01

Synaptic transmission consists of fast and slow components of neurotransmitter release. Here we show that these components are mediated by distinct exocytic proteins. The Caenorhabditis elegans unc-13 gene is required for SV exocytosis, and encodes long and short isoforms (UNC-13L and S). Fast release was mediated by UNC-13L, whereas slow release required both UNC-13 proteins and was inhibited by Tomosyn. The spatial location of each protein correlated with its effect. Proteins adjacent to the dense projection mediated fast release, while those controlling slow release were more distal or diffuse. Two UNC-13L domains accelerated release. C2A, which binds RIM (a protein associated with calcium channels), anchored UNC-13 at active zones and shortened the latency of release. A calmodulin binding site accelerated release but had little effect on UNC-13’s spatial localization. These results suggest that UNC-13L, UNC-13S, and Tomosyn form a molecular code that dictates the timing of neurotransmitter release. DOI: http://dx.doi.org/10.7554/eLife.00967.001 PMID:23951547

Euglycemia Restoration by Central Leptin in Type 1 Diabetes Requires STAT3 Signaling but Not Fast-Acting Neurotransmitter Release.

PubMed

Xu, Yuanzhong; Chang, Jeffrey T; Myers, Martin G; Xu, Yong; Tong, Qingchun

2016-04-01

Central leptin action is sufficient to restore euglycemia in insulinopenic type 1 diabetes (T1D); however, the underlying mechanism remains poorly understood. To examine the role of intracellular signal transducer and activator of transcription 3 (STAT3) pathways, we used LepRs/s mice with disrupted leptin-phosphorylated STAT3 signaling to test the effect of central leptin on euglycemia restoration. These mice developed streptozocin-induced T1D, which was surprisingly not associated with hyperglucagonemia, a typical manifestation in T1D. Further, leptin action on euglycemia restoration was abrogated in these mice, which was associated with refractory hypercorticosteronemia. To examine the role of fast-acting neurotransmitters glutamate and γ-aminobutyric acid (GABA), two major neurotransmitters in the brain, from leptin receptor (LepR) neurons, we used mice with disrupted release of glutamate, GABA, or both from LepR neurons. Surprisingly, all mice responded normally to leptin-mediated euglycemia restoration, which was associated with expected correction from hyperglucagonemia and hyperphagia. In contrast, mice with loss of glutamate and GABA appeared to develop an additive obesity effect over those with loss of single neurotransmitter release. Thus, our study reveals that STAT3 signaling, but not fast-acting neurotransmitter release, is required for leptin action on euglycemia restoration and that hyperglucagonemia is not required for T1D. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Long-Term Plasticity of Neurotransmitter Release: Emerging Mechanisms and Contributions to Brain Function and Disease.

PubMed

Monday, Hannah R; Younts, Thomas J; Castillo, Pablo E

2018-04-25

Long-lasting changes of brain function in response to experience rely on diverse forms of activity-dependent synaptic plasticity. Chief among them are long-term potentiation and long-term depression of neurotransmitter release, which are widely expressed by excitatory and inhibitory synapses throughout the central nervous system and can dynamically regulate information flow in neural circuits. This review article explores recent advances in presynaptic long-term plasticity mechanisms and contributions to circuit function. Growing evidence indicates that presynaptic plasticity may involve structural changes, presynaptic protein synthesis, and transsynaptic signaling. Presynaptic long-term plasticity can alter the short-term dynamics of neurotransmitter release, thereby contributing to circuit computations such as novelty detection, modifications of the excitatory/inhibitory balance, and sensory adaptation. In addition, presynaptic long-term plasticity underlies forms of learning and its dysregulation participates in several neuropsychiatric conditions, including schizophrenia, autism, intellectual disabilities, neurodegenerative diseases, and drug abuse. Expected final online publication date for the Annual Review of Neuroscience Volume 41 is July 8, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Ca(2+) influx and neurotransmitter release at ribbon synapses.

PubMed

Cho, Soyoun; von Gersdorff, Henrique

2012-01-01

Ca(2+) influx through voltage-gated Ca(2+) channels triggers the release of neurotransmitters at presynaptic terminals. Some sensory receptor cells in the peripheral auditory and visual systems have specialized synapses that express an electron-dense organelle called a synaptic ribbon. Like conventional synapses, ribbon synapses exhibit SNARE-mediated exocytosis, clathrin-mediated endocytosis, and short-term plasticity. However, unlike non-ribbon synapses, voltage-gated L-type Ca(2+) channel opening at ribbon synapses triggers a form of multiquantal release that can be highly synchronous. Furthermore, ribbon synapses appear to be specialized for fast and high throughput exocytosis controlled by graded membrane potential changes. Here we will discuss some of the basic aspects of synaptic transmission at different types of ribbon synapses, and we will emphasize recent evidence that auditory and retinal ribbon synapses have marked differences. This will lead us to suggest that ribbon synapses are specialized for particular operating ranges and frequencies of stimulation. We propose that different types of ribbon synapses transfer diverse rates of sensory information by expressing a particular repertoire of critical components, and by placing them at precise and strategic locations, so that a continuous supply of primed vesicles and Ca(2+) influx leads to fast, accurate, and ongoing exocytosis. Copyright © 2012 Elsevier Ltd. All rights reserved.

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.

PRRT2 Is a Key Component of the Ca(2+)-Dependent Neurotransmitter Release Machinery.

PubMed

Valente, Pierluigi; Castroflorio, Enrico; Rossi, Pia; Fadda, Manuela; Sterlini, Bruno; Cervigni, Romina Ines; Prestigio, Cosimo; Giovedì, Silvia; Onofri, Franco; Mura, Elisa; Guarnieri, Fabrizia C; Marte, Antonella; Orlando, Marta; Zara, Federico; Fassio, Anna; Valtorta, Flavia; Baldelli, Pietro; Corradi, Anna; Benfenati, Fabio

2016-04-05

Heterozygous mutations in proline-rich transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders, including epilepsy, kinesigenic dyskinesia, and migraine. Most of the mutations lead to impaired PRRT2 expression, suggesting that loss of PRRT2 function may contribute to pathogenesis. We show that PRRT2 is enriched in presynaptic terminals and that its silencing decreases the number of synapses and increases the number of docked synaptic vesicles at rest. PRRT2-silenced neurons exhibit a severe impairment of synchronous release, attributable to a sharp decrease in release probability and Ca(2+) sensitivity and associated with a marked increase of the asynchronous/synchronous release ratio. PRRT2 interacts with the synaptic proteins SNAP-25 and synaptotagmin 1/2. The results indicate that PRRT2 is intimately connected with the Ca(2+)-sensing machinery and that it plays an important role in the final steps of neurotransmitter release. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

PRRT2 Is a Key Component of the Ca2+-Dependent Neurotransmitter Release Machinery

PubMed Central

Valente, Pierluigi; Castroflorio, Enrico; Rossi, Pia; Fadda, Manuela; Sterlini, Bruno; Cervigni, Romina Ines; Prestigio, Cosimo; Giovedì, Silvia; Onofri, Franco; Mura, Elisa; Guarnieri, Fabrizia C.; Marte, Antonella; Orlando, Marta; Zara, Federico; Fassio, Anna; Valtorta, Flavia; Baldelli, Pietro; Corradi, Anna; Benfenati, Fabio

2016-01-01

Summary Heterozygous mutations in proline-rich transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders, including epilepsy, kinesigenic dyskinesia, and migraine. Most of the mutations lead to impaired PRRT2 expression, suggesting that loss of PRRT2 function may contribute to pathogenesis. We show that PRRT2 is enriched in presynaptic terminals and that its silencing decreases the number of synapses and increases the number of docked synaptic vesicles at rest. PRRT2-silenced neurons exhibit a severe impairment of synchronous release, attributable to a sharp decrease in release probability and Ca2+ sensitivity and associated with a marked increase of the asynchronous/synchronous release ratio. PRRT2 interacts with the synaptic proteins SNAP-25 and synaptotagmin 1/2. The results indicate that PRRT2 is intimately connected with the Ca2+-sensing machinery and that it plays an important role in the final steps of neurotransmitter release. PMID:27052163

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

The release of sympathetic neurotransmitters is impaired in aged rats after an inflammatory stimulus: a possible link between cytokine production and sympathetic transmission.

PubMed

Donoso, Verónica; Gomez, Christian R; Orriantia, Miguel Angel; Pérez, Viviana; Torres, Claudio; Coddou, Claudio; Nelson, Pablo; Maisey, Kevin; Morales, Bernardo; Fernandez, Ricardo; Imarai, Mónica; Huidobro-Toro, Juan Pablo; Sierra, Felipe; Acuña-Castillo, Claudio

2008-12-01

Aging results in a general decline in the response to external insults, including acute inflammatory challenges. In young animals, the inflammatory response requires activation of the sympathetic system, including neurotransmitters such as ATP, and catecholamines (epinephrine and norepinephrine). To test whether aging affects activation of this axis, and whether this in turn might affect cytokine release, we administered lipopolysaccharide (LPS) i.p. to adult, middle-aged and aged Fisher 344 rats (6-, 15- and 23-month old, respectively) and evaluated the early (0-12h) serum levels of Neuropeptide-Y (NP-Y), ATP and vanillyl mandelic acid (VMA, as an indirect measurement of catecholamine levels). In addition, we evaluated the association between these factors and serum levels of the cytokines tumor necrosis factor-alpha (TNFalpha) and interleukin-10 (IL-10). Induction of both ATP and NP-Y was markedly reduced in the serum of aged animals, when compared to their younger counterparts, while induction of VMA was not affected by age. In spite of these changes, serum levels of TNFalpha and IL-10 were strongly hyper induced and delayed in aged rats. The results suggest that during aging there is a dysregulation in sympathetic neurotransmitter regulatory mechanisms, and this might play a role in the impairment of the inflammatory response.

The release of sympathetic neurotransmitters is impaired in aged rats after an inflammatory stimulus. A possible link between cytokine production and sympathetic transmission

PubMed Central

Donoso, Verónica; Gomez, Christian R.; Orriantia, Miguel Ángel; Pérez, Viviana; Torres, Claudio; Coddou, Claudio; Nelson, Pablo; Maisey, Kevin; Morales, Bernardo; Fernandez, Ricardo; Imarai, Mónica; Huidobro-Toro, Juan Pablo; Sierra, Felipe; Acuña-Castillo, Claudio

2009-01-01

Aging results in a general decline in the response to external insults, including acute inflammatory challenges. In young animals, the inflammatory response requires activation of the sympathetic system, including neurotransmitters such as ATP, and catecholamines (epinephrine and norepinephrine). To test whether aging affects activation of this axis, and whether this in turn might affect cytokine release, we administered lipopolysaccharide (LPS) i.p. to adult, middle-aged and aged Fisher 344 rats (6, 15 and 23-month old, respectively) and evaluated the early (0–12 hours) serum levels of Neuropeptide-Y (NP-Y), ATP and vanillyl mandelic acid (VMA, as an indirect measurement of catecholamine levels). In addition, we evaluated the association between these factors and serum levels of the cytokines tumor necrosis factor-alpha (TNFα)3 and interleukin-10 (IL-10). Induction of both ATP and NP-Y was markedly reduced in the serum of aged animals, when compared to their younger counterparts, while induction of VMA was not affected by age. In spite of these changes, serum levels of TNFα and IL-10 were strongly hyper induced and delayed in aged rats. The results suggest that during aging there is a dysregulation in sympathetic neurotransmitter regulatory mechanisms, and this might play a role in the impairment of the inflammatory response. PMID:18973771

LRRK2 kinase activity regulates synaptic vesicle trafficking and neurotransmitter release through modulation of LRRK2 macro-molecular complex

PubMed Central

Cirnaru, Maria D.; Marte, Antonella; Belluzzi, Elisa; Russo, Isabella; Gabrielli, Martina; Longo, Francesco; Arcuri, Ludovico; Murru, Luca; Bubacco, Luigi; Matteoli, Michela; Fedele, Ernesto; Sala, Carlo; Passafaro, Maria; Morari, Michele; Greggio, Elisa; Onofri, Franco; Piccoli, Giovanni

2014-01-01

Mutations in Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains executing several functions, including GTP hydrolysis, kinase activity, and protein binding. Robust evidence suggests that LRRK2 acts at the synaptic site as a molecular hub connecting synaptic vesicles to cytoskeletal elements via a complex panel of protein-protein interactions. Here we investigated the impact of pharmacological inhibition of LRRK2 kinase activity on synaptic function. Acute treatment with LRRK2 inhibitors reduced the frequency of spontaneous currents, the rate of synaptic vesicle trafficking and the release of neurotransmitter from isolated synaptosomes. The investigation of complementary models lacking LRRK2 expression allowed us to exclude potential off-side effects of kinase inhibitors on synaptic functions. Next we studied whether kinase inhibition affects LRRK2 heterologous interactions. We found that the binding among LRRK2, presynaptic proteins and synaptic vesicles is affected by kinase inhibition. Our results suggest that LRRK2 kinase activity influences synaptic vesicle release via modulation of LRRK2 macro-molecular complex. PMID:24904275

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

Update on the pharmacology of selective inhibitors of MAO-A and MAO-B: focus on modulation of CNS monoamine neurotransmitter release.

PubMed

Finberg, John P M

2014-08-01

Inhibitors of monoamine oxidase (MAO) were initially used in medicine following the discovery of their antidepressant action. Subsequently their ability to potentiate the effects of an indirectly-acting sympathomimetic amine such as tyramine was discovered, leading to their limitation in clinical use, except for cases of treatment-resistant depression. More recently, the understanding that: a) potentiation of indirectly-acting sympathomimetic amines is caused by inhibitors of MAO-A but not by inhibitors of MAO-B, and b) that reversible inhibitors of MAO-A cause minimal tyramine potentiation, has led to their re-introduction to clinical use for treatment of depression (reversible MAO-A inhibitors and new dose form MAO-B inhibitor) and treatment of Parkinson's disease (MAO-B inhibitors). The profound neuroprotective properties of propargyl-based inhibitors of MAO-B in preclinical experiments have drawn attention to the possibility of employing these drugs for their neuroprotective effect in neurodegenerative diseases, and have raised the question of the involvement of the MAO-mediated reaction as a source of reactive free radicals. Despite the long-standing history of MAO inhibitors in medicine, the way in which they affect neuronal release of monoamine neurotransmitters is still poorly understood. In recent years, the detailed chemical structure of MAO-B and MAO-A has become available, providing new possibilities for synthesis of mechanism-based inhibitors. This review describes the latest advances in understanding the way in which MAO inhibitors affect the release of the monoamine neurotransmitters dopamine, noradrenaline and serotonin (5-HT) in the CNS, with an accent on the importance of these effects for the clinical actions of the drugs. Copyright © 2014 Elsevier Inc. All rights reserved.

Fife, a Drosophila Piccolo-RIM Homolog, Promotes Active Zone Organization and Neurotransmitter Release

PubMed Central

Bruckner, Joseph J.; Gratz, Scott J.; Slind, Jessica K.; Geske, Richard R.; Cummings, Alexander M.; Galindo, Samantha E.; Donohue, Laura K.; O'Connor-Giles, Kate M.

2012-01-01

Neuronal communication depends on the precisely orchestrated release of neurotransmitter at specialized sites called active zones (AZs). A small number of scaffolding and cytoskeletal proteins comprising the cytomatrix of the active zone (CAZ) are thought to organize the architecture and functional properties of AZs. The majority of CAZ proteins are evolutionarily conserved, underscoring the fundamental similarities in neurotransmission at all synapses. However, core CAZ proteins Piccolo and Bassoon have long been believed exclusive to vertebrates, raising intriguing questions about the conservation of the molecular mechanisms that regulate presynaptic properties. Here, we present the identification of a piccolo-rim-related gene in invertebrates, together with molecular phylogenetic analyses that indicate the encoded proteins may represent Piccolo orthologs. In accordance, we find that the Drosophila homolog, Fife, is neuronal and localizes to presynaptic AZs. To investigate the in vivo function of Fife, we generated a deletion of the fife locus. We find that evoked neurotransmitter release is substantially decreased in fife mutants and loss of fife results in motor deficits. Through morphological analysis of fife synapses, we identify underlying AZ abnormalities including pervasive presynaptic membrane detachments and reduced synaptic vesicle clustering. Our data demonstrate the conservation of a Piccolo-related protein in invertebrates and identify critical roles for Fife in regulating AZ structure and function. These findings suggest the CAZ is more conserved than previously thought, and open the door to a more complete understanding of how CAZ proteins regulate presynaptic structure and function through genetic studies in simpler model systems. PMID:23197698

Communication networks in the brain: neurons, receptors, neurotransmitters, and alcohol.

PubMed

Lovinger, David M

2008-01-01

Nerve cells (i.e., neurons) communicate via a combination of electrical and chemical signals. Within the neuron, electrical signals driven by charged particles allow rapid conduction from one end of the cell to the other. Communication between neurons occurs at tiny gaps called synapses, where specialized parts of the two cells (i.e., the presynaptic and postsynaptic neurons) come within nanometers of one another to allow for chemical transmission. The presynaptic neuron releases a chemical (i.e., a neurotransmitter) that is received by the postsynaptic neuron's specialized proteins called neurotransmitter receptors. The neurotransmitter molecules bind to the receptor proteins and alter postsynaptic neuronal function. Two types of neurotransmitter receptors exist-ligand-gated ion channels, which permit rapid ion flow directly across the outer cell membrane, and G-protein-coupled receptors, which set into motion chemical signaling events within the cell. Hundreds of molecules are known to act as neurotransmitters in the brain. Neuronal development and function also are affected by peptides known as neurotrophins and by steroid hormones. This article reviews the chemical nature, neuronal actions, receptor subtypes, and therapeutic roles of several transmitters, neurotrophins, and hormones. It focuses on neurotransmitters with important roles in acute and chronic alcohol effects on the brain, such as those that contribute to intoxication, tolerance, dependence, and neurotoxicity, as well as maintained alcohol drinking and addiction.

Type-3 ryanodine receptors mediate hypoxia-, but not neurotransmitter-induced calcium release and contraction in pulmonary artery smooth muscle cells.

PubMed

Zheng, Yun-Min; Wang, Qing-Song; Rathore, Rakesh; Zhang, Wan-Hui; Mazurkiewicz, Joseph E; Sorrentino, Vincenzo; Singer, Harold A; Kotlikoff, Michael I; Wang, Yong-Xiao

2005-04-01

In this study we examined the expression of RyR subtypes and the role of RyRs in neurotransmitter- and hypoxia-induced Ca2+ release and contraction in pulmonary artery smooth muscle cells (PASMCs). Under perforated patch clamp conditions, maximal activation of RyRs with caffeine or inositol triphosphate receptors (IP3Rs) with noradrenaline induced equivalent increases in [Ca2+]i and Ca2+-activated Cl- currents in freshly isolated rat PASMCs. Following maximal IP3-induced Ca2+ release, neither caffeine nor chloro-m-cresol induced a response, whereas prior application of caffeine or chloro-m-cresol blocked IP3-induced Ca2+ release. In cultured human PASMCs, which lack functional expression of RyRs, caffeine failed to affect ATP-induced increases in [Ca2+]i in the presence and absence of extracellular Ca2+. The RyR antagonists ruthenium red, ryanodine, tetracaine, and dantrolene greatly inhibited submaximal noradrenaline- and hypoxia-induced Ca2+ release and contraction in freshly isolated rat PASMCs, but did not affect ATP-induced Ca2+ release in cultured human PASMCs. Real-time quantitative RT-PCR and immunofluorescence staining indicated similar expression of all three RyR subtypes (RyR1, RyR2, and RyR3) in freshly isolated rat PASMCs. In freshly isolated PASMCs from RyR3 knockout (RyR3-/-) mice, hypoxia-induced, but not submaximal noradrenaline-induced, Ca2+ release and contraction were significantly reduced. Ruthenium red and tetracaine can further inhibit hypoxic increase in [Ca2+]i in RyR3-/- mouse PASMCs. Collectively, our data suggest that (a) RyRs play an important role in submaximal noradrenaline- and hypoxia-induced Ca2+ release and contraction; (b) all three subtype RyRs are expressed; and (c) RyR3 gene knockout significantly inhibits hypoxia-, but not submaximal noradrenaline-induced Ca2+ and contractile responses in PASMCs.

Myosin phosphatase and RhoA-activated kinase modulate neurotransmitter release by regulating SNAP-25 of SNARE complex

PubMed Central

Sipos, Adrienn; Darula, Zsuzsanna; Bécsi, Bálint; Nagy, Dénes; Iván, Judit; Erdődi, Ferenc

2017-01-01

Reversible phosphorylation of neuronal proteins plays an important role in the regulation of neurotransmitter release. Myosin phosphatase holoenzyme (MP) consists of a protein phosphatase-1 (PP1) catalytic subunit (PP1c) and a regulatory subunit, termed myosin phosphatase targeting subunit (MYPT1). The primary function of MP is to regulate the phosphorylation level of contractile proteins; however, recent studies have shown that MP is localized to neurons, and is also involved in the mediation of neuronal processes. Our goal was to investigate the effect of RhoA-activated kinase (ROK) and MP on the phosphorylation of one potential neuronal substrate, the synaptosomal-associated protein of 25 kDa (SNAP-25). SNAP-25 is a member of the SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) complex, along with synaptobrevin and syntaxin, and the primary role of SNAP25 is to mediate vesicle fusion. We showed that MYPT1 interacts with SNAP-25, as revealed by immunoprecipitation and surface plasmon resonance based binding studies. Mass spectrometry analysis and in vitro phosphorylation/dephosphorylation assays demonstrated that ROK phosphorylates, while MP dephosphorylates, SNAP-25 at Thr138. Silencing MYPT1 in B50 neuroblastoma cells increased phosphorylation of SNAP-25 at Thr138. Inhibition of PP1 with tautomycetin increased, whereas inhibition of ROK by H1152, decreased the phosphorylation of SNAP-25 at Thr138 in B50 cells, in cortical synaptosomes, and in brain slices. In response to the transduction of the MP inhibitor, kinase-enhanced PP1 inhibitor (KEPI), into synaptosomes, an increase in phosphorylation of SNAP-25 and a decrease in the extent of neurotransmitter release were detected. The interaction between SNAP-25 and syntaxin increased with decreasing phosphorylation of SNAP-25 at Thr138, upon inhibition of ROK. Our data suggest that ROK/MP play a crucial role in vesicle trafficking, fusion, and neurotransmitter release by oppositely

The Binomial Model in Fluctuation Analysis of Quantal Neurotransmitter Release

PubMed Central

Quastel, D. M. J.

1997-01-01

The mathematics of the binomial model for quantal neurotransmitter release is considered in general terms, to explore what information might be extractable from statistical aspects of data. For an array of N statistically independent release sites, each with a release probability p, the compound binomial always pertains, with = N

, p′ ≡ 1 - var(m)/ =

(1 + cvp2) and n′ ≡ /p′ = N/(1 + cvp2), where m is the output/stimulus and cvp2 is var(p)/

2. Unless n′ is invariant with ambient conditions or stimulation paradigms, the simple binomial (cvp = 0) is untenable and n′ is neither N nor the number of “active” sites or sites with a quantum available. At each site p = popA, where po is the output probability if a site is “eligible” or “filled” despite previous quantal discharge, and pA (eligibility probability) depends at least on the replenishment rate, po, and interstimulus time. Assuming stochastic replenishment, a simple algorithm allows calculation of the full statistical composition of outputs for any hypothetical combinations of po's and refill rates, for any stimulation paradigm and spontaneous release. A rise in n′ (reduced cvp) tends to occur whenever po varies widely between sites, with a raised stimulation frequency or factors tending to increase po's. Unlike and var(m) at equilibrium, output changes early in trains of stimuli, and covariances, potentially provide information about whether changes in reflect change in or in . Formulae are derived for variance and third moments of postsynaptic responses, which depend on the quantal mix in the signals. A new, easily computed function, the area product, gives noise-unbiased variance of a series of synaptic signals and its peristimulus time distribution, which is modified by the unit channel composition of quantal responses and if the signals reflect mixed responses from synapses with different quantal time course. PMID:9017200

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

Fast methods for analysis of neurotransmitters from single cell and monitoring their releases in central nervous system by capillary electrophoresis, fluorescence microscopy and luminescence imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Ziqiang

1999-12-10

Fast methods for separation and detection of important neurotransmitters and the releases in central nervous system (CNS) were developed. Enzyme based immunoassay combined with capillary electrophoresis was used to analyze the contents of amino acid neurotransmitters from single neuron cells. The release of amino acid neurotransmitters from neuron cultures was monitored by laser induced fluorescence imaging method. The release and signal transduction of adenosine triphosphate (ATP) in CNS was studied with sensitive luminescence imaging method. A new dual-enzyme on-column reaction method combined with capillary electrophoresis has been developed for determining the glutamate content in single cells. Detection was based onmore » monitoring the laser-induced fluorescence of the reaction product NADH, and the measured fluorescence intensity was related to the concentration of glutamate in each cell. The detection limit of glutamate is down to 10 -8 M level, which is 1 order of magnitude lower than the previously reported detection limit based on similar detection methods. The mass detection limit of a few attomoles is far superior to that of any other reports. Selectivity for glutamate is excellent over most of amino acids. The glutamate content in single human erythrocyte and baby rat brain neurons were determined with this method and results agreed well with literature values.« less

Inhibition of Calpains Protects Mn-Induced Neurotransmitter release disorders in Synaptosomes from Mice: Involvement of SNARE Complex and Synaptic Vesicle Fusion.

PubMed

Wang, Can; Xu, Bin; Ma, Zhuo; Liu, Chang; Deng, Yu; Liu, Wei; Xu, Zhao-Fa

2017-06-16

Overexposure to manganese (Mn) could disrupt neurotransmitter release via influencing the formation of SNARE complex, but the underlying mechanisms are still unclear. A previous study demonstrated that SNAP-25 is one of substrate of calpains. The current study investigated whether calpains were involved in Mn-induced disorder of SNARE complex. After mice were treated with Mn for 24 days, Mn deposition increased significantly in basal nuclei in Mn-treated and calpeptin pre-treated groups. Behaviorally, less time spent in the center of the area and decreased average velocity significantly in an open field test after 24 days of Mn exposure. With the increase in MnCl 2 dosage, intracellular Ca 2+ increased significantly, but pretreatment with calpeptin caused a dose-dependent decrease in calpains activity. There were fragments of N-terminal of SNAP-25 protein appearance in Mn-treated groups, but it is decreased with pretreatment of calpeptin. FM1-43-labeled synaptic vesicles also provided evidence that the treatment with Mn resulted in increasing first and then decreasing, which was consistent with Glu release and the 80 kDa protein levels of SNARE complexes. In summary, Mn induced the disorder of neurotransmitter release through influencing the formation of SNARE complex via cleaving SNAP-25 by overactivation of calpains in vivo.

SLO-2 potassium channel is an important regulator of neurotransmitter release in Caenorhabditis elegans

PubMed Central

Liu, Ping; Chen, Bojun; Wang, Zhao-Wen

2014-01-01

Slo2 channels are prominent K+ channels in mammalian neurons but their physiological functions are not well understood. Here we investigate physiological functions and regulation of the C. elegans homologue SLO-2 in motor neurons through electrophysiological analyses of wild-type and mutant worms. We find that SLO-2 is the primary K+ channel conducting delayed outward current in cholinergic motor neurons, and one of two K+ channels with this function in GABAergic motor neurons. Loss-of-function mutation of slo-2 increases the duration and charge transfer rate of spontaneous postsynaptic current bursts at the neuromuscular junction, which are physiological signals used by motor neurons to control muscle cells, without altering postsynaptic receptor sensitivity. SLO-2 activity in motor neurons depends on Ca2+ entry through EGL-19, an L-type voltage-gated Ca2+ channel (CaV1), but not on other proteins implicated in either Ca2+ entry or intracellular Ca2+ release. Thus, SLO-2 is functionally coupled with CaV1 and regulates neurotransmitter release. PMID:25300429

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

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.

Modest long-term ethanol consumption affects expression of neurotransmitter receptor genes in the rat nucleus accumbens.

PubMed

Jonsson, Susanne; Ericson, Mia; Söderpalm, Bo

2014-03-01

Over 100 million people worldwide are affected by alcohol use disorders. These conditions usually take years to develop where an initial, voluntary consumption is gradually replaced by a compulsive intake of alcohol. The exact mechanisms behind this transition remain unknown. However, ethanol (EtOH) is known to interact with several neurotransmitters and receptors in the central nervous system, and chronic EtOH consumption causes alterations in these neurotransmitter systems, proposed to contribute to the development of dependence. This study aimed to repeat previous findings that animals after long-term voluntary EtOH consumption spontaneously increase their intake. That the initial encounter with EtOH causes an elevation of dopamine in the nucleus accumbens (nAc), inducing feelings of well-being and creating an incentive to continue the behavior, has been repeatedly reported in both animals and humans. The effects of chronic EtOH consumption on this region are not as well investigated. We examined both long-term EtOH consumption behavior and its consequences on expression of neurotransmitter-related genes in the nAc of the Wistar rat using quantitative polymerase chain reaction. In general, the EtOH consumption of the animals in this study was modest with an average intake of 0.9 g/kg/d, and only 1 of the 24 rats consuming EtOH for 10 months drastically increased its intake in line with the results of Wolffgramm and Heyne (1995). Expression of the genes for dopamine receptor 2, μ-opioid receptor, and somatostatin receptor 4 were down-regulated in animals after 2 and/or 4, but not 10, months of EtOH consumption. Chronic consumption even of modest amounts of alcohol seems to affect regulation of expression of these genes, possibly leading to changes in neurotransmitter signaling. Studies are ongoing to investigate whether these alterations are specific for the nAc. Copyright © 2013 by the Research Society on Alcoholism.

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.

Stress-Induced Synaptic Dysfunction and Neurotransmitter Release in Alzheimer's Disease: Can Neurotransmitters and Neuromodulators be Potential Therapeutic Targets?

PubMed

Jha, Saurabh Kumar; Jha, Niraj Kumar; Kumar, Dhiraj; Sharma, Renu; Shrivastava, Abhishek; Ambasta, Rashmi K; Kumar, Pravir

2017-01-01

The communication between neurons at synaptic junctions is an intriguing process that monitors the transmission of various electro-chemical signals in the central nervous system. Albeit any aberration in the mechanisms associated with transmission of these signals leads to loss of synaptic contacts in both the neocortex and hippocampus thereby causing insidious cognitive decline and memory dysfunction. Compelling evidence suggests that soluble amyloid-β (Aβ) and hyperphosphorylated tau serve as toxins in the dysfunction of synaptic plasticity and aberrant neurotransmitter (NT) release at synapses consequently causing a cognitive decline in Alzheimer's disease (AD). Further, an imbalance between excitatory and inhibitory neurotransmission systems induced by impaired redox signaling and altered mitochondrial integrity is also amenable for such abnormalities. Defective NT release at the synaptic junction causes several detrimental effects associated with altered activity of synaptic proteins, transcription factors, Ca2+ homeostasis, and other molecules critical for neuronal plasticity. These detrimental effects further disrupt the normal homeostasis of neuronal cells and thereby causing synaptic loss. Moreover, the precise mechanistic role played by impaired NTs and neuromodulators (NMs) and altered redox signaling in synaptic dysfunction remains mysterious, and their possible interlink still needs to be investigated. Therefore, this review elucidates the intricate role played by both defective NTs/NMs and altered redox signaling in synaptopathy. Further, the involvement of numerous pharmacological approaches to compensate neurotransmission imbalance has also been discussed, which may be considered as a potential therapeutic approach in synaptopathy associated with AD.

Exceptionally tight membrane-binding may explain the key role of the synaptotagmin-7 C 2 A domain in asynchronous neurotransmitter release

DOE Office of Scientific and Technical Information (OSTI.GOV)

Voleti, Rashmi; Tomchick, Diana R.; Südhof, Thomas C.

Synaptotagmins (Syts) act as Ca2+ sensors in neurotransmitter release by virtue of Ca2+-binding to their two C2 domains, but their mechanisms of action remain unclear. Puzzlingly, Ca2+-binding to the C2B domain appears to dominate Syt1 function in synchronous release, whereas Ca2+-binding to the C2A domain mediates Syt7 function in asynchronous release. Here we show that crystal structures of the Syt7 C2A domain and C2AB region, and analyses of intrinsic Ca2+-binding to the Syt7 C2 domains using isothermal titration calorimetry, did not reveal major differences that could explain functional differentiation between Syt7 and Syt1. However, using liposome titrations under Ca2+ saturatingmore » conditions, we show that the Syt7 C2A domain has a very high membrane affinity and dominates phospholipid binding to Syt7 in the presence or absence of L-α-phosphatidylinositol 4,5-diphosphate (PIP2). For Syt1, the two Ca2+-saturated C2 domains have similar affinities for membranes lacking PIP2, but the C2B domain dominates binding to PIP2-containing membranes. Mutagenesis revealed that the dramatic differences in membrane affinity between the Syt1 and Syt7 C2A domains arise in part from apparently conservative residue substitutions, showing how striking biochemical and functional differences can result from the cumulative effects of subtle residue substitutions. Viewed together, our results suggest that membrane affinity may be a key determinant of the functions of Syt C2 domains in neurotransmitter release.« less

Neuro-transmitters in the central nervous system & their implication in learning and memory processes.

PubMed

Reis, Helton J; Guatimosim, Cristina; Paquet, Maryse; Santos, Magda; Ribeiro, Fabíola M; Kummer, Arthur; Schenatto, Grace; Salgado, João V; Vieira, Luciene B; Teixeira, Antônio L; Palotás, András

2009-01-01

This review article gives an overview of a number of central neuro-transmitters, which are essential for integrating many functions in the central nervous system (CNS), such as learning, memory, sleep cycle, body movement, hormone regulation and many others. Neurons use neuro-transmitters to communicate, and a great variety of molecules are known to fit the criteria to be classified as such. A process shared by all neuro-transmitters is their release by excocytosis, and we give an outline of the molecular events and protein complexes involved in this mechanism. Synthesis, transport, inactivation, and cellular signaling can be very diverse when different neuro-transmitters are compared, and these processes are described separately for each neuro-transmitter system. Here we focus on the most well known neuro-transmitters: acetyl-choline, catechol-amines (dopamine and nor-adrenalin), indole-amine (serotonin), glutamate, and gamma-amino-butyric acid (GABA). Glutamate is the major excitatory neuro-transmitter in the brain and its actions are counter-balanced by GABA, which is the major inhibitory substance in the CNS. A balance of neuronal transmission between these two neuro-transmitters is essential to normal brain function. Acetyl-choline, serotonin and catechol-amines have a more modulatory function in the brain, being involved in many neuronal circuits. Apart from summarizing the current knowledge about the synthesis, release and receptor signaling of these transmitters, some disease states due to alteration of their normal neuro-transmission are also described.

Diffusion cannot govern the discharge of neurotransmitter in fast synapses.

PubMed Central

Khanin, R; Parnas, H; Segel, L

1994-01-01

In the present work we show that diffusion cannot provide the observed fast discharge of neurotransmitter from a synaptic vesicle during neurotransmitter release, mainly because it is not sufficiently rapid nor is it sufficiently temperature-dependent. Modeling the discharge from the vesicle into the cleft as a continuous point source, we have determined that discharge should occur in 50-75 microseconds, to provide the observed high concentrations of transmitter at the critical zone. Images FIGURE 5 PMID:7811953

Aquatic contaminants alter genes involved in neurotransmitter synthesis and gonadotropin release in largemouth bass.

PubMed

Martyniuk, Christopher J; Sanchez, Brian C; Szabo, Nancy J; Denslow, Nancy D; Sepúlveda, Maria S

2009-10-19

Many aquatic contaminants potentially affect the central nervous system, however the underlying mechanisms of how toxicants alter normal brain function are not well understood. The objectives of this study were to compare the effects of emerging and prevalent environmental contaminants on the expression of brain transcripts with a role in neurotransmitter synthesis and reproduction. Adult male largemouth bass (Micropterus salmoides) were injected once for a 96 h duration with control (water or oil) or with one of two doses of a single chemical to achieve the following body burdens (microg/g): atrazine (0.3 and 3.0), toxaphene (10 and 100), cadmium (CdCl(2)) (0.000067 and 0.00067), polychlorinated biphenyl (PCB) 126 (0.25 and 2.5), and phenanthrene (5 and 50). Partial largemouth bass gene segments were cloned for enzymes involved in neurotransmitter (glutamic acid decarboxylase 65, GAD65; tyrosine hydroxylase) and estrogen (brain aromatase; CYP19b) synthesis for real-time PCR assays. In addition, neuropeptides regulating feeding (neuropeptide Y) and reproduction (chicken GnRH-II, cGnRH-II; salmon GnRH, sGnRH) were also investigated. Of the chemicals tested, only cadmium, PCB 126, and phenanthrene showed any significant effects on the genes tested, while atrazine and toxaphene did not. Cadmium (0.000067 microg/g) significantly increased cGnRH-II mRNA while PCB 126 (0.25 microg/g) decreased GAD65 mRNA. Phenanthrene decreased GAD65 and tyrosine hydroxylase mRNA levels at the highest dose (50 microg/g) but increased cGnRH-II mRNA at the lowest dose (5 microg/g). CYP19b, NPY, and sGnRH mRNA levels were unaffected by any of the treatments. A hierarchical clustering dendrogram grouped PCB 126 and phenanthrene more closely than other chemicals with respect to the genes tested. This study demonstrates that brain transcripts important for neurotransmitter synthesis neuroendocrine function are potential targets for emerging and prevalent aquatic contaminants.

Behavioral impact of neurotransmitter-activated GPCRs: Muscarinic and GABAB receptors regulate C. elegans locomotion

PubMed Central

Dittman, Jeremy S; Kaplan, Joshua M

2008-01-01

Neurotransmitter released from presynaptic terminals activates both ligand-gated ion channels (ionotropic receptors) and a variety of G protein-coupled receptors (GPCRs). These neurotransmitter receptors are expressed on both pre- and postsynaptic cells. Thus, each neurotransmitter acts on multiple receptor classes, generating a large repertoire of physiological responses. The impact of many ionotropic receptors on neuronal activity and behavior has been clearly elucidated; however, much less is known about how neurotransmitter-gated GPCRs regulate neurons and circuits. In C. elegans, both Acetylcholine (ACh) and GABA are released in the nerve cord and mediate fast neuromuscular excitation and inhibition during locomotion. Here we identify a muscarinic receptor (GAR-2) and the GABAB receptor dimer (GBB-1/2) that detect synaptically released ACh and GABA, respectively. Both GAR-2 and GBB-1/2 inhibited cholinergic motor neurons when ACh and GABA levels were enhanced. Loss of either GPCR resulted in movement defects, suggesting that these receptors are activated during locomotion. When the negative feedback provided by GAR-2 was replaced with positive feedback, animals became highly sensitive to ACh levels and locomotion was severely impaired. Thus, conserved GPCRs act in the nematode motor circuit to provide negative feedback and to regulate locomotory behaviors that underlie navigation. PMID:18614679

Palmitoylation as a Functional Regulator of Neurotransmitter Receptors

PubMed Central

Naumenko, Vladimir S.

2018-01-01

The majority of neuronal proteins involved in cellular signaling undergo different posttranslational modifications significantly affecting their functions. One of these modifications is a covalent attachment of a 16-C palmitic acid to one or more cysteine residues (S-palmitoylation) within the target protein. Palmitoylation is a reversible modification, and repeated cycles of palmitoylation/depalmitoylation might be critically involved in the regulation of multiple signaling processes. Palmitoylation also represents a common posttranslational modification of the neurotransmitter receptors, including G protein-coupled receptors (GPCRs) and ligand-gated ion channels (LICs). From the functional point of view, palmitoylation affects a wide span of neurotransmitter receptors activities including their trafficking, sorting, stability, residence lifetime at the cell surface, endocytosis, recycling, and synaptic clustering. This review summarizes the current knowledge on the palmitoylation of neurotransmitter receptors and its role in the regulation of receptors functions as well as in the control of different kinds of physiological and pathological behavior. PMID:29849559

Foods and food constituents that affect the brain and human behavior

NASA Technical Reports Server (NTRS)

Lieberman, Harris R.; Wurtman, Richard J.

1986-01-01

Until recently, it was generally believed that brain function was usually independent of day-to-day metabolic changes associated with consumption of food. Although it was acknowledged that peripheral metabolic changes associated with hunger or satiety might affect brain function, other effects of foods on the brain were considered unlikely. However, in 1971, Fernstrom and Wurtman discovered that under certain conditions, the protein-to-carbohydrate ratio of a meal could affect the concentration of a particular brain neurotransmitter. That neurotransmitter, serotonin, participates in the regulation of a variety of central nervous system (CNS) functions including sleep, pain sensitivity, aggression, and patterns of nutrient selection. The activity of other neurotransmitter systems has also been shown to be, under certain conditions, affected by dietary constituents which are given either as ordinary foods or in purified form. For example, the CNS turnover of two catecholamine neurotransmitters, dopamine and norepinephrine, can be altered by ingestion of their amino acid precursor, tyrosine, when neurons that release these monoamines are firing frequently. Similarly, lecithin, a dietary source of choline, and choline itself have been shown to increase the synthesis of acetylcholine when cholinergic neurons are very active. It is possible that other neurotransmitters could also be affected by precursor availability or other, as yet undiscovered peripheral factors governed by food consumption. The effects of food on neurotransmitters and behavior are discussed.

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

Loss of Ahi1 Impairs Neurotransmitter Release and Causes Depressive Behaviors in Mice

PubMed Central

Zhai, Lijing; Sun, Miao; Miao, Zhigang; Li, Jizhen; Xu, Xingshun

2014-01-01

Major depression is becoming one of the most prevalent forms of psychiatric disorders. However, the mechanisms of major depression are still not well-understood. Most antidepressants are only effective in some patients and produce some serious side effects. Animal models of depression are therefore essential to unravel the mechanisms of depression and to develop novel therapeutic strategies. Our previous studies showed that Abelson helper integration site-1 (Ahi1) deficiency causes depression-like behaviors in mice. In this study, we characterized the biochemical and behavioral changes in Ahi1 knockout (KO) mice. In Ahi1 KO mice, neurotransmitters including serotonin and dopamine were significantly decreased in different brain regions. However, glutamate and GABA levels were not affected by Ahi1 deficiency. The antidepressant imipramine attenuated depressive behaviors and partially restored brain serotonin level in Ahi1 KO mice. Our findings suggest that Ahi1 KO mice can be used for studying the mechanisms of depression and screening therapeutic targets. PMID:24691070

Substance P is a functional neurotransmitter in the rat parotid gland.

PubMed

Gallacher, D V

1983-09-01

The technique of electrical field stimulation was employed to stimulate the intrinsic nerves of isolated rat parotid gland fragments. Responses to field stimulation were recorded as changes in enzyme secretion (amylase release), radiolabelled ion fluxes (86Rb efflux) and electrophysiological effects (changes in acinar cell membrane potential and input resistance). All effects of field stimulation were abolished by the neurotoxin, tetrodotoxin (TTX). Selective use of pharmacological antagonists revealed that both the sympathetic and parasympathetic nerves to this tissue were being excited by field stimulation. Importantly a significant component of the response to field stimulation persisted in the presence of combined autonomic receptor blockade by atropine, phentolamine and propranolol, i.e. due to release of a non-cholinergic, non-adrenergic neurotransmitter. The non-cholinergic, non-adrenergic neurotransmitter evoked amylase release, 86Rb efflux and electrophysiological effects seen as changes in acinar cell membrane potential and conductance, i.e. stimulus-permeability coupled. Two biologically active peptides, substance P (SP) and vasoactive intestinal polypeptide (VIP) were shown to evoke amylase release in the presence of combined autonomic blockade. VIP however did not evoke any increase in 86Rb efflux, i.e. not stimulus-permeability coupled. All the effects of the non-cholinergic, non-adrenergic transmitter were mimicked by substance P which evokes 86Rb efflux and electrophysiological effects in addition to amylase release. The non-cholinergic, non-adrenergic field stimulus effects on amylase release and 86Rb efflux were abolished or markedly attenuated in tissues which had been desensitized by prior exposure to exogenous substance P. In the presence of VIP, however, the non-cholinergic, non-adrenergic effects persisted and were apparently potentiated. Acute application of the neurotoxin capsaicin first stimulated a transient release of amylase and

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.

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

[Pediatric neurotransmitter disease in Japan].

PubMed

Shintaku, Haruo

2012-09-01

Pediatric neurotransmitter disease (PND) encompasses a range of rare genetic disorders that affect the metabolism of neurotransmitters in children. While these neurological disorders are often studied independently of each other, they all manifest central nervous system symptoms and require proper diagnosis and intervention at early stages. Since clinical symptoms of PND can be nonspecific, the conditions are often under-diagnosed, leaving patients without a chance to receive effective treatment. Envisioning PND as a whole, a comprehensive research effort is underway for a better understanding of pathophysiology and epidemiology in Japan, and toward the establishment of diagnostic criteria. The early diagnosis and development of new effective therapies are of urgent importance for these rare disorders that are not covered by newborn mass screening. For rarer forms of PND, at the same time, it is important to encourage recognition and understanding of the disease concept among healthcare professionals.

Evaluation of substance P as a neurotransmitter in equine jejunum.

PubMed

Malone, E D; Kannan, M S; Brown, D R

2000-10-01

To determine whether substance P (SP) functions as a neurotransmitter in equine jejunum. Samples of jejunum obtained from horses that did not have lesions in the gastrointestinal tract. Jejunal smooth muscle strips, oriented in the plane of the circular or longitudinal muscle, were suspended isometrically in muscle baths. Neurotransmitter release was induced by electrical field stimulation (EFS) delivered at 2 intensities (30 and 70 V) and various frequencies on muscle strips that were maintained at low tension or were under contraction. A neurokinin-1 receptor blocker (CP-96,345) was added to baths prior to EFS to interrupt SP neurotransmission. Additionally, direct effects of SP on muscle strips were evaluated, and SP-like immunoreactivity was localized in intestinal tissues, using indirect immunofluorescence testing. Substance P contracted circularly and longitudinally oriented muscle strips. Prior treatment with CP-96,345 altered muscle responses to SP and EFS, suggesting that SP was released from depolarized myenteric neurons. Depending on orientation of muscle strips and stimulation variables used, CP-96,345 increased or decreased the contractile response to EFS. Substance P-like immunoreactivity was detected in the myenteric plexus and circular muscle layers. Substance P appears to function as a neurotransmitter in equine jejunum. It apparently modulates smooth muscle contractility, depending on preexisting conditions. Effects of SP may be altered in some forms of intestinal dysfunction. Altering SP neurotransmission in the jejunum may provide a therapeutic option for motility disorders of horses that are unresponsive to adrenergic and cholinergic drugs.

Newer putative central neurotransmitters: roles in thermoregulation. Hypothalamic substances in the control of body temperature: general characteristics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blatteis, C.M.

1981-11-01

Although it has been demonstrated that their central, exogenous application induces thermal responses, it is not yet established whether various substances found in the hypothalami of many species function as neurotransmitters in central thermoregulatory pathways. Available data concerning their presence, synthesis, release, possible binding sites, and inactivation are reviewed in the light of established criteria for determining a neurotransmitter role for such substances.

Focus On: Neurotransmitter Systems

PubMed Central

Valenzuela, C. Fernando; Puglia, Michael P.; Zucca, Stefano

2011-01-01

Neurotransmitter systems have been long recognized as important targets of the developmental actions of alcohol (i.e., ethanol). Short- and long-term effects of ethanol on amino acid (e.g., γ-aminobutyric acid and glutamate) and biogenic amine (e.g., serotonin and dopamine) neurotransmitters have been demonstrated in animal models of fetal alcohol spectrum disorders (FASD). Researchers have detected ethanol effects after exposure during developmental periods equivalent to the first, second, and third trimesters of human pregnancy. Results support the recommendation that pregnant women should abstain from drinking—even small quantities—as effects of ethanol on neurotransmitter systems have been detected at low levels of exposure. Recent studies have elucidated new mechanisms and/or consequences of the actions of ethanol on amino acid and biogenic amine neurotransmitter systems. Alterations in these neurotransmitter systems could, in part, be responsible for many of the conditions associated with FASD, including (1) learning, memory, and attention deficits; (2) motor coordination impairments; (3) abnormal responsiveness to stress; and (4) increased susceptibility to neuropsychiatric disorders, such as substance abuse and depression, and also neurological disorders, such as epilepsy and sudden infant death syndrome. However, future research is needed to conclusively establish a causal relationship between these conditions and developmental dysfunctions in neurotransmitter systems. PMID:23580048

Autoreceptor Modulation of Peptide/Neurotransmitter Co-release from PDF Neurons Determines Allocation of Circadian Activity in Drosophila

PubMed Central

Choi, Charles; Cao, Guan; Tanenhaus, Anne K.; McCarthy, Ellena v.; Jung, Misun; Schleyer, William; Shang, Yuhua; Rosbash, Michael; Yin, Jerry C.P.; Nitabach, Michael N.

2012-01-01

Drosophila melanogaster flies concentrate behavioral activity around dawn and dusk. This organization of daily activity is controlled by central circadian clock neurons, including the lateral ventral pacemaker neurons (LNvs) that secrete the neuropeptide PDF (Pigment Dispersing Factor). Previous studies have demonstrated the requirement for PDF signaling to PDF receptor (PDFR)-expressing dorsal clock neurons in organizing circadian activity. While LNvs also express functional PDFR, the role of these autoreceptors has remained enigmatic. Here we show that (1) PDFR activation in LNvs shifts the balance of circadian activity from evening to morning, similar to behavioral responses to summer-like environmental conditions and (2) this shift is mediated by stimulation of the Ga,s-cAMP pathway and a consequent change in PDF/neurotransmitter co-release from the LNvs. These results suggest a novel mechanism for environmental control of the allocation of circadian activity and provide new general insight into the role of neuropeptide autoreceptors in behavioral control circuits. PMID:22938867

The role of transmembrane segment 5 (TM5) in Na2 release and the conformational transition of neurotransmitter:sodium symporters toward the inward-open state

PubMed Central

Stolzenberg, Sebastian; Li, Zheng; Quick, Matthias; Malinauskaite, Lina; Nissen, Poul; Weinstein, Harel; Javitch, Jonathan A.; Shi, Lei

2017-01-01

Neurotransmitter:sodium symporters (NSSs) 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 multihydrophobic 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 transmembrane segment 5 (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 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. PMID:28320858

Treatment with the MAO-A inhibitor clorgyline elevates monoamine neurotransmitter levels and improves affective phenotypes in a mouse model of Huntington disease.

PubMed

Garcia-Miralles, Marta; Ooi, Jolene; Ferrari Bardile, Costanza; Tan, Liang Juin; George, Maya; Drum, Chester L; Lin, Rachel Yanping; Hayden, Michael R; Pouladi, Mahmoud A

2016-04-01

Abnormal monoamine oxidase A and B (MAO-A/B) activity and an imbalance in monoamine neurotransmitters have been suggested to underlie the pathobiology of depression, a major psychiatric symptom observed in patients with neurodegenerative diseases, such as Huntington disease (HD). Increased MAO-A/B activity has been observed in brain tissue from patients with HD and in human and rodent HD neural cells. Using the YAC128 mouse model of HD, we studied the effect of an irreversible MAO-A inhibitor, clorgyline, on the levels of select monoamine neurotransmitters associated with affective function. We observed a decrease in striatal levels of the MAO-A/B substrates, dopamine and norepinephrine, in YAC128 HD mice compared with wild-type mice, which was accompanied by increased anxiety- and depressive-like behaviour at five months of age. Treatment for 26 days with clorgyline restored dopamine, serotonin, and norepinephrine neurotransmitter levels in the striatum and reduced anxiety- and depressive-like behaviour in YAC128 HD mice. This study supports a potential therapeutic use for MAO-A inhibitors in the treatment of depression and anxiety in patients with HD. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Differential effects of C- and N-terminal substance P metabolites on the release of amino acid neurotransmitters from the spinal cord: potential role in nociception.

PubMed

Skilling, S R; Smullin, D H; Larson, A A

1990-04-01

Extensive evidence implicates Substance P [SP(1-11)] as a primary afferent neurotransmitter or modulator of nociceptive information, and there is increasing evidence that the excitatory amino acids aspartate (Asp) and glutamate (Glu) may also act as nociceptive neurotransmitters. We have previously demonstrated that nociceptive stimulation (metatarsal injection of formalin) caused a tetrodotoxin (TTX)-sensitive release of Asp and a TTX-insensitive release of Glu from the dorsal spinal cord. We have also shown release of Asp and Glu following the direct infusion of SP(1-11), suggesting that formalin-induced Asp or Glu changes could be secondary to an initial release of SP(1-11). In contrast to nociception, pretreatment with TTX, reported here, had no effect on the SP(1-11)-induced release of Asp, suggesting a presynaptic mechanism. Behavioral experiments, in both our laboratory, and others, now suggest that the N-terminal products of SP metabolism play a distinct role in the modulation of SP(1-11) nociception, possibly through an interaction with an opiate receptor. To test the hypothesis that N- and C-terminal fragments of SP produce opposite effects on biochemical events potentially involved in nociception, we compared the effects of infusion of the N-terminal metabolite SP(1-7) and the C-terminal metabolite SP(5-11) on changes in the ECF concentration of amino acids in the spinal cord as a measure of their apparent release, using microdialysis. Intradiaylsate infusion of SP(5-11) increased the release of Asp, Glu, asparagine (Asn), glycine (Gly), and taurine (Tau). The changes in Asp, Glu, and Tau were similar in direction and magnitude to changes produced by SP(1-11) or formalin injection, further supporting the hypothesis that the C-terminal is responsible for the nociceptive effects of SP(1-11). In contrast, infusion of SP(1-7) significantly decreased the release of Asn, Tau, Glu, and Gly. This inhibition of amino acid release is consistent with the hypothesis

Action of Neurotransmitter: A Key to Unlock the AgRP Neuron Feeding Circuit

PubMed Central

Liu, Tiemin; Wang, Qian; Berglund, Eric D.; Tong, Qingchun

2013-01-01

The current obesity epidemic and lack of efficient therapeutics demand a clear understanding of the mechanism underlying body weight regulation. Despite intensive research focus on obesity pathogenesis, an effective therapeutic strategy to treat and cure obesity is still lacking. Exciting studies in last decades have established the importance of hypothalamic agouti-related protein-expressing neurons (AgRP neurons) in the regulation of body weight homeostasis. AgRP neurons are both required and sufficient for feeding regulation. The activity of AgRP neurons is intricately regulated by nutritional hormones as well as synaptic inputs from upstream neurons. Changes in AgRP neuron activity lead to alterations in the release of mediators, including neuropeptides Neuropeptide Y (NPY) and AgRP, and fast-acting neurotransmitter GABA. Recent studies based on mouse genetics, novel optogenetics, and designer receptor exclusively activated by designer drugs have identified a critical role for GABA release from AgRP neurons in the parabrachial nucleus and paraventricular hypothalamus in feeding control. This review will summarize recent findings about AgRP neuron-mediated control of feeding circuits with a focus on the role of neurotransmitters. Given the limited knowledge on feeding regulation, understanding the action of neurotransmitters may be a key to unlock neurocircuitry that governs feeding. PMID:23346045

Studies of two naturally occurring compounds which effect release of acetylcholine from synaptosomes. [Leptinotarsa decemlineata

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koenig, M.L.

1985-01-01

Two naturally occurring compounds which effect the release of neurotransmitter from synaptosomes have been purified to apparent homogeneity. Iotrochotin (IOT) isolated from wound exudate of the Caribbean purple bleeder sponge promotes release in a manner that is independent of the extracellular Ca/sup 2 +/ ion concentration. Leptinotarsin (LPT-d), a protein taken from hemolymph of the Colorado potato beetle, Leptinotarsa decemlineata, stimulates Ca/sup 2 +/-dependent release. IOT is slightly acidic and has a molecular weight of approximately 18 kD. (/sup 3/H)acetylcholine which has been introduced into synaptosomes as (/sup 3/H)choline can be released by IOT. The toxin releasable pool of labelledmore » neurotransmitter is not depleted by depolarization of the synaptosomes with high potassium, and therefore seems to be primarily extravesicular. LPT-d is a larger protein (molecular weight = 45 kD) than IOT, and seems to effect primarily vesicular release by opening at least one type of presynaptic Ca/sup 2 +/ channel. The facilitatory effects of the toxin on synaptosomal release can be inhibited by inorganic Ca/sup 2 +/ channel antagonists, but are not generally affected by organic antagonists.« less

Neurotransmitter receptors on microglia

PubMed Central

Liu, Huan; Leak, Rehana K; Hu, Xiaoming

2016-01-01

As the resident immune cells in the central nervous system, microglia have long been hypothesised to promote neuroinflammation and exacerbate neurotoxicity. However, this traditional view has undergone recent revision as evidence has accumulated that microglia exert beneficial and detrimental effects depending on activation status, polarisation phenotype and cellular context. A variety of neurotransmitter receptors are expressed on microglia and help mediate the bidirectional communication between neurons and microglia. Here we review data supporting the importance of neurotransmitter receptors on microglia, with a special emphasis on glutamate, γ-aminobutyric acid (GABA), norepinephrine, cannabinoid and acetylcholine receptors. We summarise evidence favouring a significant role for neurotransmitter receptors in modulating microglial activation, phagocytic clearance and phenotypic polarisation. Elucidating the effects of neurotransmitter receptors on microglia and dissecting the underlying mechanisms may help accelerate the discovery of novel drugs that tap the therapeutic potential of microglia. PMID:28959464

Feeding-associated alterations in striatal neurotransmitter release

NASA Technical Reports Server (NTRS)

Acworth, I. N.; Ressler, K.; Wurtman, R. J.

1989-01-01

Published evidence suggests a role for dopaminergic (DA) brain pathways in feeding-associated behaviors. Using the novel technique of brain microdialysis of striatal extracellular fluid (ECF) as an index of DA release, Church et al. described increases in levels of DA when animals had limited access to pellets, but not with free access. Dopamine release from the nucleus accumbens did increase with free access to pellets post starvation or after food reward. We used permanently implanted microdialysis probes to measure ECF levels of DA, DOPAC, HVA, and large neutral amino acids (LNAA) for up to 72 hours after implantation among rats experiencing different dietary regimens.

Laurate Biosensors Image Brain Neurotransmitters In Vivo: Can an Antihypertensive Medication Alter Psychostimulant Behavior?

PubMed

Broderick, Patricia A; Ho, Helen; Wat, Karyn; Murthy, Vivek

2008-07-04

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 Ltryptophan (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-HT 2A/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

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

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 daily for 4 days by oral gavage to Pah(enu2/enu2) mice followed by measurement of brain biopterin, phenylalanine, tyrosine, tryptophan and monoamine neurotransmitter content. A significant increase in brain biopterin content was detected only in mice that had received the highest sapropterin dose, 100mg/kg. Blood and brain phenylalanine concentrations were unchanged by sapropterin therapy. Sapropterin therapy also did not alter the absolute amounts of dopamine and serotonin in brain but was associated with increased homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), dopamine and serotonin metabolites respectively, in both wild type and Pah(enu2/enu2) mice. Oral sapropterin therapy likely does not directly affect central nervous system monoamine synthesis in either wild type or hyperphenylalaninemic mice but may stimulate synaptic neurotransmitter release and subsequent metabolism. Copyright © 2015 Elsevier Inc. All rights reserved.

Absence of specific binding of several putative neuro-transmitters to human fibroblasts.

PubMed

Berrettini, W H; Nadi, N S; Gershon, E S

1983-01-01

Fibroblasts were examined for specific binding sites of ten putative neurotransmitters to determine whether this tissue could be used in receptor studies of neurologic and psychiatric disorders. Stereospecific saturable binding was not found for any of the ligands: arginine vasopressin, neurotensin, somatostatin, angiotensin II, thyrotropin-releasing hormone (TRH), alpha-bungarotoxin, LSD, dihydromorphine, muscimol and spiperone.

Mimicking subsecond neurotransmitter dynamics with femtosecond laser stimulated nanosystems.

PubMed

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

2014-06-23

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.

Lack of CB1 receptors increases noradrenaline release in vas deferens without affecting atrial noradrenaline release or cortical acetylcholine release

PubMed Central

Schlicker, Eberhard; Redmer, Agnes; Werner, André; Kathmann, Markus

2003-01-01

We studied whether cannabinoid CB1 receptor gene disruption (to yield CB1−/− mice) affects the electrically evoked tritium overflow from vas deferens and atrial pieces preincubated with [3H]-noradrenaline (NA) (‘noradrenaline release') and from cerebral cortex slices preincubated with [3H]-choline (‘acetylcholine release'). NA release was higher by 37% in vas deferens from CB1−/− mice than in vas deferens from CB1+/+ mice. The cannabinoid receptor agonist WIN 55,212-2 inhibited, and the CB1 receptor inverse agonist/antagonist SR 141716, increased NA release in vas deferens from CB1+/+ mice without affecting it in vas deferens from CB1−/− mice. Atrial NA release did not differ between CB1+/+ and CB1−/− mice nor did WIN 55,212-2 affect NA release in either strain. Cortical acetylcholine (Ach) release did not differ between CB1+/+ and CB1−/− mice. WIN 55,212-2 inhibited, but SR 141716 did not affect, Ach release in the cortex from CB1+/+ mice. Both drugs did not alter Ach release in the cortex from CB1−/− mice. Tritium content did not differ between CB1+/+ and CB1−/− mice in any preparation. In conclusion, the increase in NA release associated with CB1 receptor deficiency in the vas deferens, which cannot be ascribed to an alteration of tritium content of the preparations, suggests an endogenous tone at the CB1 receptors of CB1+/+ mice in this tissue. Furthermore, the effect of WIN 55,212-2 on NA release in the vas deferens and on cortical Ach release involves CB1 receptors, whereas the involvement of non-CB1–non-CB2 receptors can be excluded. PMID:12970076

Glutamate is an inhibitory neurotransmitter in the Drosophila olfactory system.

PubMed

Liu, Wendy W; Wilson, Rachel I

2013-06-18

Glutamatergic neurons are abundant in the Drosophila central nervous system, but their physiological effects are largely unknown. In this study, we investigated the effects of glutamate in the Drosophila antennal lobe, the first relay in the olfactory system and a model circuit for understanding olfactory processing. In the antennal lobe, one-third of local neurons are glutamatergic. Using in vivo whole-cell patch clamp recordings, we found that many glutamatergic local neurons are broadly tuned to odors. Iontophoresed glutamate hyperpolarizes all major cell types in the antennal lobe, and this effect is blocked by picrotoxin or by transgenic RNAi-mediated knockdown of the GluClα gene, which encodes a glutamate-gated chloride channel. Moreover, antennal lobe neurons are inhibited by selective activation of glutamatergic local neurons using a nonnative genetically encoded cation channel. Finally, transgenic knockdown of GluClα in principal neurons disinhibits the odor responses of these neurons. Thus, glutamate acts as an inhibitory neurotransmitter in the antennal lobe, broadly similar to the role of GABA in this circuit. However, because glutamate release is concentrated between glomeruli, whereas GABA release is concentrated within glomeruli, these neurotransmitters may act on different spatial and temporal scales. Thus, the existence of two parallel inhibitory transmitter systems may increase the range and flexibility of synaptic inhibition.

Tyrosine administration enhances dopamine synthesis and release in light-activated rat retina

NASA Technical Reports Server (NTRS)

Gibson, C. J.; Watkins, C. J.; Wurtman, R. J.

1983-01-01

Exposure of dark-adapted albino rats to light (350 lux) significantly elevated retinal levels of the dopamine metabolite dihydroxyphenyl acetic acid during the next hour; their return to a dark environment caused dihydroxyphenyl acetic acid levels to fall. Retinal dopamine levels were increased slightly by light exposure, suggesting that the increase in dihydroxyphenyl acetic acid reflected accelerated dopamine synthesis. Administration of tyrosine (100 mg/kg, i.p.) further elevated retinal dihydroxyphenyl acetic acid among light-exposed animals, but failed to affect dopamine release among animals in the dark. These observations show that a physiological stimulus - light exposure - can cause catecholaminergic neurons to become tyrosine-dependent; they also suggest that food consumption may affect neurotransmitter release within the retina.

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.

Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) for Intraoperative Neurochemical Monitoring

PubMed Central

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.

2010-01-01

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. PMID:19963865

GnRH dysregulation in polycystic ovarian syndrome (PCOS) is a manifestation of an altered neurotransmitter profile.

PubMed

Chaudhari, Nirja; Dawalbhakta, Mitali; Nampoothiri, Laxmipriya

2018-04-11

GnRH is the master molecule of reproduction that is influenced by several intrinsic and extrinsic factors such as neurotransmitters and neuropeptides. Any alteration in these regulatory loops may result in reproductive-endocrine dysfunction such as the polycystic ovarian syndrome (PCOS). Although low dopaminergic tone has been associated with PCOS, the role of neurotransmitters in PCOS remains unknown. The present study was therefore aimed at understanding the status of GnRH regulatory neurotransmitters to decipher the neuroendocrine pathology in PCOS. PCOS was induced in rats by oral administration of letrozole (aromatase inhibitor). Following PCOS validation, animals were assessed for gonadotropin levels and their mRNA expression. Neurotrasnmitter status was evaluated by estimating their levels, their metabolism and their receptor expression in hypothalamus, pituitary, hippocampus and frontal cortex of PCOS rat model. We demonstrate that GnRH and LH inhibitory neurotransmitters - serotonin, dopamine, GABA and acetylcholine - are reduced while glutamate, a major stimulator of GnRH and LH release, is increased in the PCOS condition. Concomitant changes were observed for neurotransmitter metabolising enzymes and their receptors as well. Our results reveal that increased GnRH and LH pulsatility in PCOS condition likely result from the cumulative effect of altered GnRH stimulatory and inhibitory neurotransmitters in hypothalamic-pituitary centre. This, we hypothesise, is responsible for the depression and anxiety-like mood disorders commonly seen in PCOS women.

The Role of Ion Selectivity of the Fusion Pore on Transmission and the Exocytosis of Neurotransmitters and Hormones

NASA Astrophysics Data System (ADS)

Delacruz, Joannalyn Bongar

Healthy nervous system function depends on proper transmission. Synaptic transmission occurs by the release of transmitters from vesicles that fuse to the plasma membrane of a pre-synaptic cell. Regulated release of neurotransmitters, neuropeptides, and hormones occurs by exocytosis, initiated by the formation of the fusion pore. The initial fusion pore has molecular dimensions with a diameter of 1-2 nm and a rapid lifetime on the millisecond time scale. It connects the vesicular lumen and extracellular space, serving as an important step for regulating the release of charged transmitters. Comprehending the molecular structure and biophysical properties of the fusion pore is essential for a mechanistic understanding of vesicle-plasma membrane fusion and transmitter release. Release of charged transmitter molecules such as glutamate, acetylcholine, dopamine, or noradrenaline through a narrow fusion pore requires compensation of change in charge. Transmitter release through the fusion pore is therefore an electrodiffusion process. If the fusion pore is selective for specific ions, then its selectivity will affect the rate of transmitter release via the voltage gradient that develops across the fusion pore. The elucidation of these mechanisms can lead to a better understanding of nervous system cell biology, neural and endocrine signaling, learning, memory, motor control, sensory function and integration, and in particular synaptic transmission. This investigation can advance our understanding of neurological disorders in which noradrenergic and dopaminergic exocytosis is disturbed, leading to neurological consequences of developmental disorders, epilepsy, Parkinson's disease, and other neurodegenerative diseases. Ultimately, understanding the role of selectivity in the fusion pore and its effects on exocytosis can contribute to the development of more effective therapies. This study investigates the selectivity of the fusion pore by observing the effects of ion

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

Drug-induced GABA transporter currents enhance GABA release to induce opioid withdrawal behaviors.

PubMed

Bagley, Elena E; Hacker, Jennifer; Chefer, Vladimir I; Mallet, Christophe; McNally, Gavan P; Chieng, Billy C H; Perroud, Julie; Shippenberg, Toni S; Christie, MacDonald J

2011-10-30

Neurotransmitter transporters can affect neuronal excitability indirectly via modulation of neurotransmitter concentrations or directly via transporter currents. A physiological or pathophysiological role for transporter currents has not been described. We found that GABA transporter 1 (GAT-1) cation currents directly increased GABAergic neuronal excitability and synaptic GABA release in the periaqueductal gray (PAG) during opioid withdrawal in rodents. In contrast, GAT-1 did not indirectly alter GABA receptor responses via modulation of extracellular GABA concentrations. Notably, we found that GAT-1-induced increases in GABAergic activity contributed to many PAG-mediated signs of opioid withdrawal. Together, these data support the hypothesis that GAT-1 activity directly produces opioid withdrawal signs through direct hyperexcitation of GABAergic PAG neurons and nerve terminals, which presumably enhances GABAergic inhibition of PAG output neurons. These data provide, to the best of our knowledge, the first evidence that dysregulation of a neurotransmitter transporter current is important for the maladaptive plasticity that underlies opiate withdrawal.

Masters or slaves? Vesicle release machinery and the regulation of presynaptic calcium channels.

PubMed

Jarvis, Scott E; Zamponi, Gerald W

2005-05-01

Calcium entry through presynaptic voltage-gated calcium channels is essential for neurotransmitter release. The two major types of presynaptic calcium channels contain a synaptic protein interaction site that physically interacts with synaptic vesicle release proteins. This is thought to tighten the coupling between the sources of calcium entry and the neurotransmitter release machinery. Conversely, the binding of synaptic proteins to presynaptic calcium channels regulates calcium channel activity. Hence, presynaptic calcium channels act not only as the masters of the synaptic release process, but also as key targets for feedback inhibition.

Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target?

PubMed

Horvath, Gabriella A; Demos, Michelle; Shyr, Casper; Matthews, Allison; Zhang, Linhua; Race, Simone; Stockler-Ipsiroglu, Sylvia; Van Allen, Margot I; Mancarci, Ogan; Toker, Lilah; Pavlidis, Paul; Ross, Colin J; Wasserman, Wyeth W; Trump, Natalie; Heales, Simon; Pope, Simon; Cross, J Helen; van Karnebeek, Clara D M

2016-01-01

We describe neurotransmitter abnormalities in two patients with drug-resistant epilepsy resulting from deleterious de novo mutations in sodium channel genes. Whole exome sequencing identified a de novo SCN2A splice-site mutation (c.2379+1G>A, p.Glu717Gly.fs*30) resulting in deletion of exon 14, in a 10-year old male with early onset global developmental delay, intermittent ataxia, autism, hypotonia, epileptic encephalopathy and cerebral/cerebellar atrophy. In the cerebrospinal fluid both homovanillic acid and 5-hydroxyindoleacetic acid were significantly decreased; extensive biochemical and genetic investigations ruled out primary neurotransmitter deficiencies and other known inborn errors of metabolism. In an 8-year old female with an early onset intractable epileptic encephalopathy, developmental regression, and progressive cerebellar atrophy, a previously unreported de novo missense mutation was identified in SCN8A (c.5615G>A; p.Arg1872Gln), affecting a highly conserved residue located in the C-terminal of the Nav1.6 protein. Aside from decreased homovanillic acid and 5-hydroxyindoleacetic acid, 5-methyltetrahydrofolate was also found to be low. We hypothesize that these channelopathies cause abnormal synaptic mono-amine metabolite secretion/uptake via impaired vesicular release and imbalance in electrochemical ion gradients, which in turn aggravate the seizures. Treatment with oral 5-hydroxytryptophan, l-Dopa/Carbidopa, and a dopa agonist resulted in mild improvement of seizure control in the male case, most likely via dopamine and serotonin receptor activated signal transduction and modulation of glutamatergic, GABA-ergic and glycinergic neurotransmission. Neurotransmitter analysis in other sodium channelopathy patients will help validate our findings, potentially yielding novel treatment opportunities. Copyright © 2015 Elsevier Inc. All rights reserved.

Harmane: an atypical neurotransmitter?

PubMed

Abu Ghazaleh, Haya; Lalies, Maggie D; Nutt, David J; Hudson, Alan L

2015-03-17

Harmane is an active component of clonidine displacing substance and a candidate endogenous ligand for imidazoline binding sites. The neurochemistry of tritiated harmane was investigated in the present study examining its uptake and release properties in the rat brain central nervous system (CNS) in vitro. At physiological temperature, [(3)H]harmane was shown to be taken up in rat brain cortex. Further investigations demonstrated that treatment with monoamine uptake blockers (citalopram, nomifensine and nisoxetine) did not alter [(3)H]harmane uptake implicating that the route of [(3)H]harmane transport was distinct from the monoamine uptake systems. Furthermore, imidazoline ligands (rilmenidine, efaroxan, 2-BFI and idazoxan) showed no prominent effect on [(3)H]harmane uptake suggesting the lack of involvement of imidazoline binding sites. Subsequent analyses showed that disruption of the Na(+) gradient using ouabain or choline chloride did not block [(3)H]harmane uptake suggesting a Na(+)-independent transport mechanism. Moreover, higher temperatures (50°C) failed to impede [(3)H]harmane uptake implying a non-physiological transporter. The failure of potassium to evoke the release of preloaded [(3)H]harmane from rat brain cortex indicates that the properties of this putative endogenous ligand for imidazoline binding sites do not resemble that of a conventional neurotransmitter. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

[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.

Dynamic SERS nanosensor for neurotransmitter sensing near neurons.

PubMed

Lussier, Félix; Brulé, Thibault; Bourque, Marie-Josée; Ducrot, Charles; Trudeau, Louis-Éric; Masson, Jean-François

2017-12-04

Current electrophysiology and electrochemistry techniques have provided unprecedented understanding of neuronal activity. However, these techniques are suited to a small, albeit important, panel of neurotransmitters such as glutamate, GABA and dopamine, and these constitute only a subset of the broader range of neurotransmitters involved in brain chemistry. Surface-enhanced Raman scattering (SERS) provides a unique opportunity to detect a broader range of neurotransmitters in close proximity to neurons. Dynamic SERS (D-SERS) nanosensors based on patch-clamp-like nanopipettes decorated with gold nanoraspberries can be located accurately under a microscope using techniques analogous to those used in current electrophysiology or electrochemistry experiments. In this manuscript, we demonstrate that D-SERS can measure in a single experiment ATP, glutamate (glu), acetylcholine (ACh), GABA and dopamine (DA), among other neurotransmitters, with the potential for detecting a greater number of neurotransmitters. The SERS spectra of these neurotransmitters were identified with a barcoding data processing method and time series of the neurotransmitter levels were constructed. The D-SERS nanosensor was then located near cultured mouse dopaminergic neurons. The detection of neurotransmitters was performed in response to a series of K + depolarisations, and allowed the detection of elevated levels of both ATP and dopamine. Control experiments were also performed near glial cells, showing only very low basal detection neurotransmitter events. This paper demonstrates the potential of D-SERS to detect neurotransmitter secretion events near living neurons, but also constitutes a strong proof-of-concept for the broad application of SERS to the detection of secretion events by neurons or other cell types in order to study normal or pathological cell functions.

A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter

NASA Astrophysics Data System (ADS)

Razavi, Asghar M.; Khelashvili, George; Weinstein, Harel

2017-01-01

The dopamine transporter (DAT) belongs to the neurotransmitter:sodium symporter (NSS) family of membrane proteins that are responsible for reuptake of neurotransmitters from the synaptic cleft to terminate a neuronal signal and enable subsequent neurotransmitter release from the presynaptic neuron. The release of one sodium ion from the crystallographically determined sodium binding site Na2 had been identified as an initial step in the transport cycle which prepares the transporter for substrate translocation by stabilizing an inward-open conformation. We have constructed Markov State Models (MSMs) from extensive molecular dynamics simulations of human DAT (hDAT) to explore the mechanism of this sodium release. Our results quantify the release process triggered by hydration of the Na2 site that occurs concomitantly with a conformational transition from an outward-facing to an inward-facing state of the transporter. The kinetics of the release process are computed from the MSM, and transition path theory is used to identify the most probable sodium release pathways. An intermediate state is discovered on the sodium release pathway, and the results reveal the importance of various modes of interaction of the N-terminus of hDAT in controlling the pathways of release.

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

Short term memory may be the depletion of the readily releasable pool of presynaptic neurotransmitter vesicles of a metastable long term memory trace pattern.

PubMed

Tarnow, Eugen

2009-09-01

The Tagging/Retagging model of short term memory was introduced earlier (Tarnow in Cogn Neurodyn 2(4):347-353, 2008) to explain the linear relationship between response time and correct response probability for word recall and recognition: At the initial stimulus presentation the words displayed tag the corresponding long term memory locations. The tagging process is linear in time and takes about one second to reach a tagging level of 100%. After stimulus presentation the tagging level decays logarithmically with time to 50% after 14 s and to 20% after 220 s. If a probe word is reintroduced the tagging level has to return to 100% for the word to be properly identified, which leads to a delay in response time. This delay is proportional to the tagging loss. The tagging level is directly related to the probability of correct word recall and recognition. Evidence presented suggests that the tagging level is the level of depletion of the Readily Releasable Pool (RRP) of neurotransmitter vesicles at presynaptic terminals. The evidence includes the initial linear relationship between tagging level and time as well as the subsequent logarithmic decay of the tagging level. The activation of a short term memory may thus be the depletion of RRP (exocytosis) and short term memory decay may be the ensuing recycling of the neurotransmitter vesicles (endocytosis). The pattern of depleted presynaptic terminals corresponds to the long term memory trace.

A Critical Assessment of Research on Neurotransmitters in Alzheimer's Disease.

PubMed

Reddy, P Hemachandra

2017-01-01

The purpose of this mini-forum, "Neurotransmitters and Alzheimer's Disease", is to critically assess the current status of neurotransmitters in Alzheimer's disease. Neurotransmitters are essential neurochemicals that maintain synaptic and cognitive functions in mammals, including humans, by sending signals across pre- to post-synaptic neurons. Authorities in the fields of synapses and neurotransmitters of Alzheimer's disease summarize the current status of basic biology of synapses and neurotransmitters, and also update the current status of clinical trials of neurotransmitters in Alzheimer's disease. This article discusses the prevalence, economic impact, and stages of Alzheimer's dementia in humans.

Actions of Steroids: New Neurotransmitters

PubMed Central

Cornil, Charlotte A.; Mittelman-Smith, Melinda A.; Rainville, Jennifer R.; Remage-Healey, Luke; Sinchak, Kevin; Micevych, Paul E.

2016-01-01

Over the past two decades, the classical understanding of steroid action has been updated to include rapid, membrane-initiated, neurotransmitter-like functions. While steroids were known to function on very short time spans to induce physiological and behavioral changes, the mechanisms by which these changes occur are now becoming more clear. In avian systems, rapid estradiol effects can be mediated via local alterations in aromatase activity, which precisely regulates the temporal and spatial availability of estrogens. Acute regulation of brain-derived estrogens has been shown to rapidly affect sensorimotor function and sexual motivation in birds. In rodents, estrogens and progesterone are critical for reproduction, including preovulatory events and female sexual receptivity. Membrane progesterone receptor as well as classical progesterone receptor trafficked to the membrane mediate reproductive-related hypothalamic physiology, via second messenger systems with dopamine-induced cell signals. In addition to these relatively rapid actions, estrogen membrane-initiated signaling elicits changes in morphology. In the arcuate nucleus of the hypothalamus, these changes are needed for lordosis behavior. Recent evidence also demonstrates that membrane glucocorticoid receptor is present in numerous cell types and species, including mammals. Further, membrane glucocorticoid receptor influences glucocorticoid receptor translocation to the nucleus effecting transcriptional activity. The studies presented here underscore the evidence that steroids behave like neurotransmitters to regulate CNS functions. In the future, we hope to fully characterize steroid receptor-specific functions in the brain. PMID:27911748

Linopirdine. A depolarization-activated releaser of transmitters for treatment of dementia.

PubMed

Tam, S W; Zaczek, R

1995-01-01

Linopirdine (DuP 996, AVIVA), currently in Phase III clinical trial for the treatment of Alzheimer's disease, is a representative of a class of novel molecules which enhances the stimulus-evoked but not basal release of several neurotransmitters including ACh, DA, 5-HT and Glu. Linopiridine has been shown to enhance ACh release in the hippocampus in vivo. In addition, linopiridine produces a number of effects including EEG patterns of enhanced vigilance, induction of c-fos expression in cerebral cortex, reduction of the increase of cerebral glucose utilization induced by hypoxia, and improved performance in animal models of learning and memory. The specific action of linopiridine on depolarized neurons but not on basal release suggests that compounds of this class will enhance normal brain activity and not lead to a non-specific activation. Furthermore, the effect of linopiridine on multiple neurotransmitter systems that are deficient in Alzheimer's disease suggests that this class of agents may be more efficacious in the treatment of dementia than therapies aimed at individual neurotransmitters systems.

Neurotransmitter-Triggered Transfer of Exosomes Mediates Oligodendrocyte–Neuron Communication

PubMed Central

Kuo, Wen Ping; Amphornrat, Jesa; Thilemann, Sebastian; Saab, Aiman S.; Kirchhoff, Frank; Möbius, Wiebke; Goebbels, Sandra; Nave, Klaus-Armin; Schneider, Anja; Simons, Mikael; Klugmann, Matthias; Trotter, Jacqueline; Krämer-Albers, Eva-Maria

2013-01-01

Reciprocal interactions between neurons and oligodendrocytes are not only crucial for myelination, but also for long-term survival of axons. Degeneration of axons occurs in several human myelin diseases, however the molecular mechanisms of axon-glia communication maintaining axon integrity are poorly understood. Here, we describe the signal-mediated transfer of exosomes from oligodendrocytes to neurons. These endosome-derived vesicles are secreted by oligodendrocytes and carry specific protein and RNA cargo. We show that activity-dependent release of the neurotransmitter glutamate triggers oligodendroglial exosome secretion mediated by Ca2+ entry through oligodendroglial NMDA and AMPA receptors. In turn, neurons internalize the released exosomes by endocytosis. Injection of oligodendroglia-derived exosomes into the mouse brain results in functional retrieval of exosome cargo in neurons. Supply of cultured neurons with oligodendroglial exosomes improves neuronal viability under conditions of cell stress. These findings indicate that oligodendroglial exosomes participate in a novel mode of bidirectional neuron-glia communication contributing to neuronal integrity. PMID:23874151

Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication.

PubMed

Frühbeis, Carsten; Fröhlich, Dominik; Kuo, Wen Ping; Amphornrat, Jesa; Thilemann, Sebastian; Saab, Aiman S; Kirchhoff, Frank; Möbius, Wiebke; Goebbels, Sandra; Nave, Klaus-Armin; Schneider, Anja; Simons, Mikael; Klugmann, Matthias; Trotter, Jacqueline; Krämer-Albers, Eva-Maria

2013-07-01

Reciprocal interactions between neurons and oligodendrocytes are not only crucial for myelination, but also for long-term survival of axons. Degeneration of axons occurs in several human myelin diseases, however the molecular mechanisms of axon-glia communication maintaining axon integrity are poorly understood. Here, we describe the signal-mediated transfer of exosomes from oligodendrocytes to neurons. These endosome-derived vesicles are secreted by oligodendrocytes and carry specific protein and RNA cargo. We show that activity-dependent release of the neurotransmitter glutamate triggers oligodendroglial exosome secretion mediated by Ca²⁺ entry through oligodendroglial NMDA and AMPA receptors. In turn, neurons internalize the released exosomes by endocytosis. Injection of oligodendroglia-derived exosomes into the mouse brain results in functional retrieval of exosome cargo in neurons. Supply of cultured neurons with oligodendroglial exosomes improves neuronal viability under conditions of cell stress. These findings indicate that oligodendroglial exosomes participate in a novel mode of bidirectional neuron-glia communication contributing to neuronal integrity.

Expression of CGRP neurotransmitter and vascular genesis marker mRNA is age-dependent in superior cervical ganglia of senescence-accelerated prone mice.

PubMed

Mitsuoka, Kazuyuki; Kikutani, Takeshi; Miwa, Yoko; Sato, Iwao

2018-01-18

Calcitonin gene-related peptide (CGRP) is a neurotransmitter that is released from the superior cervical ganglion (SCG) and causes head and neck pain. The morphological properties of human SCG neurons, including neurotransmitter content, are altered during aging. However, morphological changes in CGRP in the SCG during aging are not known. Therefore, we investigated CGRP and other markers in the SCG during aging in an aging model of senescence-accelerated prone mouse (SAMP8) and senescence-accelerated resistant mice (SAMR1) using real-time RT-PCR mRNA analyses and in situ hybridization. The abundance of neurotransmitter (CGRP, NPY, TRPV1), vascular genesis marker (CD31, LYVE-1), and cytochrome C mRNA differed between 12-week-old and 24-week-old SAMP8 and SAMR1. Abundance of TRPV1, CD31 and cytochrome C mRNAs of SAMP8 decreased between 12- and 24-week-old. The ratio of CGRP mRNA positive cells and CGRP mRNA abundance levels of the SCG of aging mouse such as SAMP8 have already been also higher than that of SAMR1 at 12-week-old. The CGRP positive shrunken ganglion cells was increased from 12- to 24-weeks-old mouse in SAMR1 and SAMP8. The SCG primarily affected the internal and external carotid arteries, larynx thyroid gland, and pharyngeal muscle during aging. Copyright © 2017 Elsevier B.V. All rights reserved.

Amino acid neurotransmitter release and learning: a study of visual imprinting.

PubMed

Meredith, R M; McCabe, B J; Kendrick, K M; Horn, G

2004-01-01

The intermediate and medial part of the hyperstriatum ventrale (IMHV) is an area of the domestic chick forebrain that stores information acquired through the learning process of imprinting. The effects of visual imprinting on the release of the amino acids aspartate, arginine, citrulline, gamma-aminobutyric acid (GABA), glutamate, glycine and taurine from the left and right IMHVs in vitro were measured at 3.5, 10 and 24 h after training. Chicks were exposed to an imprinting stimulus for 1 h, their preferences measured 10 min afterward and a preference score calculated as a measure of the strength of learning. Potassium stimulation was used to evoke amino acid release from the IMHVs of trained and untrained chicks in the presence and absence of extracellular Ca2+. Ca2+-dependent, K+-evoked release of glutamate was significantly (34.4%) higher in trained than in untrained chicks. This effect was not influenced by time after training or by side (left or right IMHV). Training influenced the evoked release of GABA and taurine from the left IMHV at both 3.5 and 10 h. The training effects at the two times were statistically homogeneous so data (< or = 10 h group) were combined for each amino acid respectively. For this < or = 10 h group, evoked release increased significantly with preference score. In contrast, for the 24 h group, evoked release of GABA and taurine was not significantly correlated with preference score. There were no significant correlations between preference score and GABA or taurine release in the right IMHV at any time, nor in the absence of extracellular calcium. No significant effects of training condition, time or side were observed for any other amino acid in the study. The present findings suggest that soon after chicks have been exposed to an imprinting stimulus glutamatergic excitatory transmission in IMHV is enhanced, and remains enhanced for at least 24 h. In contrast, the learning-related elevations in taurine and GABA release are not

Conducting polymer-based electrochemical biosensors for neurotransmitters: A review.

PubMed

Moon, Jong-Min; Thapliyal, Neeta; Hussain, Khalil Khadim; Goyal, Rajendra N; Shim, Yoon-Bo

2018-04-15

Neurotransmitters are important biochemical molecules that control behavioral and physiological functions in central and peripheral nervous system. Therefore, the analysis of neurotransmitters in biological samples has a great clinical and pharmaceutical importance. To date, various methods have been developed for their assay. Of the various methods, the electrochemical sensors demonstrated the potential of being robust, selective, sensitive, and real time measurements. Recently, conducting polymers (CPs) and their composites have been widely employed in the fabrication of various electrochemical sensors for the determination of neurotransmitters. Hence, this review presents a brief introduction to the electrochemical biosensors, with the detailed discussion on recent trends in the development and applications of electrochemical neurotransmitter sensors based on CPs and their composites. The review covers the sensing principle of prime neurotransmitters, including glutamate, aspartate, tyrosine, epinephrine, norepinephrine, dopamine, serotonin, histamine, choline, acetylcholine, nitrogen monoxide, and hydrogen sulfide. In addition, the combination with other analytical techniques was also highlighted. Detection challenges and future prospective of the neurotransmitter sensors were discussed for the development of biomedical and healthcare applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Theanine, gamma-glutamylethylamide, a unique amino acid in tea leaves, modulates neurotransmitter concentrations in the brain striatum interstitium in conscious rats.

PubMed

Yamada, T; Terashima, T; Kawano, S; Furuno, R; Okubo, T; Juneja, L R; Yokogoshi, H

2009-01-01

Theanine (gamma-glutamylethylamide) is one of the major amino acid components in green tea and can pass through the blood-brain barrier. Recent studies suggest that theanine affects the mammalian central nervous system; however, the detailed mechanism remains unclear. In this study, we demonstrated the effect of theanine on neurotransmission in the brain striatum by in vivo brain microdialysis. Theanine injection into the rat brain striatum did not increase the concentration of excitatory neurotransmitters in the perfusate. On the other hand, theanine injection increased the concentration of glycine in the perfusate. Because it has been reported that theanine promotes dopamine release in the rat striatum, we investigated the glycine and dopamine concentrations in the perfusate. Co-injection of glycine receptor antagonist, strychnine, reduced theanine-induced changes in dopamine. Moreover, AMPA receptor antagonist, which regulates glycine and GABA release from glia cells, inhibited these effects of theanine and this result was in agreement with the known inhibitory effect of theanine at AMPA receptors.

Cholesterol Alters the Dynamics of Release in Protein Independent Cell Models for Exocytosis

NASA Astrophysics Data System (ADS)

Najafinobar, Neda; Mellander, Lisa J.; Kurczy, Michael E.; Dunevall, Johan; Angerer, Tina B.; Fletcher, John S.; Cans, Ann-Sofie

2016-09-01

Neurons communicate via an essential process called exocytosis. Cholesterol, an abundant lipid in both secretory vesicles and cell plasma membrane can affect this process. In this study, amperometric recordings of vesicular dopamine release from two different artificial cell models created from a giant unilamellar liposome and a bleb cell plasma membrane, show that with higher membrane cholesterol the kinetics for vesicular release are decelerated in a concentration dependent manner. This reduction in exocytotic speed was consistent for two observed modes of exocytosis, full and partial release. Partial release events, which only occurred in the bleb cell model due to the higher tension in the system, exhibited amperometric spikes with three distinct shapes. In addition to the classic transient, some spikes displayed a current ramp or plateau following the maximum peak current. These post spike features represent neurotransmitter release from a dilated pore before constriction and show that enhancing membrane rigidity via cholesterol adds resistance to a dilated pore to re-close. This implies that the cholesterol dependent biophysical properties of the membrane directly affect the exocytosis kinetics and that membrane tension along with membrane rigidity can influence the fusion pore dynamics and stabilization which is central to regulation of neurochemical release.

Physiological and chemical analysis of neurotransmitter candidates at a fast excitatory synapse in the jellyfish Cyanea capillata (Cnidaria, Scyphozoa).

PubMed

Anderson, Peter A V; Trapido-Rosenthal, H G

2009-12-01

Motor nerve net (MNN) neurons in the jellyfish Cyanea capillata communicate with one another by way of fast, bidirectional excitatory chemical synapses. As is the case with almost all identified chemical synapses in cnidarians, the identity of the neurotransmitter at these synapses is unclear. MNN neurons are large enough for stable intracellular recordings. This, together with the fact that they can be exposed, providing unlimited access to them and to their synapses, prompted a study of the action of a variety of neurotransmitter candidates, including those typically associated with fast synapses in higher animals. Only the amino acids taurine and beta-alanine produced physiological responses consistent with those of the normal EPSP in these cells. Moreover, chemical analysis revealed that both taurine and beta-alanine are present in the neurons and released by depolarization. These various findings strongly suggest that either or both of these amino acids, or a closely related compound is the neurotransmitter at the fast chemical synapses between MNN neurons.

Proton electrochemical gradient: Driving and regulating neurotransmitter uptake.

PubMed

Farsi, Zohreh; Jahn, Reinhard; Woehler, Andrew

2017-05-01

Accumulation of neurotransmitters in the lumen of synaptic vesicles (SVs) relies on the activity of the vacuolar-type H + -ATPase. This pump drives protons into the lumen, generating a proton electrochemical gradient (Δμ H+ ) across the membrane. Recent work has demonstrated that the balance between the chemical (ΔpH) and electrical (ΔΨ) components of Δμ H+ is regulated differently by some distinct vesicle types. As different neurotransmitter transporters use ΔpH and ΔΨ with different relative efficiencies, regulation of this gradient balance has the potential to influence neurotransmitter uptake. Nevertheless, the underlying mechanisms responsible for this regulation remain poorly understood. In this review, we provide an overview of current neurotransmitter uptake models, with a particular emphasis on the distinct roles of the electrical and chemical gradients and current hypotheses for regulatory mechanisms. © 2017 WILEY Periodicals, Inc.

Lidocaine attenuates anisomycin-induced amnesia and release of norepinephrine in the amygdala

PubMed Central

Sadowski, Renee N.; Canal, Clint E.; Gold, Paul E.

2011-01-01

When administered near the time of training, protein synthesis inhibitors such as anisomycin impair later memory. A common interpretation of these findings is that memory consolidation requires new protein synthesis initiated by training. However, recent findings support an alternative interpretation that abnormally large increases in neurotransmitter release after injections of anisomycin may be responsible for producing amnesia. In the present study, a local anesthetic was administered prior to anisomycin injections in an attempt to mitigate neurotransmitter actions and thereby attenuate the resulting amnesia. Rats received lidocaine and anisomycin injections into the amygdala 130 and 120 min, respectively, prior to inhibitory avoidance training. Memory tests 48 hr later revealed that lidocaine attenuated anisomycin-induced amnesia. In other rats, in vivo microdialysis was performed at the site of amygdala infusion of lidocaine and anisomycin. As seen previously, anisomycin injections produced large increases in release of norepinephrine in the amygdala. Lidocaine attenuated the anisomycin-induced increase in release of norepinephrine but did not reverse anisomycin inhibition of protein synthesis, as assessed by c-Fos immunohistochemistry. These findings are consistent with past evidence suggesting that anisomycin causes amnesia by initiating abnormal release of neurotransmitters in response to the inhibition of protein synthesis. PMID:21453778

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 ( K d ) and limits of detection were highly dependent on functionalization (sequence). K d 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.

Naturally occurring compounds affect glutamatergic neurotransmission in rat brain.

PubMed

Martini, Lucia Helena; Jung, Fernanda; Soares, Felix Antunes; Rotta, Liane Nanci; Vendite, Deusa Aparecida; Frizzo, Marcos Emilio dos Santos; Yunes, Rosendo A; Calixto, João Batista; Wofchuk, Susana; Souza, Diogo O

2007-11-01

Natural products, including those derived from plants, have largely contributed to the development of therapeutic drugs. Glutamate is the main excitatory neurotransmitter in the central nervous system and it is also considered a nociceptive neurotransmitter, by acting on peripheral nervous system. For this reason, in this study we investigated the effects of the hydroalcoholic extracts from Drymis winteri (polygodial and drimanial), Phyllanthus (rutin and quercetine), Jathopha elliptica (jatrophone), Hedyosmum brasiliense (13HDS), Ocotea suaveolens (Tormentic acid), Protium kleinii (alphabeta-amyrin), Citrus paradise (naringin), soybean (genistein) and Crataeva nurvala (lupeol), described as having antinociceptive effects, on glutamatergic transmission parameters, such as [(3)H]glutamate binding, [(3)H]glutamate uptake by synaptic vesicles and astrocyte cultures, and synaptosomal [(3)H]glutamate release. All the glutamatergic parameters were affected by one or more of these compounds. Specifically, drimanial and polygodial presented more broad and profound effects, requiring more investigation on their mechanisms. The putative central side effects of these compounds, via the glutamatergic system, are discussed.

Functional significance and control of release of pulmonary surfactant in the lizard lung.

PubMed

Wood, P G; Daniels, C B; Orgeig, S

1995-10-01

The amount of pulmonary surfactant in the lungs of the bearded dragon (Pogona vitticeps) increases with increasing body temperature. This increase coincides with a decrease in lung compliance. The relationship between surfactant and lung compliance and the principal stimuli for surfactant release and composition (temperature, ventilatory pattern, and autonomic neurotransmitters) were investigated. We chose to investigate ventilatory pattern (which causes mechanical deformation of the type II cells) and adrenergic agents, because they are the major stimuli for surfactant release in mammals. To examine the effects of body temperature and ventilatory pattern, isolated lungs were ventilated at either 18 or 37 degrees C at different ventilatory regimens. An isolated perfused lung preparation at 27 degrees C was used to analyze the effects of autonomic neurotransmitters. Ventilatory pattern did not affect surfactant release, composition, or lung compliance at either 18 or 37 degrees C. An increase in temperature increased phospholipid reuptake and disproportionately increased cholesterol degradation/uptake. Epinephrine and acetylcholine stimulated phospholipid but not cholesterol release. Removal of surfactant caused a decrease in compliance, regardless of the experimental temperature. Temperature appears to be the principal determinant of lung compliance in the bearded dragon, acting directly to increase the tone of the smooth muscle. Increasing the ambient temperature may result in greater surfactant turnover by increasing cholesterol reuptake/degradation directly and by increasing circulating epinephrine, thereby indirectly increasing phospholipid secretion. We suggest that changing ventilatory pattern may be inadequate as a mechanism for maintaining surfactant homeostasis, given the discontinuous, highly variable reptilian breathing pattern.

Plasma membrane ordering agent pluronic F-68 (PF-68) reduces neurotransmitter uptake and release and produces learning and memory deficits in rats

NASA Technical Reports Server (NTRS)

Clarke, M. S.; Prendergast, M. A.; Terry, A. V. Jr

1999-01-01

A substantial body of evidence indicates that aged-related changes in the fluidity and lipid composition of the plasma membrane contribute to cellular dysfunction in humans and other mammalian species. In the CNS, reductions in neuronal plasma membrane order (PMO) (i.e., increased plasma membrane fluidity) have been attributed to age as well as the presence of the beta-amyloid peptide-25-35, known to play an important role in the neuropathology of Alzheimer's disease (AD). These PMO increases may influence neurotransmitter synthesis, receptor binding, and second messenger systems as well as signal transduction pathways. The effects of neuronal PMO on learning and memory processes have not been adequately investigated, however. Based on the hypothesis that an increase in PMO may alter a number of aspects of synaptic transmission, we investigated several neurochemical and behavioral effects of the membrane ordering agent, PF-68. In cell culture, PF-68 (nmoles/mg SDS extractable protein) reduced [3H]norepinephrine (NE) uptake into differentiated PC-12 cells as well as reduced nicotine stimulated [3H]NE release. The compound (800-2400 microg/kg, i.p., resulting in nmoles/mg SDS extractable protein in the brain) decreased step-through latencies and increased the frequencies of crossing into the unsafe side of the chamber in inhibitory avoidance training. In the Morris water maze, PF-68 increased the latencies and swim distances required to locate a hidden platform and reduced the time spent and distance swam in the previous target quadrant during transfer (probe) trials. PF-68 did not impair performance of a well-learned working memory task, the rat delayed stimulus discrimination task (DSDT), however. Studies with 14C-labeled PF-68 indicated that significant (pmoles/mg wet tissue) levels of the compound entered the brain from peripheral (i.p.) injection. No PF-68 related changes were observed in swim speeds or in visual acuity tests in water maze experiments, rotorod

[Exposure to ammonium persulphate by inhalation: effect on the NANC inhibitory neurotransmitters in the guinea pig trachea].

PubMed

Dellabianca, A; Tonini, S; Faniglione, M; De Amici, E; De Angelis, S; Balestra, B; Candura, S M

2007-01-01

To evaluate the effect of ammonium persulphate (AP) inhalation on NANC inhibitory (i-NANC) neurotransmitters of guinea pig airways, we exposed eight guinea pigs to AP (1 mg/m3), by aerosol inhalation for 30 minutes daily for three weeks. Control animals inhaled saline aerosol. After the last exposure, the isolated trachea was mounted in an organ bath and electrically stimulated in the presence of hyoscine, piperoxane and propranolol. The i-NANC responses were evaluated as decreases in intraluminal pressure and expressed as area under the curve (AUC, Pa x seconds). The isolated tracheae were treated with a-chymotrypsin, L-NAME, zinc protoporphyrin IX and ODQ, that inhibit the production or action of the single neurotransmitters, like peptides, NO and CO. In the exposed individuals, the NANC relaxations were below 50%, as compared to controls (P < 0.01). NO and CO were the neurotransmitters responsible for all the i-NANC responses, in similar proportions either in exposed individuals or in controls. In conclusion, ammonium persulphate exposure impairs the i-NANC control of airway tone without specifically affecting any neurotransmitter.

Aflatoxin B1-contaminated diet disrupts the blood-brain barrier and affects fish behavior: Involvement of neurotransmitters in brain synaptosomes.

PubMed

Baldissera, Matheus D; Souza, Carine F; Zeppenfeld, Carla Cristina; Descovi, Sharine N; Moreira, Karen Luise S; da Rocha, Maria Izabel U M; da Veiga, Marcelo L; da Silva, Aleksandro S; Baldisserotto, Bernardo

2018-06-01

It is known that the cytotoxic effects of aflatoxin B 1 (AFB 1 ) in endothelial cells of the blood-brain barrier (BBB) are associated with behavioral dysfunction. However, the effects of a diet contaminated with AFB 1 on the behavior of silver catfish remain unknown. Thus, the aim of this study was to evaluate whether an AFB 1 -contaminated diet (1177 ppb kg feed -1 ) impaired silver catfish behavior, as well as whether disruption of the BBB and alteration of neurotransmitters in brain synaptosomes are involved. Fish fed a diet contaminated with AFB 1 presented a behavioral impairment linked with hyperlocomotion on days 14 and 21 compared with the control group (basal diet). Neurotransmitter levels were also affected on days 14 and 21. The permeability of the BBB to Evans blue dye increased in the intoxicated animals compared with the control group, which suggests that the BBB was disrupted. Moreover, acetylcholinesterase (AChE) activity in brain synaptosomes was increased in fish fed a diet contaminated with AFB 1 , while activity of the sodium-potassium pump (Na + , K + -ATPase) was decreased. Based on this evidence, the present study shows that silver catfish fed a diet containing AFB 1 exhibit behavioral impairments related to hyperlocomotion. This diet caused a disruption of the BBB and brain lesions, which may contribute to the behavioral changes. Also, the alterations in the activities of AChE and Na + , K + -ATPase in brain synaptosomes may directly contribute to this behavior, since they may promote synapse dysfunction. In addition, the hyperlocomotion may be considered an important macroscopic marker indicating possible AFB 1 intoxication. Copyright © 2018 Elsevier B.V. All rights reserved.

In vitro screening of major neurotransmitter systems possibly involved in the mechanism of action of antibodies to S100 protein in released-active form

PubMed Central

Gorbunov, Evgeniy A; Ertuzun, Irina A; Kachaeva, Evgeniya V; Tarasov, Sergey A; Epstein, Oleg I

2015-01-01

Experimentally and clinically, it was shown that released-active form of antibodies to S100 protein (RAF of Abs to S100) exerts a wide range of pharmacological activities: anxiolytic, antiasthenic, antiaggressive, stress-protective, antihypoxic, antiischemic, neuroprotective, and nootropic. The purpose of this study was to determine the influence of RAF of Abs to S100 on major neurotransmitter systems (serotoninergic, GABAergic, dopaminergic, and on sigma receptors as well) which are possibly involved in its mechanism of pharmacological activity. Radioligand binding assays were used for assessment of the drug influence on ligand–receptor interaction. [35S]GTPγS binding assay, cyclic adenosine monophosphate HTRF™, cellular dielectric spectroscopy assays, and assays based on measurement of intracellular concentration of Ca2+ ions were used for assessment of agonist or antagonist properties of the drug toward receptors. RAF of Abs to S100 increased radioligand binding to 5-HT1F, 5-HT2B, 5-HT2Cedited, 5-HT3, and to D3 receptors by 142.0%, 131.9%, 149.3%, 120.7%, and 126.3%, respectively. Also, the drug significantly inhibited specific binding of radioligands to GABAB1A/B2 receptors by 25.8%, and to both native and recombinant human sigma1 receptors by 75.3% and 40.32%, respectively. In the functional assays, it was shown that the drug exerted antagonism at 5-HT1B, D3, and GABAB1A/B2 receptors inhibiting agonist-induced responses by 23.24%, 32.76%, and 30.2%, respectively. On the contrary, the drug exerted an agonist effect at 5-HT1A receptors enhancing receptor functional activity by 28.0%. The pharmacological profiling of RAF of Abs to S100 among 27 receptor provides evidence for drug-related modification of major neurotransmitter systems. PMID:26604768

Glucose is necessary to maintain neurotransmitter homeostasis during synaptic activity in cultured glutamatergic neurons.

PubMed

Bak, Lasse K; Schousboe, Arne; Sonnewald, Ursula; Waagepetersen, Helle S

2006-10-01

Glucose is the primary energy substrate for the adult mammalian brain. However, lactate produced within the brain might be able to serve this purpose in neurons. In the present study, the relative significance of glucose and lactate as substrates to maintain neurotransmitter homeostasis was investigated. Cultured cerebellar (primarily glutamatergic) neurons were superfused in medium containing [U-13C]glucose (2.5 mmol/L) and lactate (1 or 5 mmol/L) or glucose (2.5 mmol/L) and [U-13C]lactate (1 mmol/L), and exposed to pulses of N-methyl-D-aspartate (300 micromol/L), leading to synaptic activity including vesicular release. The incorporation of 13C label into intracellular lactate, alanine, succinate, glutamate, and aspartate was determined by mass spectrometry. The metabolism of [U-13C]lactate under non-depolarizing conditions was high compared with that of [U-13C]glucose; however, it decreased significantly during induced depolarization. In contrast, at both concentrations of extracellular lactate, the metabolism of [U-13C]glucose was increased during neuronal depolarization. The role of glucose and lactate as energy substrates during vesicular release as well as transporter-mediated influx and efflux of glutamate was examined using preloaded D-[3H]aspartate as a glutamate tracer and DL-threo-beta-benzyloxyaspartate to inhibit glutamate transporters. The results suggest that glucose is essential to prevent depolarization-induced reversal of the transporter (efflux), whereas vesicular release was unaffected by the choice of substrate. In conclusion, the present study shows that glucose is a necessary substrate to maintain neurotransmitter homeostasis during synaptic activity and that synaptic activity does not induce an upregulation of lactate metabolism in glutamatergic neurons.

Wireless Instantaneous Neurotransmitter Concentration System–based amperometric detection of dopamine, adenosine, and glutamate for intraoperative neurochemical monitoring

PubMed Central

Agnesi, Filippo; Tye, Susannah J.; Bledsoe, Jonathan M.; Griessenauer, Christoph J.; Kimble, Christopher J.; Sieck, Gary C.; Bennet, Kevin E.; Garris, Paul A.; Blaha, Charles D.; Lee, Kendall H.

2009-01-01

Object In a companion study, the authors describe the development of a new instrument named the Wireless Instantaneous Neurotransmitter Concentration System (WINCS), which couples digital telemetry with fast-scan cyclic voltammetry (FSCV) to measure extracellular concentrations of dopamine. In the present study, the authors describe the extended capability of the WINCS to use fixed potential amperometry (FPA) to measure extracellular concentrations of dopamine, as well as glutamate and adenosine. Compared with other electrochemical techniques such as FSCV or high-speed chronoamperometry, FPA offers superior temporal resolution and, in combination with enzyme-linked biosensors, the potential to monitor nonelectroactive analytes in real time. Methods The WINCS design incorporated a transimpedance amplifier with associated analog circuitry for FPA; a microprocessor; a Bluetooth transceiver; and a single, battery-powered, multilayer, printed circuit board. The WINCS was tested with 3 distinct recording electrodes: 1) a carbon-fiber microelectrode (CFM) to measure dopamine; 2) a glutamate oxidase enzyme-linked electrode to measure glutamate; and 3) a multiple enzyme-linked electrode (adenosine deaminase, nucleoside phosphorylase, and xanthine oxidase) to measure adenosine. Proof-of-principle analyses included noise assessments and in vitro and in vivo measurements that were compared with similar analyses by using a commercial hardwired electrochemical system (EA161 Picostat, eDAQ; Pty Ltd). In urethane-anesthetized rats, dopamine release was monitored in the striatum following deep brain stimulation (DBS) of ascending dopaminergic fibers in the medial forebrain bundle (MFB). In separate rat experiments, DBS-evoked adenosine release was monitored in the ventrolateral thalamus. To test the WINCS in an operating room setting resembling human neurosurgery, cortical glutamate release in response to motor cortex stimulation (MCS) was monitored using a large-mammal animal

Wireless Instantaneous Neurotransmitter Concentration System-based amperometric detection of dopamine, adenosine, and glutamate for intraoperative neurochemical monitoring.

PubMed

Agnesi, Filippo; Tye, Susannah J; Bledsoe, Jonathan M; Griessenauer, Christoph J; Kimble, Christopher J; Sieck, Gary C; Bennet, Kevin E; Garris, Paul A; Blaha, Charles D; Lee, Kendall H

2009-10-01

In a companion study, the authors describe the development of a new instrument named the Wireless Instantaneous Neurotransmitter Concentration System (WINCS), which couples digital telemetry with fast-scan cyclic voltammetry (FSCV) to measure extracellular concentrations of dopamine. In the present study, the authors describe the extended capability of the WINCS to use fixed potential amperometry (FPA) to measure extracellular concentrations of dopamine, as well as glutamate and adenosine. Compared with other electrochemical techniques such as FSCV or high-speed chronoamperometry, FPA offers superior temporal resolution and, in combination with enzyme-linked biosensors, the potential to monitor nonelectroactive analytes in real time. The WINCS design incorporated a transimpedance amplifier with associated analog circuitry for FPA; a microprocessor; a Bluetooth transceiver; and a single, battery-powered, multilayer, printed circuit board. The WINCS was tested with 3 distinct recording electrodes: 1) a carbon-fiber microelectrode (CFM) to measure dopamine; 2) a glutamate oxidase enzyme-linked electrode to measure glutamate; and 3) a multiple enzyme-linked electrode (adenosine deaminase, nucleoside phosphorylase, and xanthine oxidase) to measure adenosine. Proof-of-principle analyses included noise assessments and in vitro and in vivo measurements that were compared with similar analyses by using a commercial hardwired electrochemical system (EA161 Picostat, eDAQ; Pty Ltd). In urethane-anesthetized rats, dopamine release was monitored in the striatum following deep brain stimulation (DBS) of ascending dopaminergic fibers in the medial forebrain bundle (MFB). In separate rat experiments, DBS-evoked adenosine release was monitored in the ventrolateral thalamus. To test the WINCS in an operating room setting resembling human neurosurgery, cortical glutamate release in response to motor cortex stimulation (MCS) was monitored using a large-mammal animal model, the pig. The

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

PubMed Central

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

2015-01-01

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. PMID:25869126

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,more » 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.« less

Altered neurotransmitter metabolism in adolescents with high-functioning autism

PubMed Central

Drenthen, Gerhard S.; Barendse, Evelien M.; Aldenkamp, Albert P.; van Veenendaal, Tamar M.; Puts, Nicolaas A.J.; Edden, Richard A.E.; Zinger, Svitlana; Thoonen, Geert; Hendriks, Marc P.H.; Kessels, Roy P.C.; Jansen, Jacobus F.A.

2017-01-01

Previous studies have suggested that alterations in excitatory/inhibitory neurotransmitters might play a crucial role in autism spectrum disorder (ASD). Proton magnetic resonance spectroscopy (1H-MRS) can provide valuable information about abnormal brain metabolism and neurotransmitter concentrations. However, few 1H-MRS studies have been published on the imbalance of the two most abundant neurotransmitters in ASD: glutamate (Glu) and gamma-aminobutyric acid (GABA). Moreover, to our knowledge none of these published studies is performed with a study population consisting purely of high-functioning autism (HFA) adolescents. Selecting only individuals with HFA eliminates factors possibly related to intellectual impairment instead of ASD. This study aims to assess Glu and GABA neurotransmitter concentrations in HFA. Occipital concentrations of Glu and GABA plus macromolecules (GABA+) were obtained using 1H-MRS relative to creatine (Cr) in adolescents with HFA (n=15 and n=13 respectively) and a healthy control group (n=17). Multiple linear regression revealed significantly higher Glu/Cr and lower GABA+/Glu concentrations in the HFA group compared to the controls. These results imply that imbalanced neurotransmitter levels of excitation and inhibition are associated with HFA in adolescents. PMID:27685800

Neurotransmitters and neuromodulators controlling the hypoxic respiratory response in anaesthetized cats.

PubMed

Richter, D W; Schmidt-Garcon, P; Pierrefiche, O; Bischoff, A M; Lalley, P M

1999-01-15

1. The contributions of neurotransmitters and neuromodulators to the responses of the respiratory network to acute hypoxia were analysed in anaesthetized cats. 2. Samples of extracellular fluid were collected at 1-1.5 min time intervals by microdialysis in the medullary region of ventral respiratory group neurones and analysed for their content of glutamate, gamma-aminobutyric acid (GABA), serotonin and adenosine by high performance liquid chromatography. Phrenic nerve activity was correlated with these measurements. 3. Levels of glutamate and GABA increased transiently during early periods of hypoxia, coinciding with augmented phrenic nerve activity and then fell below control during central apnoea. Serotonin and adenosine increased slowly and steadily with onset of hypoxic depression of phrenic nerve activity. 4. The possibility that serotonin contributes to hypoxic respiratory depression was tested by microinjecting the 5-HT-1A receptor agonist 8-OH-DPAT into the medullary region that is important for rhythmogenesis. Hypoxic activation of respiratory neurones and phrenic nerve activity were suppressed. Microinjections of NAN-190, a 5-HT-1A receptor blocker, enhanced hypoxic augmentation resulting in apneustic prolongation of inspiratory bursts. 5. The results reveal a temporal sequence in the release of neurotransmitters and neuromodulators and suggest a specific role for each of them in the sequential development of hypoxic respiratory disturbances.

Sniffer patch laser uncaging response (SPLURgE): an assay of regional differences in allosteric receptor modulation and neurotransmitter clearance

PubMed Central

Christian, Catherine A.

2013-01-01

Allosteric modulators exert actions on neurotransmitter receptors by positively or negatively altering the effective response of these receptors to their respective neurotransmitter. γ-Aminobutyric acid (GABA) type A ionotropic receptors (GABAARs) are major targets for allosteric modulators such as benzodiazepines, neurosteroids, and barbiturates. Analysis of substances that produce similar effects has been hampered by the lack of techniques to assess the localization and function of such agents in brain slices. Here we describe measurement of the sniffer patch laser uncaging response (SPLURgE), which combines the sniffer patch recording configuration with laser photolysis of caged GABA. This methodology enables the detection of allosteric GABAAR modulators endogenously present in discrete areas of the brain slice and allows for the application of exogenous GABA with spatiotemporal control without altering the release and localization of endogenous modulators within the slice. Here we demonstrate the development and use of this technique for the measurement of allosteric modulation in different areas of the thalamus. Application of this technique will be useful in determining whether a lack of modulatory effect on a particular category of neurons or receptors is due to insensitivity to allosteric modulation or a lack of local release of endogenous ligand. We also demonstrate that this technique can be used to investigate GABA diffusion and uptake. This method thus provides a biosensor assay for rapid detection of endogenous GABAAR modulators and has the potential to aid studies of allosteric modulators that exert effects on other classes of neurotransmitter receptors, such as glutamate, acetylcholine, or glycine receptors. PMID:23843428

Sniffer patch laser uncaging response (SPLURgE): an assay of regional differences in allosteric receptor modulation and neurotransmitter clearance.

PubMed

Christian, Catherine A; Huguenard, John R

2013-10-01

Allosteric modulators exert actions on neurotransmitter receptors by positively or negatively altering the effective response of these receptors to their respective neurotransmitter. γ-Aminobutyric acid (GABA) type A ionotropic receptors (GABAARs) are major targets for allosteric modulators such as benzodiazepines, neurosteroids, and barbiturates. Analysis of substances that produce similar effects has been hampered by the lack of techniques to assess the localization and function of such agents in brain slices. Here we describe measurement of the sniffer patch laser uncaging response (SPLURgE), which combines the sniffer patch recording configuration with laser photolysis of caged GABA. This methodology enables the detection of allosteric GABAAR modulators endogenously present in discrete areas of the brain slice and allows for the application of exogenous GABA with spatiotemporal control without altering the release and localization of endogenous modulators within the slice. Here we demonstrate the development and use of this technique for the measurement of allosteric modulation in different areas of the thalamus. Application of this technique will be useful in determining whether a lack of modulatory effect on a particular category of neurons or receptors is due to insensitivity to allosteric modulation or a lack of local release of endogenous ligand. We also demonstrate that this technique can be used to investigate GABA diffusion and uptake. This method thus provides a biosensor assay for rapid detection of endogenous GABAAR modulators and has the potential to aid studies of allosteric modulators that exert effects on other classes of neurotransmitter receptors, such as glutamate, acetylcholine, or glycine receptors.

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…

Peptides and neurotransmitters that affect renin secretion

NASA Technical Reports Server (NTRS)

Ganong, W. F.; Porter, J. P.; Bahnson, T. D.; Said, S. I.

1984-01-01

Substance P inhibits renin secretion. This polypeptide is a transmitter in primary afferent neurons and is released from the peripheral as well as the central portions of these neurons. It is present in afferent nerves from the kidneys. Neuropeptide Y, which is a cotransmitter with norepinephrine and epinephrine, is found in sympathetic neurons that are closely associated with and presumably innervate the juxtagolmerular cells. Its effect on renin secretion is unknown, but it produces renal vasoconstriction and natriuresis. Vasoactive intestinal polypeptide (VIP) is a cotransmitter with acetylocholine in cholinergic neurons, and this polypeptide stimulates renin secretion. We cannot find any evidence for its occurence in neurons in the kidneys, but various stimuli increase plasma VIP to levels comparable to those produced by doses of exogenous VIP which stimulated renin secretion. Neostigmine increases plasma VIP and plasma renin activity, and the VIP appears to be responsible for the increase in renin secretion, since the increase is not blocked by renal denervation or propranolol. Stimulation of various areas in the brain produces sympathetically mediated increases in plasma renin activity associated with increases in blood pressure. However, there is pharmacological evidence that the renin response can be separated from the blood pressure response. In anaesthetized dogs, drugs that increase central serotonergic discharge increase renin secretion without increasing blood pressure. In rats, activation of sertonergic neurons in the dorsal raphe nucleus increases renin secretion by a pathway that projects from this nucleus to the ventral hypothalamus, and from there to the kidneys via the sympathetic nervous system. The serotonin releasing drug parachloramphetamine also increases plasma VIP, but VIP does not appear to be the primary mediator of the renin response. There is preliminary evidence that the serotonergic neurons in the dorsal raphe nucleus are part of the

Characteristics of basal taurine release in the rat striatum measured by microdialysis.

PubMed

Molchanova, S; Oja, S S; Saransaari, P

2004-12-01

Taurine is a sulfur-containing amino acid thought to be an osmoregulator, neurotransmitter or neuromodulator in the brain. Our objective was to establish how much taurine is released in the striatum and examine the mechanisms controlling extracellular taurine concentrations under resting conditions. The experiments were made on rats by microdialysis in vivo. Changes in taurine were compared with those in glutamate, glycine and the non-neuroactive amino acid threonine. Using the zero net flux approach we showed the extracellular concentration of taurine to be 25.2 +/- 5.1 muM. Glutamate was increased by tetrodotoxin and decreased by Ca2+ omission, glycine and threonine were not affected and both treatments increased extracellular taurine. The basal taurine release was increased by the taurine transport inhibitor guanidinoethanesulfonate and reduced by the anion channel blocker 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid.

Atrial natriuretic peptide stimulates salt secretion by shark rectal gland by releasing VIP

DOE Office of Scientific and Technical Information (OSTI.GOV)

Silva, P.; Stoff, J.S.; Solomon, R.J.

1987-01-01

Salt secretion by the isolated perfused rectal gland of the spiny dogfish shark, Squalus acanthias, is stimulated by synthetic rat atrial natriuretic peptide (ANP II) as well as extracts of shark heart, but not by 8-bromo-cyclic guanosine 5'-monophosphate. Cardiac peptides have no effect on isolated rectal gland cells or perfused tubules, suggesting that stimulation requires an intact gland. The stimulation of secretion by ANP II is eliminated by maneuvers that block neurotransmitter release. Cardiac peptides stimulate the release of vasoactive intestinal peptide (VIP), known to be present in rectal glands nerves, into the venous effluent of perfused glands in parallelmore » with their stimulation of salt secretion, but the release of VIP induced by ANP II is prevented by perfusion with procaine. VIP was measured by radioimmunoassay. Cardiac peptides thus appear to regulate rectal gland secretion by releasing VIP from neural stores within the gland. It is possible that other physiological effects of these hormones might be explained by an action to enhanced local release of neurotransmitters.« less

Investigation of factors affecting in vitro doxorubicin release from PEGylated liposomal doxorubicin for the development of in vitro release testing conditions.

PubMed

Shibata, Hiroko; Izutsu, Ken-Ichi; Yomota, Chikako; Okuda, Haruhiro; Goda, Yukihiro

2015-01-01

Establishing appropriate drug release testing methods of liposomal products for assuring quality and performance requires the determination of factors affecting in vitro drug release. In this study, we investigated the effects of test conditions (human plasma lot, pH/salt concentration in the test media, dilution factor, temperature, ultrasound irradiation, etc.), and liposomal preparation conditions (pH/concentration of ammonium sulfate solution), on doxorubicin (DXR) release from PEGylated liposomal DXR. Higher temperature and lower pH significantly increased DXR release. The evaluation of DXR solubility indicated that the high DXR release induced by low pH may be attributed to the high solubility of DXR at low pH. Ultrasound irradiation induced rapid DXR release in an amplitude-dependent manner. The salt concentration in the test solution, human plasma lot, and dilution factor had a limited impact on DXR-release. Variations in the ammonium sulfate concentration used in solutions for the formation/hydration of liposomes significantly affected DXR release behavior, whereas differences in pH did not. In addition, heating condition in phosphate-buffered saline at lower pH (<6.5) exhibited higher discriminative ability for the release profiles from various liposomes with different concentrations of ammonium sulfate than did ultrasound irradiation. These results are expected to be helpful in the process of establishing appropriate drug release testing methods for PEGylated liposomal DXR.

GABA release in the zona incerta of the sheep in response to the sight and ingestion of food and salt.

PubMed

Kendrick, K M; Hinton, M R; Baldwin, B A

1991-05-31

In order to establish which neurotransmitters may influence the activity of zona incerta neurones in the sheep which respond selectively to the sight or ingestion of food, we have measured the release of amino acid and monoamine neurotransmitters from this region using microdialysis sampling. Co-ordinates for the placement of microdialysis probes in regions of the zona incerta where cells respond to the sight or ingestion of food were first established by making single-unit extracellular recordings. When animals were food-deprived results showed that release of gamma-aminobutyric acid (GABA) was increased in response to the sight and ingestion of food but not of aspartate, glutamate, taurine, noradrenaline, dopamine or serotonin. This release of GABA was absent when the animals were shown non-food objects or saw or ingested salt solutions. When the same animals were physiologically sodium-depleted GABA release was evoked by the sight and ingestion of salt solutions and release following the sight and ingestion of food was significantly reduced. These results provide further evidence that GABA is an important neurotransmitter in neural circuits controlling the regulation of food intake.

Repeated aerosol-vapor JP-8 jet fuel exposure affects neurobehavior and neurotransmitter levels in a rat model.

PubMed

Baldwin, Carol M; Figueredo, Aurelio J; Wright, Lynda S; Wong, Simon S; Witten, Mark L

2007-07-01

Four groups of Fischer Brown Norway hybrid rats were exposed for 5, 10, 15, or 20 d to aerosolized-vapor jet propulsion fuel 8 (JP-8) compared to freely moving (5 and 10-d exposures) or sham-confined controls (15 and 20-d exposures). Behavioral testing utilized the U.S. Environmental Protection Agency Functional Observational Battery. Exploratory ethological factor analysis identified three salient factors (central nervous system [CNS] excitability, autonomic 1, and autonomic 2) for use in profiling JP-8 exposure in future studies. The factors were used as dependent variables in general linear modeling. Exposed animals were found to engage in more rearing and hyperaroused behavior compared to controls, replicating prior JP-8 exposure findings. Exposed animals also showed increasing but rapidly decelerating stool output (autonomic 1), and a significant increasing linear trend for urine output (autonomic 2). No significant trends were noted for either of the control groups for the autonomic factors. Rats from each of the groups for each of the time frames were randomly selected for tissue assay from seven brain regions for neurotransmitter levels. Hippocampal DOPAC was significantly elevated after 4-wk JP-8 exposure compared to both control groups, suggesting increased dopamine release and metabolism. Findings indicate that behavioral changes do not appear to manifest until wk 3 and 4 of exposure, suggesting the need for longitudinal studies to determine if these behaviors occur due to cumulative exposure, or due to behavioral sensitization related to repeated exposure to aerosolized-vapor JP-8.

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.

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

Role of external and internal calcium on heterocarrier-mediated transmitter release.

PubMed

Fassio, A; Bonanno, G; Fontana, G; Usai, C; Marchi, M; Raiteri, M

1996-04-01

Release-regulating heterocarriers exist on brain nerve endings. We have investigated in this study the mechanisms involved in the neurotransmitter release evoked by GABA heterocarrier activation. GABA increased the basal release of [3H]acetylcholine and [3H]noradrenaline from rat hippocampal synaptosomes and of [3H]dopamine from striatal synaptosomes. These GABA effects, insensitive to GABA receptor antagonists, were prevented by inhibiting GABA uptake but not by blocking noradrenaline, choline, or dopamine transport. Lack of extracellular Ca2+ or addition of tetrodotoxin selectively abolished the GABA-evoked release of [3H]noradrenaline, leaving unaffected that of [3H]acetylcholine or [3H]dopamine. 1,2-Bis(2-aminophenoxyl)-ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) or vesamicol attenuated the release of [3H]acetylcholine elicited by GABA. Reserpine, but not BAPTA-AM, prevented the effect of GABA on [3H] dopamine release. Autoreceptor activation inhibited the GABA-evoked release of [3H]noradrenaline but not that of [3H]acetylcholine or [3H]dopamine. It is concluded that (a) the release of [3H]noradrenaline consequent to activation of GABA heterocarriers sited on noradrenergic terminals meets the criteria of a conventional exocytotic process, (b) the extracellular [Ca2+]-independent releases of [3H]acetylcholine and [3H]dopamine appear to occur from vesicles possibly through involvement of intraterminal Ca2+, and (c) autoreceptor activation only affects heterocarrier-mediated vesicular release linked to entry of extracellular Ca2+.

How neurosecretory vesicles release their cargo.

PubMed

Scalettar, Bethe A

2006-04-01

Neurons and related cell types often contain two major classes of neurosecretory vesicles, synaptic vesicles (SVs) and dense-core granules (DCGs), which store and release distinct cargo. SVs store and release classic neurotransmitters, which facilitate propagation of action potentials across the synaptic cleft, whereas DCGs transport, store, and release hormones, proteins, and neuropeptides, which facilitate neuronal survival, synaptic transmission, and learning. Over the past few years, there has been a major surge in our understanding of many of the key molecular mechanisms underlying cargo release from SVs and DCGs. This surge has been driven largely by the use of fluorescence microscopy (especially total internal reflection fluorescence microscopy) to visualize SVs or DCGs in living cells. This review highlights some of the recent insights into cargo release from neurosecretory vesicles provided by fluorescence microscopy, with emphasis on DCGs.

Nicotine induces self-renewal of pancreatic cancer stem cells via neurotransmitter-driven activation of sonic hedgehog signalling.

PubMed

Al-Wadei, Mohammed H; Banerjee, Jheelam; Al-Wadei, Hussein A N; Schuller, Hildegard M

2016-01-01

A small subpopulation of pancreatic cancer cells with characteristics of stem cells drive tumour initiation, progression and metastasis. A better understanding of the regulation of cancer stem cells may lead to more effective cancer prevention and therapy. We have shown that the proliferation and migration of pancreatic cancer cell lines is activated by the nicotinic receptor-mediated release of stress neurotransmitters, responses reversed by γ-aminobutyric acid (GABA). However, the observed cancer inhibiting effects of GABA will only succeed clinically if GABA inhibits pancreatic cancer stem cells (PCSCs) in addition to the more differentiated cancer cells that comprise the majority of cancer tissues and cell lines. Using PCSCs isolated from two pancreatic cancer patients by cell sorting and by spheroid formation assay from pancreatic cancer cell line Panc-1, we tested the hypothesis that nicotine induces the self-renewal of PCSCs. Nicotinic acetylcholine receptors (nAChRs) α3, α4, α5 and α7 were expressed and chronic exposure to nicotine increased the protein expression of these receptors. Immunoassays showed that PCSCs produced the stress neurotransmitters epinephrine and norepinephrine and the inhibitory neurotransmitter GABA. Chronic nicotine significantly increased the production of stress neurotransmitters and sonic hedgehog (SHH) while inducing Gli1 protein and decreasing GABA. GABA treatment inhibited the induction of SHH and Gli1. Spheroid formation and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide assays showed significant nicotine-induced increases in self renewal and cell proliferation, responses blocked by GABA. Our data suggest that nicotine increases the SHH-mediated malignant potential of PCSCs and that GABA prevents these effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

Functional relevance of neurotransmitter receptor heteromers in the central nervous system.

PubMed

Ferré, Sergi; Ciruela, Francisco; Woods, Amina S; Lluis, Carme; Franco, Rafael

2007-09-01

The existence of neurotransmitter receptor heteromers is becoming broadly accepted and their functional significance is being revealed. Heteromerization of neurotransmitter receptors produces functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Neurotransmitter receptor heteromers can function as processors of computations that modulate cell signaling. Thus, the quantitative or qualitative aspects of the signaling generated by stimulation of any of the individual receptor units in the heteromer are different from those obtained during coactivation. Furthermore, recent studies demonstrate that some neurotransmitter receptor heteromers can exert an effect as processors of computations that directly modulate both pre- and postsynaptic neurotransmission. This is illustrated by the analysis of striatal receptor heteromers that control striatal glutamatergic neurotransmission.

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

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. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

Effects of their nutrient precursors on the synthesis and release of serotonin, the catecholamines, and acetylcholine - Implications for behavioral disorders

NASA Technical Reports Server (NTRS)

Wurtman, Richard J.

1988-01-01

Authentic foods affect brain serotonin synthesis by modifying brain tryptophan levels, carbohydrates increasing and proteins decreasing these levels. The carbohydrate-induced rise in brain serotonin tends to diminish the likelihood that one carbohydrate-rich, protein-poor meal or snack will be followed by another. This mechanism is apparently disturbed in carbohydrate-craving obesity, which may explain why this syndrome responds well to d-fenfluramine, a serotoninergic drug. Pure nutrients like tyrosine or choline can also affect the rates at which their neurotransmitter products, the catecholamines and acetylcholine, are synthesized in and released from nerve terminals, suggesting that these compounds may find uses as drugs.

Development of the Wireless Instantaneous Neurotransmitter Concentration System for intraoperative neurochemical monitoring using fast-scan cyclic voltammetry.

PubMed

Bledsoe, Jonathan M; Kimble, Christopher J; Covey, Daniel P; Blaha, Charles D; Agnesi, Filippo; Mohseni, Pedram; Whitlock, Sidney; Johnson, David M; Horne, April; Bennet, Kevin E; Lee, Kendall H; Garris, Paul A

2009-10-01

Emerging evidence supports the hypothesis that modulation of specific central neuronal systems contributes to the clinical efficacy of deep brain stimulation (DBS) and motor cortex stimulation (MCS). Real-time monitoring of the neurochemical output of targeted regions may therefore advance functional neurosurgery by, among other goals, providing a strategy for investigation of mechanisms, identification of new candidate neurotransmitters, and chemically guided placement of the stimulating electrode. The authors report the development of a device called the Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for intraoperative neurochemical monitoring during functional neurosurgery. This device supports fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM) for real-time, spatially and chemically resolved neurotransmitter measurements in the brain. The FSCV study consisted of a triangle wave scanned between -0.4 and 1 V at a rate of 300 V/second and applied at 10 Hz. All voltages were compared with an Ag/AgCl reference electrode. The CFM was constructed by aspirating a single carbon fiber (r = 2.5 mum) into a glass capillary and pulling the capillary to a microscopic tip by using a pipette puller. The exposed carbon fiber (that is, the sensing region) extended beyond the glass insulation by approximately 100 microm. The neurotransmitter dopamine was selected as the analyte for most trials. Proof-of-principle tests included in vitro flow injection and noise analysis, and in vivo measurements in urethane-anesthetized rats by monitoring dopamine release in the striatum following high-frequency electrical stimulation of the medial forebrain bundle. Direct comparisons were made to a conventional hardwired system. The WINCS, designed in compliance with FDA-recognized consensus standards for medical electrical device safety, consisted of 4 modules: 1) front-end analog circuit for FSCV (that is, current-to-voltage transducer); 2

Development of the Wireless Instantaneous Neurotransmitter Concentration System for intraoperative neurochemical monitoring using fast-scan cyclic voltammetry

PubMed Central

Bledsoe, Jonathan M.; Kimble, Christopher J.; Covey, Daniel P.; Blaha, Charles D.; Agnesi, Filippo; Mohseni, Pedram; Whitlock, Sidney; Johnson, David M.; Horne, April; Bennet, Kevin E.; Lee, Kendall H.; Garris, Paul A.

2009-01-01

Object Emerging evidence supports the hypothesis that modulation of specific central neuronal systems contributes to the clinical efficacy of deep brain stimulation (DBS) and motor cortex stimulation (MCS). Real-time monitoring of the neurochemical output of targeted regions may therefore advance functional neurosurgery by, among other goals, providing a strategy for investigation of mechanisms, identification of new candidate neurotransmitters, and chemically guided placement of the stimulating electrode. The authors report the development of a device called the Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for intraoperative neurochemical monitoring during functional neurosurgery. This device supports fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM) for real-time, spatially and chemically resolved neurotransmitter measurements in the brain. Methods The FSCV study consisted of a triangle wave scanned between −0.4 and 1 V at a rate of 300 V/second and applied at 10 Hz. All voltages were compared with an Ag/AgCl reference electrode. The CFM was constructed by aspirating a single carbon fiber (r = 2.5 μm) into a glass capillary and pulling the capillary to a microscopic tip by using a pipette puller. The exposed carbon fiber (that is, the sensing region) extended beyond the glass insulation by ~ 100 μm. The neurotransmitter dopamine was selected as the analyte for most trials. Proof-of-principle tests included in vitro flow injection and noise analysis, and in vivo measurements in urethane-anesthetized rats by monitoring dopamine release in the striatum following high-frequency electrical stimulation of the medial forebrain bundle. Direct comparisons were made to a conventional hardwired system. Results The WINCS, designed in compliance with FDA-recognized consensus standards for medical electrical device safety, consisted of 4 modules: 1) front-end analog circuit for FSCV (that is, current-to-voltage transducer

Dynamic neurotransmitter interactions measured with PET

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 intomore » 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

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

PubMed Central

Grauel, M. Katharina; Reddy-Alla, Suneel; Willmes, Claudia G.; Brockmann, Marisa M.; Trimbuch, Thorsten; Rosenmund, Tanja; Pangalos, Maria; Vardar, Gülçin; Stumpf, Alexander; Walter, Alexander M.; Rost, Benjamin R.; Eickholt, Britta J.; Haucke, Volker; Schmitz, Dietmar; Sigrist, Stephan J.; Rosenmund, Christian

2016-01-01

The tight spatial coupling of synaptic vesicles and voltage-gated Ca2+ channels (CaVs) ensures efficient action potential-triggered neurotransmitter release from presynaptic active zones (AZs). Rab-interacting molecule-binding proteins (RIM-BPs) interact with Ca2+ channels and via RIM with other components of the release machinery. Although human RIM-BPs have been implicated in autism spectrum disorders, little is known about the role of mammalian RIM-BPs in synaptic transmission. We investigated RIM-BP2–deficient murine hippocampal neurons in cultures and slices. Short-term facilitation is significantly enhanced in both model systems. Detailed analysis in culture revealed a reduction in initial release probability, which presumably underlies the increased short-term facilitation. Superresolution microscopy revealed an impairment in CaV2.1 clustering at AZs, which likely alters Ca2+ nanodomains at release sites and thereby affects release probability. Additional deletion of RIM-BP1 does not exacerbate the phenotype, indicating that RIM-BP2 is the dominating RIM-BP isoform at these synapses. PMID:27671655

An Investigation into the Effects of Peptide Neurotransmitters and Intracellular Second Messengers in Rat Central Neurons in Culture.

DTIC Science & Technology

1988-02-04

Purkinje neurons. 3. Neuromodulation of synaptic efficacy in an invertebrate preparation that may be a useful model system for the actions of histamine in...neurotransmitters, neuromodulators , affect brain function. Nerve cells are the functional units of the brain, and changes in neuronal activity are ultimately

Selectivity of phenothiazine cholinesterase inhibitors for neurotransmitter systems.

PubMed

Darvesh, Sultan; Macdonald, Ian R; Martin, Earl

2013-07-01

Synthetic derivatives of phenothiazine have been used for over a century as well-tolerated drugs against a variety of human ailments from psychosis to cancer. This implies a considerable diversity in the mechanisms of action produced by structural changes to the phenothiazine scaffold. For example, chlorpromazine treatment of psychosis is related to its interaction with dopaminergic receptors. On the other hand, antagonistic action of such drugs on cholinergic receptor systems would be counter-productive for treatment of Alzheimer's disease. In a search for phenothiazines that are inhibitors of cholinesterases, especially butyrylcholinesterase, with potential to treat Alzheimer's disease, we wished to ascertain that such molecules could be devoid of neurotransmitter receptor interactions. To that end, a number of our synthetic N-10-carbonyl phenothiazine derivatives, with cholinesterase inhibitory activity, were tested for interaction with a variety of neurotransmitter receptor systems. We demonstrate that phenothiazines can be prepared without significant neurotransmitter receptor interactions while retaining high potency as cholinesterase ligands for treatment of Alzheimer's disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

Presynaptic Protein Synthesis Is Required for Long-Term Plasticity of GABA Release.

PubMed

Younts, Thomas J; Monday, Hannah R; Dudok, Barna; Klein, Matthew E; Jordan, Bryen A; Katona, István; Castillo, Pablo E

2016-10-19

Long-term changes of neurotransmitter release are critical for proper brain function. However, the molecular mechanisms underlying these changes are poorly understood. While protein synthesis is crucial for the consolidation of postsynaptic plasticity, whether and how protein synthesis regulates presynaptic plasticity in the mature mammalian brain remain unclear. Here, using paired whole-cell recordings in rodent hippocampal slices, we report that presynaptic protein synthesis is required for long-term, but not short-term, plasticity of GABA release from type 1 cannabinoid receptor (CB 1 )-expressing axons. This long-term depression of inhibitory transmission (iLTD) involves cap-dependent protein synthesis in presynaptic interneuron axons, but not somata. Translation is required during the induction, but not maintenance, of iLTD. Mechanistically, CB 1 activation enhances protein synthesis via the mTOR pathway. Furthermore, using super-resolution STORM microscopy, we revealed eukaryotic ribosomes in CB 1 -expressing axon terminals. These findings suggest that presynaptic local protein synthesis controls neurotransmitter release during long-term plasticity in the mature mammalian brain. Copyright © 2016 Elsevier Inc. All rights reserved.

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

Chronic Effect of Aspartame on Ionic Homeostasis and Monoamine Neurotransmitters in the Rat Brain.

PubMed

Abhilash, M; Alex, Manju; Mathews, Varghese V; Nair, R Harikumaran

2014-07-01

Aspartame is one of the most widely used artificial sweeteners globally. Data concerning acute neurotoxicity of aspartame is controversial, and knowledge on its chronic effect is limited. In the current study, we investigated the chronic effects of aspartame on ionic homeostasis and regional monoamine neurotransmitter concentrations in the brain. Our results showed that aspartame at high dose caused a disturbance in ionic homeostasis and induced apoptosis in the brain. We also investigated the effects of aspartame on brain regional monoamine synthesis, and the results revealed that there was a significant decrease of dopamine in corpus striatum and cerebral cortex and of serotonin in corpus striatum. Moreover, aspartame treatment significantly alters the tyrosine hydroxylase activity and amino acids levels in the brain. Our data suggest that chronic use of aspartame may affect electrolyte homeostasis and monoamine neurotransmitter synthesis dose dependently, and this might have a possible effect on cognitive functions. © The Author(s) 2014.

Triazines facilitate neurotransmitter release of synaptic terminals located in hearts of frog (Rana ridibunda) and honeybee (Apis mellifera) and in the ventral nerve cord of a beetle (Tenebrio molitor).

PubMed

Papaefthimiou, Chrisovalantis; Zafeiridou, Georgia; Topoglidi, Aglaia; Chaleplis, George; Zografou, Stella; Theophilidis, George

2003-07-01

Three triazine herbicides, atrazine, simazine and metribuzine, and some of their major metabolites (cyanuric acid and 6-azauracil) were investigated for their action on synaptic terminals using three different isolated tissue preparations from the atria of the frog, Rana ridibunda, the heart of the honeybee, Apis mellifera macedonica, and the ventral nerve cord of the beetle, Tenebrio molitor. The results indicate that triazines facilitate the release of neurotransmitters from nerve terminals, as already reported for the mammalian central nervous system. The no observed effect concentration, the maximum concentration of the herbicide diluted in the saline that has no effect on the physiological properties of the isolated tissue, was estimated for each individual preparation. According to their relative potency, the three triazines tested can be ranked as follows: atrazine (cyanuric acid), simazine>metribuzine (6-azauracil). The action of these compounds on the cholinergic (amphibians, insects), adrenergic (amphibian) and octopaminergic (insects) synaptic terminals is discussed.

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.

Antidepressant Binding Site in a Bacterial Homologue of Neurotransmitter Transporters

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 inhibitionmore » 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

Acetylcholine from the mesopontine tegmental nuclei differentially affects methamphetamine induced locomotor activity and neurotransmitter levels in the mesolimbic pathway

PubMed Central

Dobbs, Lauren K.; Mark, Gregory P.

2012-01-01

Methamphetamine (MA) increases dopamine (DA) levels within the mesolimbic pathway and acetylcholine (ACh), a neurotransmitter known to increase DA cell firing and release and mediate reinforcement, within the ventral tegmental area (VTA). The laterodorsal tegmental (LDT) and pedunculopontine tegmental (PPT) nuclei provide cholinergic input to the VTA; however, the contribution of LDT- and PPT-derived ACh to MA-induced DA and ACh levels and locomotor activation remains unknown. The first experiment examined the role of LDT-derived ACh in MA locomotor activation by reversibly inhibiting these neurons with bilateral intra-LDT microinjections of the M2 receptor agonist oxotremorine (OXO). Male C57BL/6 J mice were given a bilateral 0.1 µl OXO (0, 1, or 10 nM/side) microinjection immediately prior to IP saline or MA (2 mg/kg). The highest OXO concentration significantly inhibited both saline-and MA-primed locomotor activity. In a second set of experiments we characterized the individual contributions of ACh originating in the LDT or pedunculopontine tegmental nucleus (PPT) to MA-induced levels of ACh and DA by administering intra-LDT or PPT OXO and performing in vivo microdialysis in the VTA and NAc. Intra-LDT OXO dose-dependently attenuated the MA-induced increase in ACh within the VTA but had no effect on DA in NAc. Intra-PPT OXO had no effect on ACh or DA levels within the VTA or NAc, respectively. We conclude that LDT, but not PPT, ACh is important in locomotor behavior and the cholinergic, but not dopaminergic, response to systemic MA. PMID:21945297

(Neuro)transmitter systems in circulating immune cells: a target of immunopharmacological interventions?

PubMed

Tayebati, Seyed Khosrow; Amenta, Francesco

2008-01-01

Increasing evidence indicates the existence of an association between nervous and immune systems. The two systems communicate with each-other to maintain immune homeostasis. Activated immune cells secrete cytokines that influence central nervous system activity. Nervous system, through its peripheral and/or autonomic divisions activates output regulating levels of immune cell activity and the subsequent magnitude of an immune response. On the other hand, neurotransmitters, which represent the main substances involved in nerve cell communications, can influence immune function. Immune organs and circulating immune cells express several (neuro)transmitter systems that can be involved in regulating their activity. The expression of neurotransmitter systems by different subsets of circulating immune cells was reviewed. The regulatory role of different families of (neuro)transmitters (catecholamines, 5-hydroxytryptamine, acetylcholine, histamine and neuropeptides) in modulating levels of immune mediators or specific immune responses is discussed.

Genes affecting sensitivity to serotonin in Caenorhabditis elegans.

PubMed

Schafer, W R; Sanchez, B M; Kenyon, C J

1996-07-01

Regulating the response of a postsynaptic cell to neurotransmitter is an important mechanism for controlling synaptic strength, a process critical to learning. We have begun to define and characterize genes that may control sensitivity to the neurotransmitter serotonin in the nematode Caenorhabditis elegans by identifying serotonin-hypersensitive mutants. We reported previously that mutations in the gene unc-2, which encodes a putative calcium channel subunit, result in hypersensitivity to serotonin. Here we report that mutants defective in the unc-36 gene, which encodes a homologue of a calcium channel auxiliary subunit, are also serotonin-hypersensitive. Moreover, the unc-36 gene appears to be required in the same cells as unc-2 for control of the same behaviors. Mutations in several other genes, including unc-8, unc-10, unc-20, unc-35, unc-75, unc-77, and snt-1 also result in hypersensitivity to serotonin. Several of these mutations have previously been shown to confer resistance to acetylcholinesterase inhibitors, suggesting that they may affect acetylcholine release. Moreover, we found that mutations that decrease acetylcholine synthesis cause defective egg-laying and serotonin hypersensitivity. Thus, acetylcholine appears to negatively regulate the response to serotonin and may participate in the process of serotonin desensitization.

Genes Affecting Sensitivity to Serotonin in Caenorhabditis Elegans

PubMed Central

Schafer, W. R.; Sanchez, B. M.; Kenyon, C. J.

1996-01-01

Regulating the response of a postsynaptic cell to neurotransmitter is an important mechanism for controlling synaptic strength, a process critical to learning. We have begun to define and characterize genes that may control sensitivity to the neurotransmitter serotonin in the nematode Caenorhabditis elegans by identifying serotonin-hypersensitive mutants. We reported previously that mutations in the gene unc-2, which encodes a putative calcium channel subunit, result in hypersensitivity to serotonin. Here we report that mutants defective in the unc-36 gene, which encodes a homologue of a calcium channel auxiliary subunit, are also serotonin-hypersensitive. Moreover, the unc-36 gene appears to be required in the same cells as unc-2 for control of the same behaviors. Mutations in several other genes, including unc-8, unc-10, unc-20, unc-35, unc-75, unc-77, and snt-1 also result in hypersensitivity to serotonin. Several of these mutations have previously been shown to confer resistance to acetylcholinesterase inhibitors, suggesting that they may affect acetylcholine release. Moreover, we found that mutations that decrease acetylcholine synthesis cause defective egg-laying and serotonin hypersensitivity. Thus, acetylcholine appears to negatively regulate the response to serotonin and may participate in the process of serotonin desensitization. PMID:8807295

Modification of rat detrusor muscle contraction by ascorbic acid and citric acid involving enhanced neurotransmitter release and Ca2+ influx.

PubMed

Dasgupta, Jaydip; Elliott, Ruth A; Tincello, Douglas G

2009-01-01

Consumption of carbonated soft drinks is independently associated with the development of overactive bladder (OR 1.41, 95% Cl 1.02-1.95). We have shown previously that artificial sweeteners, present in carbonated soft drinks, enhanced detrusor muscle contraction. Other constituents of soft drinks are preservatives and antioxidants, we evaluated the effects of two of these, ascorbic acid and citric acid, on the contractile response of isolated rat bladder muscle strips. Detrusor muscle strips were suspended in a perfusion organ bath. We determined the effect of ascorbic acid and citric acid on the contractile responses to electrical field stimulation (EFS) in the absence and presence of atropine, carbachol, alpha, beta methylene ATP, potassium and calcium. Ascorbic acid and citric acid (10(-7) M to 10(-3) M) enhanced the contractile response to 10 Hz EFS compared to control (P < 0.01). The frequency and amplitude of spontaneous bladder contractions were enhanced in the presence of ascorbic acid and citric acid by 14%, 21%, 21%, and 11% respectively. Ascorbic acid 10(-4) M significantly increased the atropine resistant response to EFS 5 Hz by 37% (P < 0.01) and inhibited contraction in response to carbachol 10(-4) M by 24%, (P < 0.05). Both ascorbic acid 10(-4) M and citric acid 10(-5) M significantly enhanced maximum contractile responses to alpha, beta methylene ATP, KCI and calcium compared to control. Ascorbic acid and citric acid augmented bladder muscle contraction possibly by enhanced Ca(2+) influx. Presynaptic neurotransmitter release was enhanced by ascorbic acid. Carbonated beverages containing preservatives may aggravate symptoms of OAB. (c) 2009 Wiley-Liss, Inc.

[Effects of aluminum on neurobehavioral function and metabolism of monoamine neurotransmitter].

PubMed

Yang, H; Zheng, Y; Liang, Y

1998-03-01

To evaluate the effects of occupational exposure to aluminum on neurobahavioral function and metabolism of monoamine neurotransmitter. Thirty-three workers exposed to aluminum and 40 controls were studied. Air aluminum concentrations in workplace environment were detected with an atomic absorption spectrophotometer, homovanillic acid (HVA) and vanilylmandellic acid (VMA) in urine and aluminum in serum and urine were detected with high perfolmance liquid chromatography. Neurobehavioral function was tested with Neurobehavioral Core Test Battery recommended by WHO. Geometric time-weighted average of aluminum in workplace environment was 0.95 mg/m3, ranging from 0.31 to 4.12 mg/m3, and urine aluminum levels in workers exposed to aluminum averaged 12.25 micrograms/L, significantly higher than that in controls (5.78 micrograms/L). There was no significant difference in serum aluminum between the exposed and controls. Both urine VMA and HVA levels were higher in the workers exposed to aluminum, and urine VMA level in the exposed was significantly higher than that in controls. There was significant difference in neurobehavioral test, including Santa Ana, digit symbol and Benton tests between the exposed and control workers. It suggests that occupational exposure to low level of aluminum can affect the neurobehavioral function and metabolism of monoamine neurotransmitter.

[Effect of bitumen fume on neurotransmitter and ultrastructure in mice brain].

PubMed

Li, Hai-Ling; Guo, Xiang-Yun; Feng, San-Wei; Liu, Chang-Hai

2006-12-01

To observe the effects of bitumen fume on neurotransmitter and ultrastructure of mice brain and to investigate the toxicity of bitumen fume on nerve system of mice brain. The experimental mice were forced to inhale the bitumen fume at different exposure level and in different time periods. The contents of the three transmitters dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT) in mice brain were measured by the fluorescence meanwhile ultrastructure of mice brain was observed by electronic microscope. The ultrastructure of mice brain was observed under transmission electron microscopy. The contents of DA, NE and 5-HT in all groups decreased with the increasing of dose and prolonging of time (after 8 week, with the increasing of exposure lever, the content of DA, NE, 5-HT was respectively 2.194, 2.190, 2.181, 2.178 microg/g and 1.148, 1.138, 1.135 and 1.407, 1.403, 1.395 microg), but the results did not show significant differences. The structure of the mitochondria changes included the swollen mitochondria, chromatin margination, pyknosis and apoptosis in neuro cells and the processes of swollen astrocyte cells. The bitumen fume could induce changes of the ultrastructure of mice brain and affect the contents of neurotransmitter of mice brain.

Computational Modeling of Neurotransmitter Release Evoked by Electrical Stimulation: Nonlinear Approaches to Predicting Stimulation-Evoked Dopamine Release.

PubMed

Trevathan, James K; Yousefi, Ali; Park, Hyung Ook; Bartoletta, John J; Ludwig, Kip A; Lee, Kendall H; Lujan, J Luis

2017-02-15

Neurochemical changes evoked by electrical stimulation of the nervous system have been linked to both therapeutic and undesired effects of neuromodulation therapies used to treat obsessive-compulsive disorder, depression, epilepsy, Parkinson's disease, stroke, hypertension, tinnitus, and many other indications. In fact, interest in better understanding the role of neurochemical signaling in neuromodulation therapies has been a focus of recent government- and industry-sponsored programs whose ultimate goal is to usher in an era of personalized medicine by creating neuromodulation therapies that respond to real-time changes in patient status. A key element to achieving these precision therapeutic interventions is the development of mathematical modeling approaches capable of describing the nonlinear transfer function between neuromodulation parameters and evoked neurochemical changes. Here, we propose two computational modeling frameworks, based on artificial neural networks (ANNs) and Volterra kernels, that can characterize the input/output transfer functions of stimulation-evoked neurochemical release. We evaluate the ability of these modeling frameworks to characterize subject-specific neurochemical kinetics by accurately describing stimulation-evoked dopamine release across rodent (R 2 = 0.83 Volterra kernel, R 2 = 0.86 ANN), swine (R 2 = 0.90 Volterra kernel, R 2 = 0.93 ANN), and non-human primate (R 2 = 0.98 Volterra kernel, R 2 = 0.96 ANN) models of brain stimulation. Ultimately, these models will not only improve understanding of neurochemical signaling in healthy and diseased brains but also facilitate the development of neuromodulation strategies capable of controlling neurochemical release via closed-loop strategies.

Breathing is affected by dopamine D2-like receptors in the basolateral amygdala.

PubMed

Sugita, Toshihisa; Kanamaru, Mitsuko; Iizuka, Makito; Sato, Kanako; Tsukada, Setsuro; Kawamura, Mitsuru; Homma, Ikuo; Izumizaki, Masahiko

2015-04-01

The precise mechanisms underlying how emotions change breathing patterns remain unclear, but dopamine is a candidate neurotransmitter in the process of emotion-associated breathing. We investigated whether basal dopamine release occurs in the basolateral amygdala (BLA), where sensory-related inputs are received and lead to fear or anxiety responses, and whether D1- and D2-like receptor antagonists affect breathing patterns and dopamine release in the BLA. Adult male mice (C57BL/6N) were perfused with artificial cerebrospinal fluid, a D1-like receptor antagonist (SCH 23390), or a D2-like receptor antagonist ((S)-(-)-sulpiride) through a microdialysis probe in the BLA. Respiratory variables were measured using a double-chamber plethysmograph. Dopamine release was measured by an HPLC. Perfusion of (S)-(-)-sulpiride in the BLA, not SCH 23390, specifically decreased respiratory rate without changes in local release of dopamine. These results suggest that basal dopamine release in the BLA, at least partially, increases respiratory rates only through post-synaptic D2-like receptors, not autoreceptors, which might be associated with emotional responses. Copyright © 2014 Elsevier B.V. All rights reserved.

Polymorphic variants of neurotransmitter receptor genes may affect sexual function in aging males: data from the HALS study.

PubMed

Jóźków, Paweł; Słowińska-Lisowska, Małgorzata; Łaczmański, Łukasz; Mędraś, Marek

2013-01-01

Human behavior is influenced by a number of brain neurotransmitters. Central dopamine, serotonin and melanocortin systems have special importance for male sexual function. We searched for associations between male aging symptoms and polymorphic sites of serotonin (5-HTR1B), melanocortin (MC4R) and dopamine (DRD2, DRD4) receptors. In a population-based sample, genotyping of 5-HTR1B (polymorphism: G861C), MC4R (polymorphisms: C-2745T, Val103Ile), DRD2 (polymorphism: C313T) and DRD4 (polymorphism: 48-bp VNTR) was performed in 387 healthy men. The Aging Males' Symptoms (AMS) scale was used to evaluate specific ailments of aging men. We analyzed answers to questions from the AMS scale. Five points of the questionnaire addressed sexual symptoms of the aging male: feeling of passing one's peak, decrease in beard growth, decrease in ability/frequency to perform sexually, decrease in the number of morning erections, and decrease in sexual desire/libido (lacking pleasure in sex, lacking desire for sexual intercourse). Relations between reported symptoms and variants of the polymorphic sites of the studied genes were assessed. After adjusting for confounding factors (education, arterial hypertension, physical activity, weight, waist circumference) an association between the sexual dimension of AMS and genetic variants of 5-HTR1B G861C (p = 0.04) was observed. Variability of neurotransmitter receptor genes may be associated with sexual symptoms of aging in men. Copyright © 2013 S. Karger AG, Basel.

Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release

PubMed Central

Lee, Sang-Hun; Ledri, Marco; Tóth, Blanka; Marchionni, Ivan; Henstridge, Christopher M.; Dudok, Barna; Kenesei, Kata; Barna, László; Szabó, Szilárd I.; Renkecz, Tibor; Oberoi, Michelle; Watanabe, Masahiko; Limoli, Charles L.; Horvai, George; Soltesz, Ivan

2015-01-01

intracellular membrane cisternae at perisomatic GABAergic symmetrical synapses. Interestingly, neither AM251, JZL184, nor PF3845 affected CB1-positive dendritic interneuron synapses. Together, these findings are consistent with the possibility that constitutively active CB1 receptors substantially influence perisomatic GABA release probability and indicate that the synaptic effects of tonic 2-AG release are tightly controlled by presynaptic MGL activity and also by postsynaptic endovanilloid signaling and FAAH activity. SIGNIFICANCE STATEMENT Tonic cannabinoid signaling plays a critical role in the regulation of synaptic transmission. However, the mechanistic details of how persistent CB1 cannabinoid receptor activity inhibits neurotransmitter release have remained elusive. Therefore, electrophysiological recordings, lipid measurements, and super-resolution imaging were combined to elucidate those signaling molecules and mechanisms that underlie tonic cannabinoid signaling. The findings indicate that constitutive CB1 activity has pivotal function in the tonic control of hippocampal GABA release. Moreover, the endocannabinoid 2-arachidonoylglycerol (2-AG) is continuously generated postsynaptically, but its synaptic effect is regulated strictly by presynaptic monoacylglycerol lipase activity. Finally, anandamide signaling antagonizes tonic 2-AG signaling via activation of postsynaptic transient receptor potential vanilloid TRPV1 receptors. This unexpected mechanistic diversity may be necessary to fine-tune GABA release probability under various physiological and pathophysiological conditions. PMID:26157003

Amino acid neurotransmitters and new approaches to anticonvulsant drug action.

PubMed

Meldrum, B

1984-01-01

Amino acids provide the most universal and important inhibitory (gamma-aminobutyric acid (GABA), glycine) and excitatory (glutamate, aspartate, cysteic acid, cysteine sulphinic acid) neurotransmitters in the brain. An anticonvulsant action may be produced (1) by enhancing inhibitory (GABAergic) processes, and (2) by diminishing excitatory transmission. Possible pharmacological mechanisms for enhancing GABA-mediated inhibition include (1) GABA agonist action, (2) GABA prodrugs, (3) drugs facilitating GABA release from terminals, (4) inhibition of GABA-transaminase, (5) allosteric enhancement of the efficacy of GABA at the receptor complex, (6) direction action on the chloride ionophore, and (7) inhibition of GABA reuptake. Examples of these approaches include the use of irreversible GABA-transaminase inhibitors, such as gamma-vinyl GABA, and the development of anticonvulsant beta-carbolines that interact with the "benzodiazepine receptor." Pharmacological mechanisms for diminishing excitatory transmission include (1) enzyme inhibitors that decrease the maximal rate of synthesis of glutamate or aspartate, (2) drugs that decrease the synaptic release of glutamate or aspartate, and (3) drugs that block the post-synaptic action of excitatory amino acids. Compounds that selectively antagonise excitation due to dicarboxylic amino acids have recently been developed. Those that selectively block excitation produced by N-methyl-D-aspartate (and aspartate) have proved to be potent anticonvulsants in many animal models of epilepsy. This provides a novel approach to the design of anticonvulsant drugs.

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.

A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo.

PubMed

Gautam, Dinesh; Han, Sung-Jun; Hamdan, Fadi F; Jeon, Jongrye; Li, Bo; Li, Jian Hua; Cui, Yinghong; Mears, David; Lu, Huiyan; Deng, Chuxia; Heard, Thomas; Wess, Jürgen

2006-06-01

One of the hallmarks of type 2 diabetes is that pancreatic beta cells fail to release sufficient amounts of insulin in the presence of elevated blood glucose levels. Insulin secretion is modulated by many hormones and neurotransmitters including acetylcholine, the major neurotransmitter of the peripheral parasympathetic nervous system. The physiological role of muscarinic acetylcholine receptors expressed by pancreatic beta cells remains unclear at present. Here, we demonstrate that mutant mice selectively lacking the M3 muscarinic acetylcholine receptor subtype in pancreatic beta cells display impaired glucose tolerance and greatly reduced insulin release. In contrast, transgenic mice selectively overexpressing M3 receptors in pancreatic beta cells show a profound increase in glucose tolerance and insulin release. Moreover, these mutant mice are resistant to diet-induced glucose intolerance and hyperglycemia. These findings indicate that beta cell M3 muscarinic receptors play a key role in maintaining proper insulin release and glucose homeostasis.

Disturbed Neurotransmitter Transporter Expression in Alzheimer Disease Brain

PubMed Central

Chen, Kevin H.; Reese, Edmund A.; Kim, Hyung-Wook; Rapoport, Stanley I.; Rao, Jagadeesh S.

2011-01-01

Alzheimer disease (AD) is a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia. An imbalance of different neurotransmitters – glutamate, acetylcholine, dopamine, and serotonin - has been proposed as the neurobiological basis of behavioral symptoms in AD. The molecular changes associated with neurotransmission imbalance in AD are not clear. We hypothesized that altered reuptake of neurotransmitters by vesicular glutamate transporters (VGLUTs), excitatory amino acid transporters (EAATs), the vesicular acetylcholine transporter (VAChT), the serotonin reuptake transporter (SERT), or the dopamine reuptake transporter (DAT)) are involved in the neurotransmission imbalance in AD. We tested this hypothesis by examining protein and mRNA levels of these transporters in postmortem prefrontal cortex from 10 AD patients and 10 matched non-AD controls. Compared with controls, protein and mRNA levels of VGLUTs, EAAT1–3, VAChT, and SERT were reduced significantly in AD. Expression of DAT and catechol O-methyltransferase (COMT) was unchanged. Reduced VGLUTs and EAATs may contribute to an alteration in glutamatergic recycling, and reduced SERT could exacerbate depressive symptoms in AD. The reduced VAChT expression could contribute to the recognized cholinergic deficit in AD. Altered neurotransmitter transporters could contribute to the pathophysiology of AD and are potential targets for therapy. PMID:21743130

Effects of subchronic benzo(a)pyrene exposure on neurotransmitter receptor gene expression in the rat hippocampus related with spatial learning and memory change.

PubMed

Qiu, Chongying; Cheng, Shuqun; Xia, Yinyin; Peng, Bin; Tang, Qian; Tu, Baijie

2011-11-18

Exposure of laboratory rats to Benzo(a)pyrene (BaP), an environmental contaminant with its high lipophilicify which is widely dispersed in the environment and can easily cross the blood brain barrier presenting in the central nervous system, is associated with impaired learning and memory. The purpose of the research was to examine whether subchronic exposure to BaP affects spatial learning and memory, and how it alters normal gene expression in hippocampus, as well as selection of candidate genes involving neurotransmitter receptor attributed to learning and memory. Morris water maze (MWM) was used to evaluate behavioral differences between BaP-treated and vehicle-treated groups. To gain a better insight into the mechanism of BaP-induced neurotoxicity on learning and memory, we used whole genome oligo microarrays as well as Polymerase Chain Reaction (PCR) to assess the global impact of gene expression. Male Sprague-Dawley rats were intraperitoneally injected with 6.25mg/kg of BaP or vehicle for 14 weeks. The results from the Morris water maze (MWM) test showed that rats treated with BaP exhibited significantly higher mean latencies as compared to vehicle controls. BaP exposure significantly decreased the number of crossing the platform and the time spent in the target area. After the hippocampus was collected from each rat, total RNA was isolated. Microarray and PCR revealed that exposure to BaP affected mRNA expression of neurotransmitter receptors. The web tool DAVID was used to analyze the significantly enriched gene ontology (GO) and KEGG pathways in the differentially expressed genes. Analysis showed that the most significantly affected gene ontology category was behavior. Furthermore, the fourth highest significantly affected gene ontology category was learning and memory. KEGG molecular pathway analysis showed that "neuroactive ligand-receptor interaction" was affected by BaP with highest statistical significance, and 9 candidate neurotransmitter receptor

Setting radon-specific release criteria and demonstrating compliance for land affected by NORM.

PubMed

García-Talavera, M; Martínez, M; Matarranz, J L M; Ramos, L

2008-11-01

Residues from industrial activities involving naturally occurring radioactive materials (NORMs) may cause radiation exposures to members of the public, particularly when NORM-affected land is brought into residential use. To provide an adequate protection against radiation in such situations, the following limiting criteria are currently required in Spain for releasing NORM-affected land: (i) no more than a 300 microSv yr(-1) increase (excluding radon doses) over the natural background; (ii) (222)Rn concentrations in hypothetical future dwellings lower than 200 Bq m(-3); and (iii) reduction of all radiation exposures to as low as reasonable achievable. This paper addresses some of the problems encountered in translating the (222)Rn criterion into site-specific release limits and in demonstrating compliance with them.

Altered neurotransmitter release, vesicle recycling and presynaptic structure in the pilocarpine model of temporal lobe epilepsy

PubMed Central

Upreti, Chirag; Otero, Rafael; Partida, Carlos; Skinner, Frank; Thakker, Ravi; Pacheco, Luis F.; Zhou, Zhen-yu; Maglakelidze, Giorgi; Velíšková, Jana; Velíšek, Libor; Romanovicz, Dwight; Jones, Theresa; Stanton, Patric K.

2012-01-01

In searching for persistent seizure-induced alterations in brain function that might be causally related to epilepsy, presynaptic transmitter release has relatively been neglected. To measure directly the long-term effects of pilocarpine-induced status epilepticus on vesicular release and recycling in hippocampal mossy fibre presynaptic boutons, we used (i) two-photon imaging of FM1-43 vesicular release in rat hippocampal slices; and (ii) transgenic mice expressing the genetically encoded pH-sensitive fluorescent reporter synaptopHluorin preferentially at glutamatergic synapses. In this study we found that, 1–2 months after pilocarpine-induced status epilepticus, there were significant increases in mossy fibre bouton size, faster rates of action potential-driven vesicular release and endocytosis. We also analysed the ultrastructure of rat mossy fibre boutons using transmission electron microscopy. Pilocarpine-induced status epilepticus led to a significant increase in the number of release sites, active zone length, postsynaptic density area and number of vesicles in the readily releasable and recycling pools, all correlated with increased release probability. Our data show that presynaptic release machinery is persistently altered in structure and function by status epilepticus, which could contribute to the development of the chronic epileptic state and may represent a potential new target for antiepileptic therapies. PMID:22344585

Enzymatic inactivation of tachykinin neurotransmitters in the isolated spinal cord of the newborn rat.

PubMed

Yanagisawa, M; Yoshioka, K; Kurihara, T; Saito, K; Seno, N; Suzuki, H; Hosoki, R; Otsuka, M

1992-12-01

A mixture of peptidase inhibitors increased the magnitude of the saphenous nerve-evoked slow depolarization of a lumbar ventral root and prolonged the similarly evoked inhibition of monosynaptic reflex (MSR) in the isolated spinal cord of the newborn rat in the presence of naloxone. The saphenous nerve-evoked MSR inhibition was curtailed by a tachykinin antagonist, GR71251, and after the treatment with GR71251, the peptidase inhibitor mixture no more prolonged the MSR inhibition. The present results suggest that enzymatic degradation plays a role in the termination of action of tachykinins released from primary afferents in the newborn rat spinal cord. The results provide a further support for the notion that tachykinins serve as neurotransmitters in the spinal cord of the newborn rat.

Calcium and protons affect the interaction of neurotransmitters and anesthetics with anionic lipid membranes.

PubMed

Pérez-Isidoro, Rosendo; Ruiz-Suárez, J C

2016-09-01

We study how zwitterionic and anionic biomembrane models interact with neurotransmitters (NTs) and anesthetics (ATs) in the presence of Ca(2+) and different pH conditions. As NTs we used acetylcholine (ACh), γ-aminobutyric acid (GABA), and l-glutamic acid (LGlu). As ATs, tetracaine (TC), and pentobarbital (PB) were employed. By using differential scanning calorimetry (DSC), we analyzed the changes such molecules produce in the thermal properties of the membranes. We found that calcium and pH play important roles in the interactions of NTs and ATs with the anionic lipid membranes. Changes in pH promote deprotonation of the phosphate groups in anionic phospholipids inducing electrostatic interactions between them and NTs; but if Ca(2+) ions are in the system, these act as bridges. Such interactions impact the physical properties of the membranes in a similar manner that anesthetics do. Beyond the usual biochemical approach, we claim that these effects should be taken into account to understand the excitatory-inhibitory orchestrated balance in the nervous system. Copyright © 2016 Elsevier B.V. All rights reserved.

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.

Hypothalamic neural systems controlling the female reproductive life cycle: Gonadotropin-releasing hormone, glutamate, and GABA

PubMed Central

Maffucci, Jacqueline A.; Gore, Andrea C.

2009-01-01

The hypothalamic-pituitary-gonadal (HPG) axis undergoes a number of changes throughout the reproductive life cycle that are responsible for the development, puberty, adulthood, and senescence of reproductive systems. This natural progression is dictated by the neural network controlling the hypothalamus including the cells that synthesize and release gonadotropin-releasing hormone (GnRH) and their regulatory neurotransmitters. Glutamate and GABA are the primary excitatory and inhibitory neurotransmitters in the central nervous system, and as such contribute a great deal to modulating this axis throughout the lifetime via their actions on receptors in the hypothalamus, both directly on GnRH neurons as well as indirectly though other hypothalamic neural networks. Interactions among GnRH neurons, glutamate, and GABA, including the regulation of GnRH gene and protein expression, hormone release, and modulation by estrogen, are critical to age-appropriate changes in reproductive function. Here, we present evidence for the modulation of GnRH neurosecretory cells by the balance of glutamate and GABA in the hypothalamus, and the functional consequences of these interactions on reproductive physiology across the life cycle. PMID:19349036

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

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.

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.

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.

Low dietary protein is associated with an increase in food intake and a decrease in the in vitro release of radiolabeled glutamate and GABA from the lateral hypothalamus.

PubMed

White, B D; Du, F; Higginbotham, D A

2003-12-01

Moderately low-protein diets lead to a rapid increase in food intake and body fat. The increase in feeding is associated with a decrease in the concentration of serum urea nitrogen, suggesting that the low-protein-induced increase in food intake may be related to the decreased metabolism of nitrogen from amino acids. We hypothesized that low dietary protein would be associated with a decrease in the synaptic release of two nitrogen-containing neurotransmitters, GABA and glutamate, whose nitrogen can be derived from amino acids. In this study, we examined the effects of a low-protein diet (10% casein) in Sprague-Dawley rats on the in vitro release of 3H-GABA and 14C-glutamate from the lateral and medial hypothalamus. The low-protein diet increased food intake by about 25% after one day. After four days, the in vitro release of radiolabeled GABA and glutamate was assessed. The calcium-dependent, potassium-stimulated release of radiolabeled GABA and glutamate from the lateral hypothalamus was decreased in rats fed the low-protein diet. The magnitude of neurotransmitter release from the lateral hypothalamus inversely correlated with food intake. No dietary differences in the release of neurotransmitters from the medial hypothalamus were observed. These results support the contention that alterations in nitrogen metabolism are associated with low-protein-induced feeding.

The effects of endomorphins on striatal [3H]GABA release induced by electrical stimulation: an in vitro superfusion study in rats.

PubMed

Bagosi, Zsolt; Jászberényi, Miklós; Telegdy, Gyula

2009-05-01

The endomorphins (EM1 and EM2) are selective endogenous ligands for mu-opioid receptors (MOR1 and MOR2) with neurotransmitter and neuromodulator roles in mammals. In the present study we investigated the potential actions of EMs on striatal GABA release and the implication of different MORs in these processes. Rat striatal slices were preincubated with tritium-labelled GABA ([(3)H]GABA), pretreated with selective MOR1 and MOR2 antagonist beta-funaltrexamine and selective MOR1 antagonist naloxonazine and then superfused with the selective MOR agonists, EM1 and EM2. EM1 significantly decreased the striatal [(3)H]GABA release induced by electrical stimulation. Beta-funaltrexamine antagonized the inhibitory action of EM1, but naloxonazine did not affect it considerably. EM2 was ineffective, even in case of specific enzyme inhibitor diprotin A pretreatment. The results demonstrate that EM1 decreases GABA release in the basal ganglia through MOR2, while EM2 does not influence it.

Purinergic and muscarinic modulation of ATP release from the urothelium and its paracrine actions

PubMed Central

Sui, Guiping; Fry, Chris H.; Montgomery, Bruce; Roberts, Max; Wu, Rui

2013-01-01

The urothelium is a newly recognized sensory structure that detects bladder fullness. Pivotal to this sensory role is the release of ATP from the urothelium. However, the routes for urothelial ATP release, its modulation by receptor-mediated pathways, and the autocrine/paracrine role of ATP are poorly understood, especially in native tissue. We examined the action of key neurotransmitters: purinergic and muscarinic agonists on ATP release and its paracrine effect. Guinea pig and human urothelial mucosa were mounted in a perfusion trough; superfusate ATP was measured using a luciferin-luciferase assay, and tissue contractions were recorded with a tension transducer. Intracellular Ca2+ was measured in isolated urothelial cells with fura-2. The P2Y agonist UTP but not the P2X agonist α,β-methylene-ATP generated ATP release. The muscarinic agonist carbachol and the M2-preferential agonist oxotremorine also generated ATP release, which was antagonized by the M2-specific agent methoctramine. Agonist-evoked ATP release was accompanied by mucosal contractions. Urothelial ATP release was differentially mediated by intracellular Ca2+ release, cAMP, exocytosis, or connexins. Urothelium-attached smooth muscle exhibited spontaneous contractions that were augmented by subthreshold concentrations of carbachol, which had little direct effect on smooth muscle. This activity was attenuated by desensitizing P2X receptors on smooth muscle. Urothelial ATP release was increased in aging bladders. Purinergic and muscarinic agents produced similar effects in human urothelial tissue. This is the first demonstration of specific modulation of urothelial ATP release in native tissue by purinergic and muscarinic neurotransmitters via distinct mechanisms. Released ATP produces paracrine effects on underlying tissues. This process is altered during aging and has relevance to human bladder pathologies. PMID:24285497

Purinergic and muscarinic modulation of ATP release from the urothelium and its paracrine actions.

PubMed

Sui, Guiping; Fry, Chris H; Montgomery, Bruce; Roberts, Max; Wu, Rui; Wu, Changhao

2014-02-01

The urothelium is a newly recognized sensory structure that detects bladder fullness. Pivotal to this sensory role is the release of ATP from the urothelium. However, the routes for urothelial ATP release, its modulation by receptor-mediated pathways, and the autocrine/paracrine role of ATP are poorly understood, especially in native tissue. We examined the action of key neurotransmitters: purinergic and muscarinic agonists on ATP release and its paracrine effect. Guinea pig and human urothelial mucosa were mounted in a perfusion trough; superfusate ATP was measured using a luciferin-luciferase assay, and tissue contractions were recorded with a tension transducer. Intracellular Ca²⁺ was measured in isolated urothelial cells with fura-2. The P2Y agonist UTP but not the P2X agonist α,β-methylene-ATP generated ATP release. The muscarinic agonist carbachol and the M₂-preferential agonist oxotremorine also generated ATP release, which was antagonized by the M₂-specific agent methoctramine. Agonist-evoked ATP release was accompanied by mucosal contractions. Urothelial ATP release was differentially mediated by intracellular Ca²⁺ release, cAMP, exocytosis, or connexins. Urothelium-attached smooth muscle exhibited spontaneous contractions that were augmented by subthreshold concentrations of carbachol, which had little direct effect on smooth muscle. This activity was attenuated by desensitizing P2X receptors on smooth muscle. Urothelial ATP release was increased in aging bladders. Purinergic and muscarinic agents produced similar effects in human urothelial tissue. This is the first demonstration of specific modulation of urothelial ATP release in native tissue by purinergic and muscarinic neurotransmitters via distinct mechanisms. Released ATP produces paracrine effects on underlying tissues. This process is altered during aging and has relevance to human bladder pathologies.

Loud Noise Exposure Produces DNA, Neurotransmitter and Morphological Damage within Specific Brain Areas.

PubMed

Frenzilli, Giada; Ryskalin, Larisa; Ferrucci, Michela; Cantafora, Emanuela; Chelazzi, Silvia; Giorgi, Filippo S; Lenzi, Paola; Scarcelli, Vittoria; Frati, Alessandro; Biagioni, Francesca; Gambardella, Stefano; Falleni, Alessandra; Fornai, Francesco

2017-01-01

Exposure to loud noise is a major environmental threat to public health. Loud noise exposure, apart from affecting the inner ear, is deleterious for cardiovascular, endocrine and nervous systems and it is associated with neuropsychiatric disorders. In this study we investigated DNA, neurotransmitters and immune-histochemical alterations induced by exposure to loud noise in three major brain areas (cerebellum, hippocampus, striatum) of Wistar rats. Rats were exposed to loud noise (100 dBA) for 12 h. The effects of noise on DNA integrity in all three brain areas were evaluated by using Comet assay. In parallel studies, brain monoamine levels and morphology of nigrostriatal pathways, hippocampus and cerebellum were analyzed at different time intervals (24 h and 7 days) after noise exposure. Loud noise produced a sudden increase in DNA damage in all the brain areas under investigation. Monoamine levels detected at 7 days following exposure were differently affected depending on the specific brain area. Namely, striatal but not hippocampal dopamine (DA) significantly decreased, whereas hippocampal and cerebellar noradrenaline (NA) was significantly reduced. This is in line with pathological findings within striatum and hippocampus consisting of a decrease in striatal tyrosine hydroxylase (TH) combined with increased Bax and glial fibrillary acidic protein (GFAP). Loud noise exposure lasting 12 h causes immediate DNA, and long-lasting neurotransmitter and immune-histochemical alterations within specific brain areas of the rat. These alterations may suggest an anatomical and functional link to explain the neurobiology of diseases which prevail in human subjects exposed to environmental noise.

Chemosterilization of male sea lampreys (Petromyzon marinus) does not affect sex pheromone release

USGS Publications Warehouse

Siefkes, Michael J.; Bergstedt, Roger A.; Twohey, Michael B.; Li, Weiming

2003-01-01

Release of males sterilized by injection with bisazir is an important experimental technique in management of sea lamprey (Petromyzon marinus), an invasive, nuisance species in the Laurentian Great Lakes. Sea lampreys are semelparous and sterilization can theoretically eliminate a male's reproductive capacity and, if the ability to obtain mates is not affected, waste the sex products of females spawning with him. It has been demonstrated that spermiating males release a sex pheromone that attracts ovulating females. We demonstrated that sterilized, spermiating males also released the pheromone and attracted ovulating females. In a two-choice maze, ovulating females increased searching behavior and spent more time in the side of the maze containing chemical stimuli from sterilized, spermiating males. This attraction response was also observed in spawning stream experiments. Also, electro-olfactograms showed that female olfactory organs were equally sensitive to chemical stimuli from sterilized and nonsterilized, spermiating males. Finally, fast atom bombardment mass spectrometry showed that extracts from water conditioned with sterilized and nonsterilized, spermiating males contained the same pheromonal molecule at similar levels. We concluded that injection of bisazir did not affect the efficacy of sex pheromone in sterilized males.

Developmental vitamin D deficiency alters multiple neurotransmitter systems in the neonatal rat brain.

PubMed

Kesby, James P; Turner, Karly M; Alexander, Suzanne; Eyles, Darryl W; McGrath, John J; Burne, Thomas H J

2017-11-01

Epidemiological evidence suggests that developmental vitamin D (DVD) deficiency is a risk factor for neuropsychiatric disorders, such as schizophrenia. DVD deficiency in rats is associated with altered brain structure and adult behaviours indicating alterations in dopamine and glutamate signalling. Developmental alterations in dopamine neurotransmission have also been observed in DVD-deficient rats but a comprehensive assessment of brain neurochemistry has not been undertaken. Thus, the current study determined the regional concentrations of dopamine, noradrenaline, serotonin, glutamine, glutamate and γ-aminobutyric acid (GABA), and associated metabolites, in DVD-deficient neonates. Sprague-Dawley rats were fed a vitamin D deficient diet or control diet six weeks prior to mating until birth and housed under UVB-free lighting conditions. Neurotransmitter concentration was assessed by high-performance liquid chromatography on post-mortem neonatal brain tissue. Ubiquitous reductions in the levels of glutamine (12-24%) were observed in DVD-deficient neonates compared with control neonates. Similarly, in multiple brain regions DVD-deficient neonates had increased levels of noradrenaline and serine compared with control neonates. In contrast, increased levels of dopamine and decreased levels of serotonin in DVD-deficient neonates were limited to striatal subregions compared with controls. Our results confirm that DVD deficiency leads to changes in multiple neurotransmitter systems in the neonate brain. Importantly, this regionally-based assessment in DVD-deficient neonates identified both widespread neurotransmitter changes (glutamine/noradrenaline) and regionally selective neurotransmitter changes (dopamine/serotonin). Thus, vitamin D may have both general and local actions depending on the neurotransmitter system being investigated. Taken together, these data suggest that DVD deficiency alters neurotransmitter systems relevant to schizophrenia in the developing rat

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

Neurotransmitter contents in the retina of RCS rat.

PubMed

Okada, M; Okuma, Y; Osumi, Y; Nishihara, M; Yokotani, K; Ueno, H

2000-12-01

Retinitis pigmentosa is a hereditary disease characterized by gradually developing degeneration of photoreceptors. The Royal College of Surgeons (RCS) rat is an experimental model of retinitis pigmentosa. However, there is a paucity of information concerning neurotransmitter contents in the retina of RCS rats. Thus, we determined the retinal contents of neurotransmitters in RCS rats at 4 and 23 weeks postnatally and in age-matched congenic control rats. Dopamine (DA) and acetylcholine (ACh) were electrochemically measured by high-performance liquid chromatography (HPLC). Neuroactive amino acids, including gamma-aminobutyric acid (GABA) and taurine, were determined by means of an HPLC-precolumn derivatization method. Contents of DA, ACh, glutamate, aspartate and GABA in the retina of RCS rats 4 weeks postnatally were within normal ranges. At 23 weeks, the retinal contents of DA, glutamate and aspartate in the RCS rats were significantly lower than in the age-matched control rats, while the contents of ACh and GABA were unaffected even at this later stage. On the other hand, the retinal content of glycine in the RCS rats at 23 weeks was significantly higher than that in the age-matched control rats. It is interesting to note that the content of taurine in the RCS rats had already decreased at 4 weeks postnatally and the decrease was more marked at 23 weeks. The decrease in taurine content is probably the first sign of degeneration revealed by the retinal neurotransmitters of RCS rats.

Exercise and neuromodulators: choline and acetylcholine in marathon runners

NASA Technical Reports Server (NTRS)

Conlay, L. A.; Sabounjian, L. A.; Wurtman, R. J.

1992-01-01

Certain neurotransmitters (i.e., acetylcholine, catecholamines, and serotonin) are formed from dietary constituents (i.e., choline, tyrosine and tryptophan). Changing the consumption of these precursors alters release of their respective neurotransmitter products. The neurotransmitter acetylcholine is released from the neuromuscular junction and from brain. It is formed from choline, a common constituent in fish, liver, and eggs. Choline is also incorporated into cell membranes; membranes may likewise serve as an alternative choline source for acetylcholine synthesis. In trained athletes, running a 26 km marathon reduced plasma choline by approximately 40%, from 14.1 to 8.4 uM. Changes of similar magnitude have been shown to reduce acetylcholine release from the neuromuscular junction in vivo. Thus, the reductions in plasma choline associated with strenuous exercise may reduce acetylcholine release, and could thereby affect endurance or performance.

Rab3A Inhibition of Ca2+ -Dependent Dopamine Release From PC12 Cells Involves Interaction With Synaptotagmin I.

PubMed

Dai, Zhipan; Tang, Xia; Chen, Jia; Tang, Xiaochao; Wang, Xianchun

2017-11-01

Rab3 and synaptotagmin have been suggested to play important roles in the regulation of neurotransmitter release and, however, the molecular mechanism has not been completely clear. Here, we studied the effects of Rab3A and synaptotagmin I (Syt I) on dopamine release using PC12 cells as a model system. Rab3A was demonstrated to have effects on both Ca 2+ -independent and Ca 2+ -dependent dopamine releases from the PC12 cells. Application of Rab3A (up to 2500 nM) gradually decreased the amount of Ca 2+ -dependently released dopamine, indicating that Rab3A is a negative modulator that was further supported by the increase in dopamine release caused by Rab3A knockdown. Syt I knockdown weakened the Ca 2+ -dependent dopamine release, suggesting that Syt I plays a positive regulatory role in the cellular process. Treatment of the Syt I-knocked down PC12 cells with Rab3A further decreased Ca 2+ -dependent dopamine release and, however, the decrease magnitude was significantly reduced compared with that before Syt I knockdown, thus for the first time demonstrating that the inhibitory effect of Rab3A on Ca 2+ -dependent dopamine release involves the interaction with Syt I. This work has shed new light on the molecular mechanism for Rab3 and synaptotamin regulation of neurotransmitter release. J. Cell. Biochem. 118: 3696-3705, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Artificial neural network and classical least-squares methods for neurotransmitter mixture analysis.

PubMed

Schulze, H G; Greek, L S; Gorzalka, B B; Bree, A V; Blades, M W; Turner, R F

1995-02-01

Identification of individual components in biological mixtures can be a difficult problem regardless of the analytical method employed. In this work, Raman spectroscopy was chosen as a prototype analytical method due to its inherent versatility and applicability to aqueous media, making it useful for the study of biological samples. Artificial neural networks (ANNs) and the classical least-squares (CLS) method were used to identify and quantify the Raman spectra of the small-molecule neurotransmitters and mixtures of such molecules. The transfer functions used by a network, as well as the architecture of a network, played an important role in the ability of the network to identify the Raman spectra of individual neurotransmitters and the Raman spectra of neurotransmitter mixtures. Specifically, networks using sigmoid and hyperbolic tangent transfer functions generalized better from the mixtures in the training data set to those in the testing data sets than networks using sine functions. Networks with connections that permit the local processing of inputs generally performed better than other networks on all the testing data sets. and better than the CLS method of curve fitting, on novel spectra of some neurotransmitters. The CLS method was found to perform well on noisy, shifted, and difference spectra.

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.

Acetylcholine is released from taste cells, enhancing taste signalling

PubMed Central

Dando, Robin; Roper, Stephen D

2012-01-01

Acetylcholine (ACh), a candidate neurotransmitter that has been implicated in taste buds, elicits calcium mobilization in Receptor (Type II) taste cells. Using RT-PCR analysis and pharmacological interventions, we demonstrate that the muscarinic acetylcholine receptor M3 mediates these actions. Applying ACh enhanced both taste-evoked Ca2+ responses and taste-evoked afferent neurotransmitter (ATP) secretion from taste Receptor cells. Blocking muscarinic receptors depressed taste-evoked responses in Receptor cells, suggesting that ACh is normally released from taste cells during taste stimulation. ACh biosensors confirmed that, indeed, taste Receptor cells secrete acetylcholine during gustatory stimulation. Genetic deletion of muscarinic receptors resulted in significantly diminished ATP secretion from taste buds. The data demonstrate a new role for acetylcholine as a taste bud transmitter. Our results imply specifically that ACh is an autocrine transmitter secreted by taste Receptor cells during gustatory stimulation, enhancing taste-evoked responses and afferent transmitter secretion. PMID:22570381

Opioid modulation of GABA release in the rat inferior colliculus

PubMed Central

Tongjaroenbungam, Walaiporn; Jongkamonwiwat, Nopporn; Cunningham, Joanna; Phansuwan-Pujito, Pansiri; Dodson, Hilary C; Forge, Andrew; Govitrapong, Piyarat; Casalotti, Stefano O

2004-01-01

Background The inferior colliculus, which receives almost all ascending and descending auditory signals, plays a crucial role in the processing of auditory information. While the majority of the recorded activities in the inferior colliculus are attributed to GABAergic and glutamatergic signalling, other neurotransmitter systems are expressed in this brain area including opiate peptides and their receptors which may play a modulatory role in neuronal communication. Results Using a perfusion protocol we demonstrate that morphine can inhibit KCl-induced release of [3H]GABA from rat inferior colliculus slices. DAMGO ([D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin) but not DADLE ([D-Ala2, D-Leu5]-enkephalin or U69593 has the same effect as morphine indicating that μ rather than δ or κ opioid receptors mediate this action. [3H]GABA release was diminished by 16%, and this was not altered by the protein kinase C inhibitor bisindolylmaleimide I. Immunostaining of inferior colliculus cryosections shows extensive staining for glutamic acid decarboxylase, more limited staining for μ opiate receptors and relatively few neurons co-stained for both proteins. Conclusion The results suggest that μ-opioid receptor ligands can modify neurotransmitter release in a sub population of GABAergic neurons of the inferior colliculus. This could have important physiological implications in the processing of hearing information and/or other functions attributed to the inferior colliculus such as audiogenic seizures and aversive behaviour. PMID:15353008

Peripheral Nerve Fibers and Their Neurotransmitters in Osteoarthritis Pathology

PubMed Central

Grässel, Susanne; Muschter, Dominique

2017-01-01

The importance of the nociceptive nervous system for maintaining tissue homeostasis has been known for some time, and it has also been suggested that organogenesis and tissue repair are under neuronal control. Changes in peripheral joint innervation are supposed to be partly responsible for degenerative alterations in joint tissues which contribute to development of osteoarthritis. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters, allowing response to peripheral neuronal stimuli. Among them are mesenchymal stem cells, synovial fibroblasts, bone cells and chondrocytes of different origin, which express distinct subtypes of adrenoceptors (AR), receptors for vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP). Some of these cell types synthesize and secrete neuropeptides such as SP, and they are positive for tyrosine-hydroxylase (TH), the rate limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters are involved in the pathology of inflammatory diseases such as rheumatoid arthritis (RA) which manifests mainly in the joints. In addition, they seem to play a role in pathogenesis of priori degenerative joint disorders such as osteoarthritis (OA). Altogether it is evident that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for joint tissue and bone homeostasis. They modulate articular cartilage, subchondral bone and synovial tissue properties in physiological and pathophysiological conditions, in addition to their classical neurological features. PMID:28452955

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. © 2013 International Society for Neurochemistry.

Effect of the alkaloid (-)cathinone on the release of radioactivity from rabbit atria prelabelled with /sup 3/H-norepinephrine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kalix, P.

1983-02-14

In certain countries of East Africa and the Arab Peninsula, fresh leaves of the khat shrub are used as a stimulant. The effect of the plant material can be explained by the presence of the phenylalklamine alkaloid (-)cathinone in the leaves, since this substance has been shown to have an amphetamine-like releasing effect on CNS tissue prelabelled with /sup 3/H-dopamine. Characteristically, the chewing of khat is accompanied by sympathomimetic effects, especially at the cardiovascular level. To test whether these might be due to release of neurotransmitter from adrenergic nerve endings, the effect of (-)cathinone on the efflux of radioactivity frommore » isolated rabbit atrium tissue prelabelled with /sup 3/H-norepinephrine was investigated. It was found that, at concentrations below 1 ..mu..M, (-)cathinone caused an immediate increase of efflux. The effect was dose-dependent and was potentiated by pretreatment of the rabbits with reserpine. Preincubation of the tissue with desipramine and cocaine prevented the induction of release by (-)cathinone. The results indicate that the alkaloid (-)cathinone has an amphetamine-like releasing effect on noradrenergic nerve endings and they suggest that the cardiovascular symptoms observed during khat consumption are due to release of neurotransmitter from physiologicl storage sites.« less

Monoamine Release during Unihemispheric Sleep and Unihemispheric Waking in the Fur Seal

PubMed Central

Lyamin, Oleg I.; Lapierre, Jennifer L.; Kosenko, Peter O.; Kodama, Tohru; Bhagwandin, Adhil; Korneva, Svetlana M.; Peever, John H.; Mukhametov, Lev M.; Siegel, Jerome M.

2016-01-01

Study Objectives: Our understanding of the role of neurotransmitters in the control of the electroencephalogram (EEG) has been entirely based on studies of animals with bilateral sleep. The study of animals with unihemispheric sleep presents the opportunity of separating the neurochemical substrates of waking and sleep EEG from the systemic, bilateral correlates of sleep and waking states. Methods: The release of histamine (HI), norepinephrine (NE), and serotonin (5HT) in cortical and subcortical areas (hypothalamus, thalamus and caudate nucleus) was measured in unrestrained northern fur seals (Callorhinus ursinus) using in vivo microdialysis, in combination with, polygraphic recording of EEG, electrooculogram, and neck electromyogram. Results: The pattern of cortical and subcortical HI, NE, and 5HT release in fur seals is similar during bilaterally symmetrical states: highest in active waking, reduced in quiet waking and bilateral slow wave sleep, and lowest in rapid eye movement (REM) sleep. Cortical and subcortical HI, NE, and 5HT release in seals is highly elevated during certain waking stimuli and behaviors, such as being sprayed with water and feeding. However, in contrast to acetylcholine (ACh), which we have previously studied, the release of HI, NE, and 5HT during unihemispheric sleep is not lateralized in the fur seal. Conclusions: Among the studied neurotransmitters most strongly implicated in waking control, only ACh release is asymmetric in unihemispheric sleep and waking, being greatly increased on the activated side of the brain. Commentary: A commentary on this article appears in this issue on page 491. Citation: Lyamin OI, Lapierre JL, Kosenko PO, Kodama T, Bhagwandin A, Korneva SM, Peever JH, Mukhametov LM, Siegel JM. Monoamine release during unihemispheric sleep and unihemispheric waking in the fur seal. SLEEP 2016;39(3):625–636. PMID:26715233

Radioenzymatic analysis of neurotransmitters

DOE Office of Scientific and Technical Information (OSTI.GOV)

Philips, S.R.

Since the late 1960's, radioenzymatic assays have gradually come to replace the less sensitive and less specific spectrofluorometric and bioassay procedures previously used to determine many of the neurotransmitters. These assays provide the means to measure picogram quantities of most of these substances, and have enabled determinations to be made in very small volumes of body fluids, in brain perfusates and individual brain nuclei, and in large individual cells of some simple animals. This paper reviews briefly some of the radioenzymatic techniques presently available for assaying norepinephrine (NE), epinephrine (E), dopamine (DA), serotonin, and the trace amines octopamine (OA), phenylethanolaminemore » (PEOHA), phenylethylamine (PEA), tyramine (TA) and tryptamine (T).« less

Neuronal activity determines distinct gliotransmitter release from a single astrocyte

PubMed Central

Covelo, Ana

2018-01-01

Accumulating evidence indicates that astrocytes are actively involved in brain function by regulating synaptic activity and plasticity. Different gliotransmitters, such as glutamate, ATP, GABA or D-serine, released form astrocytes have been shown to induce different forms of synaptic regulation. However, whether a single astrocyte may release different gliotransmitters is unknown. Here we show that mouse hippocampal astrocytes activated by endogenous (neuron-released endocannabinoids or GABA) or exogenous (single astrocyte Ca2+ uncaging) stimuli modulate putative single CA3-CA1 hippocampal synapses. The astrocyte-mediated synaptic modulation was biphasic and consisted of an initial glutamate-mediated potentiation followed by a purinergic-mediated depression of neurotransmitter release. The temporal dynamic properties of this biphasic synaptic regulation depended on the firing frequency and duration of the neuronal activity that stimulated astrocytes. Present results indicate that single astrocytes can decode neuronal activity and, in response, release distinct gliotransmitters to differentially regulate neurotransmission at putative single synapses. PMID:29380725

Trafficking of presynaptic AMPA receptors mediating neurotransmitter release: neuronal selectivity and relationships with sensitivity to cyclothiazide.

PubMed

Pittaluga, Anna; Feligioni, Marco; Longordo, Fabio; Luccini, Elisa; Raiteri, Maurizio

2006-03-01

Postsynaptic glutamate AMPA receptors (AMPARs) can recycle between plasma membrane and intracellular pools. In contrast, trafficking of presynaptic AMPARs has not been investigated. AMPAR surface expression involves interactions between the GluR2 carboxy tail and various proteins including glutamate receptor-interacting protein (GRIP), AMPA receptor-binding protein (ABP), protein interacting with C kinase 1 (PICK1), N-ethyl-maleimide-sensitive fusion protein (NSF). Here, peptides known to selectively block the above interactions were entrapped into synaptosomes to study the effects on the AMPA-evoked release of [3H]noradrenaline ([3H]NA) and [3H]acetylcholine ([3H]ACh) from rat hippocampal and cortical synaptosomes, respectively. Internalization of pep2-SVKI to prevent GluR2-GRIP/ABP/PICK1 interactions potentiated the AMPA-evoked release of [3H]NA but left unmodified that of [3H]ACh. Similar potentiation was caused by pep2-AVKI, the blocker of GluR2-PICK1 interaction. Conversely, a decrease in the AMPA-evoked release of [3H]NA, but not of [3H]ACh, was caused by pep2m, a selective blocker of the GluR2-NSF interaction. In the presence of pep2-SVKI the presynaptic AMPARs on noradrenergic terminals lost sensitivity to cyclothiazide. AMPARs releasing [3H]ACh, but not those releasing [3H]NA, were sensitive to spermine, suggesting that they are GluR2-lacking AMPARs. To conclude: (i) release-regulating presynaptic AMPARs constitutively cycle in isolated nerve terminals; (ii) the process exhibits neuronal selectivity; (iii) AMPAR trafficking and desensitization may be interrelated.

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.

Intravenously administered oxotremorine and atropine, in doses known to affect pain threshold, affect the intraspinal release of acetylcholine in rats.

PubMed

Abelson, Klas S P; Höglund, A Urban

2002-04-01

Both systemically and intrathecally administered cholinergic agonists produce antinociception while cholinergic antagonists decrease pain threshold. The mechanism and the site of action of these substances are not known. In the present study it was hypothesized that systemically administered muscarinic agonists and antagonists modify nociceptive threshold by affecting intraspinal release of acetylcholine (ACh). Catheters were inserted into the femoral vein in rats maintained on isoflurane anaesthesia for administration of oxotremorine (10-300 microg/kg) and atropine (0.1, 10, 5000 microg/kg). Spinal microdialysis probes were placed intraspinally at approximately the C2-C5 spinal level for sampling of acetylcholine and dialysis delivery of atropine (0.1, 1, 10 nM). Additionally, the tail-flick behaviour was tested on conscious rats injected intraperitoneally with saline, atropine (10, 100 and 5000 microg/kg), or subcutaneously with oxotremorine (30, 100, 300 microg/kg). Subcutaneous administration of oxotremorine (30, 100, 300 microg/kg) significantly increased the tail-flick latency. These doses of oxotremorine dose-dependently increased the intraspinal release of acetylcholine. Intravenously administered atropine, in a dose that produced hyperalgesia (5000 microg/kg) in the tail-flick test, significantly decreased the intraspinal release of acetylcholine. Our results suggest an association between pain threshold and acetylcholine release in spinal cord. It is also suggested that an approximately 30% increase in basal ACh release produces antinociception and that a 30% decrease in basal release produces hyperalgesia.

Three Gaseous Neurotransmitters, Nitric oxide, Carbon Monoxide, and Hydrogen Sulfide, Are Involved in the Neurogenic Relaxation Responses of the Porcine Internal Anal Sphincter.

PubMed

Folasire, Oladayo; Mills, Kylie A; Sellers, Donna J; Chess-Williams, Russ

2016-01-31

The internal anal sphincter (IAS) plays an important role in maintaining continence and a number of neurotransmitters are known to regulate IAS tone. The aim of this study was to determine the relative importance of the neurotransmitters involved in the relaxant and contractile responses of the porcine IAS. Responses of isolated strips of IAS to electrical field stimulation (EFS) were obtained in the absence and presence of inhibitors of neurotransmitter systems. Contractile responses of the sphincter to EFS were unaffected by the muscarinic receptor antagonist, atropine (1 μM), but were almost completely abolished by the adrenergic neuron blocker guanethidine (10 μM). Contractile responses were also reduced (by 45% at 5 Hz, P < 0.01) following desensitisation of purinergic receptors with α,β-methylene-ATP (10 μM). In the presence of guanethidine, atropine, and α,β-methylene-ATP, the remaining relaxatory responses to EFS were examined. These responses were not altered by the cyclooxygenase inhibitor, indomethacin (5 μM), the vasoactive intestinal polypeptide receptor antagonist, [D-p-Cl-Phe(6),Leu(17)]-vasoactive intestinal peptide (PheLeu-VIP; 100 nM), or the purinoceptor antagonists, 8-phenyltheophyline (P1 receptors) or suramin (P2 receptors). However, relaxation responses were reduced by Nω-nitro-L-arginine (L-NNA; 100 μM), an inhibitor of nitric oxide synthesis (40-50% reduction), zinc protoprophyrin IX (10 μM), an inhibitor of carbon monoxide synthesis (20-40% reduction), and also propargylglycine (30 μM) and aminooxyacetic acid (30 μM), inhibitors of hydrogen sulphide synthesis (15-20% reduction). Stimulation of IAS efferent nerves releases excitatory and inhibitory neurotransmitters: noradrenaline is the predominant contractile transmitter with a smaller component from ATP, whilst 3 gases mediate relaxation responses to EFS, with the combined contributions being nitric oxide > carbon monoxide > hydrogen sulfide.

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

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.

Neurotransmitters couple brain activity to subventricular zone neurogenesis

PubMed Central

Young, Stephanie Z.; Taylor, M. Morgan; Bordey, Angélique

2011-01-01

Adult neurogenesis occurs in two privileged microenvironments, the hippocampal subgranular zone of the dentate gyrus and the subventricular zone (SVZ) along the lateral ventricle. This review focuses on accumulating evidence suggesting that the activity of specific brain regions or bodily states influences SVZ cell proliferation and neurogenesis. Neuromodulators such as dopamine and serotonin have been shown to have long-range effects through neuronal projections into the SVZ. Local GABA and glutamate signaling have demonstrated effects on SVZ proliferation and neurogenesis, but an extra-niche source of these neurotransmitters remains to be explored and options will be discussed. There is also accumulating evidence that diseases and bodily states such as Alzheimer's disease, seizures, sleep, and pregnancy influence SVZ cell proliferation. With such complex behavior and environmentally-driven factors that control subregion-specific activity, it will become necessary to account for overlapping roles of multiple neurotransmitter systems on neurogenesis when developing cell therapies or drug treatments. PMID:21395856

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

Lighting up the brain: genetically encoded fluorescent sensors for imaging neurotransmitters and neuromodulators.

PubMed

Wang, Huan; Jing, Miao; Li, Yulong

2018-06-01

Measuring the precise dynamics of specific neurotransmitters and neuromodulators in the brain is essential for understanding how information is transmitted and processed. Thanks to the development and optimization of various genetically encoded sensors, we are approaching the stage in which a few key neurotransmitters/neuromodulators can be imaged with high cell specificity and good signal-to-noise ratio. Here, we summarize recent progress regarding these sensors, focusing on their design principles, properties, potential applications, and current limitations. We also highlight the G protein-coupled receptor (GPCR) scaffold as a promising platform that may enable the scalable development of the next generation of sensors, enabling the rapid, sensitive, and specific detection of a large repertoire of neurotransmitters/neuromodulators in vivo at cellular or even subcellular resolution. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

Activity-dependent regulation of release probability at excitatory hippocampal synapses: a crucial role of FMRP in neurotransmission

PubMed Central

Wang, Xiao-Sheng; Peng, Chun-Zi; Cai, Wei-Jun; Xia, Jian; Jin, Daozhong; Dai, Yuqiao; Luo, Xue-Gang; Klyachko, Vitaly A.; Deng, Pan-Yue

2014-01-01

Transcriptional silencing of the Fmr1 gene encoding fragile X mental retardation protein (FMRP) causes Fragile X Syndrome (FXS), the most common form of inherited intellectual disability and the leading genetic cause of autism. FMRP has been suggested to play important roles in regulating neurotransmission and short-term synaptic plasticity at excitatory hippocampal and cortical synapses. However, the origins and the mechanisms of these FMRP actions remain incompletely understood, and the role of FMRP in regulating synaptic release probability and presynaptic function remains debated. Here we used variance-mean analysis and peak scaled nonstationary variance analysis to examine changes in both pre- and postsynaptic parameters during repetitive activity at excitatory CA3-CA1 hippocampal synapses in a mouse model of FXS. Our analyses revealed that loss of FMRP did not affect the basal release probability or basal synaptic transmission, but caused an abnormally elevated release probability specifically during repetitive activity. These abnormalities were not accompanied by changes in EPSC kinetics, quantal size or postsynaptic AMPA receptor conductance. Our results thus indicate that FMRP regulates neurotransmission at excitatory hippocampal synapses specifically during repetitive activity via modulation of release probability in a presynaptic manner. Our study suggests that FMRP function in regulating neurotransmitter release is an activity-dependent phenomenon that may contribute to the pathophysiology of FXS. PMID:24646437

Nutrients affecting brain composition and behavior

NASA Technical Reports Server (NTRS)

Wurtman, R. J.

1987-01-01

This review examines the changes in brain composition and in various brain functions, including behavior, that can follow the ingestion of particular foods or nutrients. It details those that are best understood: the increases in serotonin, catecholamine, or acetylcholine synthesis that can occur subsequent to food-induced increases in brain levels of tryptophan, tyrosine, or choline; it also discusses the various processes that must intervene between the mouth and the synapse, so to speak, in order for a nutrient to affect neurotransmission, and it speculates as to additional brain chemicals that may ultimately be found to be affected by changes in the availability of their nutrient precursors. Because the brain chemicals best known to be nutrient dependent overlap with those thought to underlie the actions of most of the drugs used to treat psychiatric diseases, knowledge of this dependence may help the psychiatrist to understand some of the pathologic processes occurring in his/her patients, particularly those with appetitive symptoms. At the very least, such knowledge should provide the psychiatrist with objective criteria for judging when to take seriously assertions that particular foods or nutrients do indeed affect behavior (e.g., in hyperactive children). If the food can be shown to alter neurotransmitter release, it may be behaviorally-active; however, if it lacks a discernible neurochemical effect, the likelihood that it really alters behavior is small.

A neuropeptide-mediated stretch response links muscle contraction to changes in neurotransmitter release

PubMed Central

Hu, Zhitao; Pym, Edward C.G.; Babu, Kavita; Vashlishan Murray, Amy B.; Kaplan, Joshua M.

2011-01-01

Although C. elegans has been utilized extensively to study synapse formation and function, relatively little is known about synaptic plasticity in C. elegans. We show that a brief treatment with the cholinesterase inhibitor aldicarb induces a form of presynaptic potentiation whereby ACh release at neuromuscular junctions (NMJs) is doubled. Aldicarb-induced potentiation was eliminated by mutations that block processing of pro-neuropeptides, by mutations inactivating a single pro-neuropeptide (NLP-12), and by those inactivating an NLP-12 receptor (CKR-2). NLP-12 expression is limited to a single stretch-activated neuron, DVA. Analysis of a YFP-tagged NLP-12 suggests that aldicarb stimulates DVA secretion of NLP-12. Mutations disrupting the DVA mechanoreceptor (TRP-4) decreased aldicarb-induced NLP-12 secretion and blocked aldicarb-induced synaptic potentiation. Mutants lacking NLP-12 or CKR-2 have decreased locomotion rates. Collectively, these results suggest that NLP-12 mediates a mechanosensory feedback loop that couples muscle contraction to changes in presynaptic release, thereby providing a mechanism for proprioceptive control of locomotion. PMID:21745640

Genetic variants of neurotransmitter-related genes and miRNAs in Egyptian autistic patients.

PubMed

Salem, Ahmed M; Ismail, Samira; Zarouk, Waheba A; Abdul Baky, Olwya; Sayed, Ahmed A; Abd El-Hamid, Sawsan; Salem, Sohair

2013-01-01

Autism is a neurodevelopmental disorder with indisputable evidence for a genetic component. This work studied the association of autism with genetic variations in neurotransmitter-related genes, including MAOA uVNTR, MAOB rs1799836, and DRD2 TaqI A in 53 autistic patients and 30 healthy individuals. The study also analyzed sequence variations of miR-431 and miR-21. MAOA uVNTR was genotyped by PCR, MAOB and DRD2 polymorphisms were analyzed by PCR-based RFLP, and miR-431 and miR-21 were sequenced. Low expressing allele of MAOA uVNTR was frequently higher in female patients compared to that in controls (OR = 2.25). MAOB G allele frequency was more significantly increased in autistic patients than in controls (P < 0.001 for both males and females). DRD2 A1+ genotype increased autism risk (OR = 5.1). Severity of autism tends to be slightly affected by MAOA/B genotype. Plasma MAOB activity was significantly reduced in G than in A allele carrying males. There was no significant difference in patients and maternal plasma MAOA/B activity compared to controls. Neither mutations nor SNPs in miR-431 and miR-21 were found among studied patients. This study threw light on some neurotransmitter-related genes suggesting their potential role in Autism pathogenesis that warrants further studies and much consideration.

Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction.

PubMed

Amenta, F; Tayebati, S K

2008-01-01

Acetylcholine (ACh) is a neurotransmitter widely diffused in central, peripheral, autonomic and enteric nervous system. This paper has reviewed the main mechanisms of ACh synthesis, storage, and release. Presynaptic choline transport supports ACh production and release, and cholinergic terminals express a unique transporter critical for neurotransmitter release. Neurons cannot synthesize choline, which is ultimately derived from the diet and is delivered through the blood stream. ACh released from cholinergic synapses is hydrolyzed by acetylcholinesterase into choline and acetyl coenzyme A and almost 50% of choline derived from ACh hydrolysis is recovered by a high-affinity choline transporter. Parallel with the development of cholinergic hypothesis of geriatric memory dysfunction, cholinergic precursor loading strategy was tried for treating cognitive impairment occurring in Alzheimer's disease. Controlled clinical studies denied clinical usefulness of choline and lecithin (phosphatidylcholine), whereas for other phospholipids involved in choline biosynthetic pathways such as cytidine 5'-diphosphocholine (CDP-choline) or alpha-glyceryl-phosphorylcholine (choline alphoscerate) a modest improvement of cognitive dysfunction in adult-onset dementia disorders is documented. These inconsistencies have probably a metabolic explanation. Free choline administration increases brain choline availability but it does not increase ACh synthesis/or release. Cholinergic precursors to serve for ACh biosynthesis should be incorporate and stored into phospholipids in brain. It is probable that appropriate ACh precursors and other correlated molecules (natural or synthesized) could represent a tool for developing therapeutic strategies by revisiting and updating treatments/supplementations coming out from this therapeutic stalemate.

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.

Noncovalent Complexation of Monoamine Neurotransmitters and Related Ammonium Ions by Tetramethoxy Tetraglucosylcalix[4]arene

NASA Astrophysics Data System (ADS)

Torvinen, Mika; Kalenius, Elina; Sansone, Francesco; Casnati, Alessandro; Jänis, Janne

2012-02-01

The noncovalent complexation of monoamine neurotransmitters and related ammonium and quaternary ammonium ions by a conformationally flexible tetramethoxy glucosylcalix[4]arene was studied by electrospray ionization Fourier transform ion cyclotron resonance (ESI-FTICR) mass spectrometry. The glucosylcalixarene exhibited highest binding affinity towards serotonin, norepinephrine, epinephrine, and dopamine. Structural properties of the guests, such as the number, location, and type of hydrogen bonding groups, length of the alkyl spacer between the ammonium head-group and the aromatic ring structure, and the degree of nitrogen substitution affected the complexation. Competition experiments and guest-exchange reactions indicated that the hydroxyl groups of guests participate in intermolecular hydrogen bonding with the glucocalixarene.

Non-quantal release of acetylcholine in rat atrial myocardium is inhibited by noradrenaline.

PubMed

Borodinova, Anastasia A; Abramochkin, Denis V; Sukhova, Galina S

2013-12-01

In the mammalian myocardium, ACh, which is the main neurotransmitter of cardiac parasympathetic postganglionic fibres, can be released via both quantal (vesicular) and non-quantal (non-vesicular) mechanisms of secretion. Non-quantal release is continuous and independent of vagus activity and exocytosis of ACh-containing vesicles. During the incubation of myocardium in the presence of acetylcholinesterase (AChE) inhibitors, non-quantal ACh release leads to accumulation of ACh in the myocardium and cholinergic effects, which are proportional to the intensity of non-quantal secretion. The aim of the present study was to reveal whether non-quantal release of ACh can be modulated by another major cardioregulator, noradrenaline, or whether it represents uncontrolled leakage of ACh from cholinergic fibres. Cholinergic changes of electrical activity induced by the AChE inhibitor paraoxon (5 × 10(-6) M) in isolated rat right atrial preparations were determined by means of a standard microlectrode technique and used as a measure of the intensity of non-quantal release. Noradrenaline (10(-7) and 10(-6) M) substantially suppressed, but did not abolish, effects of paraoxon via stimulation of α-adrenoceptors, because all experiments were conducted in the presence of the β-blocker propranolol (5 × 10(-6) M). A blocker of ganglionic transmission, hexamethonium bromide (10(-4) M), failed to alter the inhibitory effect of noradrenaline, indicating that only non-quantal ACh release is suppressed by this neurotransmitter. The effects of noradrenaline could be reduced by the α2-antagonist yohimbine (10(-6) M). However, both the α1-agonist phenylephrine (10(-6) M) and the α2-agonist clonidine (10(-6) M) significantly inhibited the cholinergic effects of paraoxon, indicating the possible involvement of both α-adrenoceptor subtypes in mediation of the adrenergic inhibition of non-quantal ACh release. Thus, cardiac non-quantal ACh release can be negatively regulated by

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

Microfabricated FSCV-Compatible Microelectrode Array for Real-time Monitoring of Heterogeneous Dopamine Release

PubMed Central

Zachek, Matthew K.; Park, Jinwoo; Takmakov, Pavel; Wightman, R. Mark; McCarty, Gregory S.

2010-01-01

Fast scan cyclic voltammetry (FSCV) has been used previously to detect neurotransmitter release and reuptake in vivo. An advantage that FSCV has over other electrochemical techniques is its ability to distinguish neurotransmitters of interest (i.e. monoamines) from their metabolites using their respective characteristic cyclic voltammogram. While much has been learned with this technique, it has generally only been used in a single working electrode arrangement. Additionally, traditional electrode fabrication techniques tend to be difficult and somewhat irreproducible. Described in this report is a fabrication method for a FSCV compatible microelectrode array (FSCV-MEA) that is capable of functioning in vivo. The microfabrication techniques employed here allow for better reproducibility than traditional fabrication methods of carbon fiber microelectrodes, and enable batch fabrication of electrode arrays. The reproducibility and electrochemical qualities of the probes were assessed along with cross talk in vitro. Heterogeneous release of electrically stimulated dopamine was observed in real-time in the striatum of an anesthetized rat using the FSCV-MEA. The heterogeneous effects of pharmacology on the striatum was also observed and shown to be consistent across multiple animals. PMID:20464031

Reduced sympathetic innervation after alteration of target cell neurotransmitter phenotype in transgenic mice.

PubMed Central

Cho, S; Son, J H; Park, D H; Aoki, C; Song, X; Smith, G P; Joh, T H

1996-01-01

Neurotransmitters play a variety of important roles during nervous system development. In the present study, we hypothesized that neurotransmitter phenotype of both projecting and target cells is an important factor for the final synaptic linkage and its specificity. To test this hypothesis, we used transgenic techniques to convert serotonin/melatonin-producing cells of the pineal gland into cells that also produce dopamine and investigated the innervation of the phenotypically altered target cells. This phenotypic alteration markedly reduced the noradrenergic innervation originating from the superior cervical ganglia. Although the mechanism by which the reduction occurs is presently unknown, quantitative enzyme-linked immunoassay showed the presence of the equivalent amounts of nerve growth factor (NGF) in the control and transgenic pineal glands, suggesting that it occurred in a NGF-independent manner. The results suggest that target neurotransmitter phenotype influences the formation of afferent connections during development. Images Fig. 3 Fig. 4 PMID:8610132

[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.

Setting accelerated dissolution test for PLGA microspheres containing peptide, investigation of critical parameters affecting drug release rate and mechanism.

PubMed

Tomic, I; Vidis-Millward, A; Mueller-Zsigmondy, M; Cardot, J-M

2016-05-30

The objective of this study was development of accelerated in vitro release method for peptide loaded PLGA microspheres using flow-through apparatus and assessment of the effect of dissolution parameters (pH, temperature, medium composition) on drug release rate and mechanism. Accelerated release conditions were set as pH 2 and 45°C, in phosphate buffer saline (PBS) 0.02M. When the pH was changed from 2 to 4, diffusion controlled phases (burst and lag) were not affected, while release rate during erosion phase decreased two-fold due to slower ester bonds hydrolyses. Decreasing temperature from 45°C to 40°C, release rate showed three-fold deceleration without significant change in release mechanism. Effect of medium composition on drug release was tested in PBS 0.01M (200 mOsm/kg) and PBS 0.01M with glucose (380 mOsm/kg). Buffer concentration significantly affected drug release rate and mechanism due to the change in osmotic pressure, while ionic strength did not have any effect on peptide release. Furthermore, dialysis sac and sample-and-separate techniques were used, in order to evaluate significance of dissolution technique choice on the release process. After fitting obtained data to different mathematical models, flow-through method was confirmed as the most appropriate for accelerated in vitro dissolution testing for a given formulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Neurotransmitter Switching? No Surprise

PubMed Central

Spitzer, Nicholas C.

2015-01-01

Among the many forms of brain plasticity, changes in synaptic strength and changes in synapse number are particularly prominent. However, evidence for neurotransmitter respecification or switching has been accumulating steadily, both in the developing nervous system and in the adult brain, with observations of transmitter addition, loss, or replacement of one transmitter with another. Natural stimuli can drive these changes in transmitter identity, with matching changes in postsynaptic transmitter receptors. Strikingly, they often convert the synapse from excitatory to inhibitory or vice versa, providing a basis for changes in behavior in those cases in which it has been examined. Progress has been made in identifying the factors that induce transmitter switching and in understanding the molecular mechanisms by which it is achieved. There are many intriguing questions to be addressed. PMID:26050033

The Dynamics of Autism Spectrum Disorders: How Neurotoxic Compounds and Neurotransmitters Interact

PubMed Central

Quaak, Ilona; Brouns, Madeleine R.; de Bor, Margot Van

2013-01-01

In recent years concern has risen about the increasing prevalence of Autism Spectrum Disorders (ASD). Accumulating evidence shows that exposure to neurotoxic compounds is related to ASD. Neurotransmitters might play a key role, as research has indicated a connection between neurotoxic compounds, neurotransmitters and ASD. In the current review a literature overview with respect to neurotoxic exposure and the effects on neurotransmitter systems is presented. The aim was to identify mechanisms and related factors which together might result in ASD. The literature reported in the current review supports the hypothesis that exposure to neurotoxic compounds can lead to alterations in the GABAergic, glutamatergic, serotonergic and dopaminergic system which have been related to ASD in previous work. However, in several studies findings were reported that are not supportive of this hypothesis. Other factors also might be related, possibly altering the mechanisms at work, such as time and length of exposure as well as dose of the compound. Future research should focus on identifying the pathway through which these factors interact with exposure to neurotoxic compounds making use of human studies. PMID:23924882

Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain.

PubMed

Kato, Yuri; Hiasa, Miki; Ichikawa, Reiko; Hasuzawa, Nao; Kadowaki, Atsushi; Iwatsuki, Ken; Shima, Kazuhiro; Endo, Yasuo; Kitahara, Yoshiro; Inoue, Tsuyoshi; Nomura, Masatoshi; Omote, Hiroshi; Moriyama, Yoshinori; Miyaji, Takaaki

2017-07-18

Despite the high incidence of neuropathic and inflammatory pain worldwide, effective drugs with few side effects are currently unavailable for the treatment of chronic pain. Recently, researchers have proposed that inhibitors of purinergic chemical transmission, which plays a key role in the pathological pain response, may allow for targeted treatment of pathological neuropathic and inflammatory pain. However, such therapeutic analgesic agents have yet to be developed. In the present study, we demonstrated that clodronate, a first-generation bisphosphonate with comparatively fewer side effects than traditional treatments, significantly attenuates neuropathic and inflammatory pain unrelated to bone abnormalities via inhibition of vesicular nucleotide transporter (VNUT), a key molecule for the initiation of purinergic chemical transmission. In vitro analyses indicated that clodronate inhibits VNUT at a half-maximal inhibitory concentration of 15.6 nM without affecting other vesicular neurotransmitter transporters, acting as an allosteric modulator through competition with Cl - A low concentration of clodronate impaired vesicular ATP release from neurons, microglia, and immune cells. In vivo analyses revealed that clodronate is more effective than other therapeutic agents in attenuating neuropathic and inflammatory pain, as well as the accompanying inflammation, in wild-type but not VNUT -/- mice, without affecting basal nociception. These findings indicate that clodronate may represent a unique treatment strategy for chronic neuropathic and inflammatory pain via inhibition of vesicular ATP release.

Flaxseed oil reduces oxidative stress and enhances brain monoamines release in streptozotocin-induced diabetic rats.

PubMed

Badawy, E A; Rasheed, W I; Elias, T R; Hussein, J; Harvi, M; Morsy, S; Mahmoud, Ya El-Latif

2015-11-01

This study was performed to investigate the biochemical effect of flaxseed oil on oxidative stress and brain monoamines release in streptozotocin-induced diabetic rats. Sixty male albino rats were divided into following four groups (15 for each group): control group, flaxseed oil group, diabetic group, and flaxseed oil-treated diabetic group. Serum glucose, insulin, pentosidine, plasma advanced oxidation protein products (AOPPs), and plasma total antioxidant capacity were estimated. Brain neurotransmitters, malondialdehyde (MDA), and nitric oxide (NO) were also determined. The mean values of serum pentosidine and plasma AOPP showed a significant decrease in treated diabetic group as compared to their values in the diabetic group. Also, brain neurotransmitters levels were improved after treatment with flaxseed. Brain MDA and NO were increased significantly in the diabetic group, while they were significantly decreased after treatment. Brain NO and brain MDA had a significant positive correlation with pentosidine, AOPP, and neurotransmitters. We concluded that flaxseed oil supplementation may be useful in the treatment of brain dysfunction in diabetes. © The Author(s) 2015.

MicroRNA's impact on neurotransmitter and neuropeptide systems: small but mighty mediators of anxiety.

PubMed

Martinetz, Stefanie

2016-06-01

Psychiatric disorders rank among the most common severe diseases worldwide, with millions of people affected worldwide every year. The symptoms are manifold, and the outcome for the patients is often unclear. As a high and yearly rising cost burden for society, anxiety disorders, depression and their related mental disorders are currently a well-researched topic in order to develop new functional pharmacological therapies as alternatives to those that are in use and bear many unpleasant side effects. Brain circuitries, such as those underlying anxiety formations, are mainly driven by the interplay of various neurotransmitter systems and the interaction of different brain loci, as well as the modulating impact of neuropeptides. Targeting those networks is a complex but promising way to regulate mood. Alterations on molecular level of the neuronal cell in response to respective receptor activation, especially at post-transcriptional level via the highly regulatory function of non-coding RNAs such as microRNAs (miRNAs) seem to hold a promising future in the development of novel therapeutic strategies and are therefore under intensified investigation. This review focusses on the impact of miRNAs on the neurotransmitter and neuropeptide systems of the central nervous system relevant for the formation of anxiety disorders and discusses the potential of miRNAs for the development of new therapeutic strategies for anxiety and mood disorders.

Visualization of Oxytocin Release that Mediates Paired Pulse Facilitation in Hypothalamic Pathways to Brainstem Autonomic Neurons

PubMed Central

Piñol, Ramón A.; Jameson, Heather; Popratiloff, Anastas; Lee, Norman H.; Mendelowitz, David

2014-01-01

Recent work has shown that oxytocin is involved in more than lactation and uterine contraction. The paraventricular nucleus of the hypothalamus (PVN) contains neuroendocrine neurons that control the release of hormones, including vasopressin and oxytocin. Other populations of PVN neurons do not release hormones, but rather project to and release neurotransmitters onto other neurons in the CNS involved in fluid retention, thermoregulation, sexual behavior and responses to stress. Activation of oxytocin receptors can be cardioprotective and reduces the adverse cardiovascular consequences of anxiety and stress, yet how oxytocin can affect heart rate and cardiac function is unknown. While anatomical work has shown the presence of peptides, including oxytocin, in the projections from the PVN to parasympathetic nuclei, electrophysiological studies to date have only demonstrated release of glutamate and activation of fast ligand gated receptors in these pathways. In this study, using rats, we directly show, using sniffer CHO cells that express oxytocin receptors and the Ca2+ indicator R-GECO, that optogenetic activation of channelrhodopsin-2 (ChR2) expressing PVN fibers in the brainstem activates oxytocin receptors in the dorsomotor nucleus of the vagus (DMNV). We also demonstrate that while a single photoactivation of PVN terminals only activates glutamatergic receptors in brainstem cardiac vagal neurons (CVNs), neurons that dominate the neural control of heart rate, both the paired pulse facilitation, and sustained enhancement of glutamate release in this pathway is mediated by activation of oxytocin receptors. Our results provide direct evidence that a pathway from the PVN likely releases oxytocin and enhances short-term plasticity of this critical autonomic connection. PMID:25379676

Spontaneous and evoked release are independently regulated at individual active zones.

PubMed

Melom, Jan E; Akbergenova, Yulia; Gavornik, Jeffrey P; Littleton, J Troy

2013-10-30

Neurotransmitter release from synaptic vesicle fusion is the fundamental mechanism for neuronal communication at synapses. Evoked release following an action potential has been well characterized for its function in activating the postsynaptic cell, but the significance of spontaneous release is less clear. Using transgenic tools to image single synaptic vesicle fusion events at individual release sites (active zones) in Drosophila, we characterized the spatial and temporal dynamics of exocytotic events that occur spontaneously or in response to an action potential. We also analyzed the relationship between these two modes of fusion at single release sites. A majority of active zones participate in both modes of fusion, although release probability is not correlated between the two modes of release and is highly variable across the population. A subset of active zones is specifically dedicated to spontaneous release, indicating a population of postsynaptic receptors is uniquely activated by this mode of vesicle fusion. Imaging synaptic transmission at individual release sites also revealed general rules for spontaneous and evoked release, and indicate that active zones with similar release probability can cluster spatially within individual synaptic boutons. These findings suggest neuronal connections contain two information channels that can be spatially segregated and independently regulated to transmit evoked or spontaneous fusion signals.

Rab3-GAP controls the progression of synaptic homeostasis at a late stage of vesicle release.

PubMed

Müller, Martin; Pym, Edward C G; Tong, Amy; Davis, Graeme W

2011-02-24

Homeostatic signaling systems stabilize neural function through the modulation of neurotransmitter receptor abundance, ion channel density, and presynaptic neurotransmitter release. Molecular mechanisms that drive these changes are being unveiled. In theory, molecular mechanisms may also exist to oppose the induction or expression of homeostatic plasticity, but these mechanisms have yet to be explored. In an ongoing electrophysiology-based genetic screen, we have tested 162 new mutations for genes involved in homeostatic signaling at the Drosophila NMJ. This screen identified a mutation in the rab3-GAP gene. We show that Rab3-GAP is necessary for the induction and expression of synaptic homeostasis. We then provide evidence that Rab3-GAP relieves an opposing influence on homeostasis that is catalyzed by Rab3 and which is independent of any change in NMJ anatomy. These data define roles for Rab3-GAP and Rab3 in synaptic homeostasis and uncover a mechanism, acting at a late stage of vesicle release, that opposes the progression of homeostatic plasticity. Copyright © 2011 Elsevier Inc. All rights reserved.

Involvement of enzymatic degradation in the inactivation of tachykinin neurotransmitters in neonatal rat spinal cord.

PubMed

Suzuki, H; Yoshioka, K; Yanagisawa, M; Urayama, O; Kurihara, T; Hosoki, R; Saito, K; Otsuka, M

1994-09-01

1. The possible involvement of enzymatic degradation in the inactivation of tachykinin neurotransmitters was examined in the spinal cord of the neonatal rat. 2. The magnitude of substance P (SP)- or neurokinin A (NKA)-evoked depolarization of a lumbar ventral root in the isolated spinal cord preparation was increased by a mixture of peptidase inhibitors, consisting of actinonin (6 microM), arphamenine B (6 microM), bestatin (10 microM), captopril (10 microM) and thiorphan (0.3 microM). The mixture augmented the response to NKA more markedly than that to SP. 3. In the isolated spinal cord-cutaneous nerve preparation, the saphenous nerve-evoked slow depolarization of the L3 ventral root was augmented by the mixture of peptidase inhibitors in the presence of naloxone (0.5 microM) but not in the presence of both naloxone and a tachykinin receptor antagonist, GR71251 (5 microM). 4. Application of capsaicin (0.5 microM) for 6 min to the spinal cord evoked an increase in the release of SP from the spinal cord. The amount of SP released was significantly augmented by the mixture of peptidase inhibitors. 5. Synaptic membrane fractions were prepared from neonatal rat spinal cords. These fractions showed degrading activities for SP and NKA and the activities were inhibited by the mixture of peptidase inhibitors. The degrading activity for NKA was higher than that for SP and the inhibitory effect of the mixture for NKA was more marked than that for SP. Although some other fractions obtained from homogenates of spinal cords showed higher degrading activities for SP, these activities were insensitive to the mixture of peptidase inhibitors. 6. Effects of individual peptidase inhibitors on the enzymatic degradation of SP and NKA by synaptic membrane fractions were examined. Thiorphan, actinonin and captopril inhibited SP degradation, while thiorphan and actinonin, but not captopril, inhibited NKA degradation. The potency of the inhibition of each peptidase inhibitor was lower than

Multiple metal exposures and their correlation with monoamine neurotransmitter metabolism in Chinese electroplating workers.

PubMed

Wu, Lin-Lin; Gong, Wei; Shen, Si-Peng; Wang, Zhong-He; Yao, Jia-Xi; Wang, Jun; Yu, Jing; Gao, Rong; Wu, Gang

2017-09-01

Excessive metal exposure has been recognized as one of the detrimental factors for brain damage. However, the potential adverse effects induced by heavy metals on monoamine neurotransmitter pathways remains poorly understood. Our study aimed to investigate the possible association between metal exposure and neurotransmitter metabolism. By a cross-sectional investigation, 224 electroplating workers and 213 non-electroplating exposure workers were recruited in the exposure and control groups. Metal exposure levels were analyzed using inductively-coupled plasma mass spectrometry and monoamine neurotransmitter pathway metabolites were measured by ultra-performance liquid chromatography tandem mass spectrometry in human urine samples. Multivariate linear regression model was used to assess the dose-response relationships of urinary metals and neurotransmitter pathway metabolites. Significant dose-dependent trends of urinary vanadium quartiles with all metabolites were observed, and the trends demonstrated significance after multiple testing correction. It also showed that urinary chromium levels were significantly associated with decreased serotonin level and cadmium was positively associated with norepinephrine and epinephrine. In addition, arsenic was positively associated with tryptophan, serotonin, dopamine and norepinephrine. Iron was positively associated with increased homovanillic acid (HVA) and epinephrine while nickel was negatively associated with increased epinephrine levels. Zinc was positively related to tryptophan, kynurenin (KYN), 5-hydroxyindole acetic acid (5-HIAA), dopamine, HVA and norepinephrine. There was no significant association between urinary copper with any other metabolites after adjusting of multiple metal models. Metal exposure may be associated with neurotransmitter metabolism disturbances. The present work is expected to provide some support in the prevention and management of metal-associated neurological diseases. Copyright © 2017

Reduction of Phosphorylated Synapsin I (Ser-553) Leads to Spatial Memory Impairment by Attenuating GABA Release after Microwave Exposure in Wistar Rats

PubMed Central

Qiao, Simo; Peng, Ruiyun; Yan, Haitao; Gao, Yabing; Wang, Changzhen; Wang, Shuiming; Zou, Yong; Xu, Xinping; Zhao, Li; Dong, Ji; Su, Zhentao; Feng, Xinxin; Wang, Lifeng; Hu, Xiangjun

2014-01-01

Background Abnormal release of neurotransmitters after microwave exposure can cause learning and memory deficits. This study investigated the mechanism of this effect by exploring the potential role of phosphorylated synapsin I (p-Syn I). Methods Wistar rats, rat hippocampal synaptosomes, and differentiated (neuronal) PC12 cells were exposed to microwave radiation for 5 min at a mean power density of 30 mW/cm2. Sham group rats, synaptosomes, and cells were otherwise identically treated and acted as controls for all of the following post-exposure analyses. Spatial learning and memory in rats was assessed using the Morris Water Maze (MWM) navigation task. The protein expression and presynaptic distribution of p-Syn I and neurotransmitter transporters were examined via western blotting and immunoelectron microscopy, respectively. Levels amino acid neurotransmitter release from rat hippocampal synaptosomes and PC12 cells were measured using high performance liquid chromatograph (HPLC) at 6 hours after exposure, with or without synapsin I silencing via shRNA transfection. Results In the rat experiments, there was a decrease in spatial memory performance after microwave exposure. The expression of p-Syn I (ser-553) was decreased at 3 days post-exposure and elevated at later time points. Vesicular GABA transporter (VGAT) was significantly elevated after exposure. The GABA release from synaptosomes was attenuated and p-Syn I (ser-553) and VGAT were both enriched in small clear synaptic vesicles, which abnormally assembled in the presynaptic terminal after exposure. In the PC12 cell experiments, the expression of p-Syn I (ser-553) and GABA release were both attenuated at 6 hours after exposure. Both microwave exposure and p-Syn I silencing reduced GABA release and maximal reduction was found for the combination of the two, indicating a synergetic effect. Conclusion p-Syn I (ser-553) was found to play a key role in the impaired GABA release and cognitive dysfunction that was

Reduction of phosphorylated synapsin I (ser-553) leads to spatial memory impairment by attenuating GABA release after microwave exposure in Wistar rats.

PubMed

Qiao, Simo; Peng, Ruiyun; Yan, Haitao; Gao, Yabing; Wang, Changzhen; Wang, Shuiming; Zou, Yong; Xu, Xinping; Zhao, Li; Dong, Ji; Su, Zhentao; Feng, Xinxin; Wang, Lifeng; Hu, Xiangjun

2014-01-01

Abnormal release of neurotransmitters after microwave exposure can cause learning and memory deficits. This study investigated the mechanism of this effect by exploring the potential role of phosphorylated synapsin I (p-Syn I). Wistar rats, rat hippocampal synaptosomes, and differentiated (neuronal) PC12 cells were exposed to microwave radiation for 5 min at a mean power density of 30 mW/cm2. Sham group rats, synaptosomes, and cells were otherwise identically treated and acted as controls for all of the following post-exposure analyses. Spatial learning and memory in rats was assessed using the Morris Water Maze (MWM) navigation task. The protein expression and presynaptic distribution of p-Syn I and neurotransmitter transporters were examined via western blotting and immunoelectron microscopy, respectively. Levels amino acid neurotransmitter release from rat hippocampal synaptosomes and PC12 cells were measured using high performance liquid chromatograph (HPLC) at 6 hours after exposure, with or without synapsin I silencing via shRNA transfection. In the rat experiments, there was a decrease in spatial memory performance after microwave exposure. The expression of p-Syn I (ser-553) was decreased at 3 days post-exposure and elevated at later time points. Vesicular GABA transporter (VGAT) was significantly elevated after exposure. The GABA release from synaptosomes was attenuated and p-Syn I (ser-553) and VGAT were both enriched in small clear synaptic vesicles, which abnormally assembled in the presynaptic terminal after exposure. In the PC12 cell experiments, the expression of p-Syn I (ser-553) and GABA release were both attenuated at 6 hours after exposure. Both microwave exposure and p-Syn I silencing reduced GABA release and maximal reduction was found for the combination of the two, indicating a synergetic effect. p-Syn I (ser-553) was found to play a key role in the impaired GABA release and cognitive dysfunction that was induced by microwave exposure.

The regulation of ATP release from the urothelium by adenosine and transepithelial potential.

PubMed

Dunning-Davies, Bryony M; Fry, Christopher H; Mansour, Dina; Ferguson, Douglas R

2013-03-01

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Stretch of the urothelium, as occurs during bladder filling, is associated with a release of ATP that is postulated to act as a sensory neurotransmitter. The regulation of ATP release is poorly understood and in particular if there is a feedback mechanism provided by ATP itself. Adenosine, a breakdown product of ATP, is a potent inhibitor of stretch-induced ATP release, acting through and A1 receptor; endogenous levels are about 0.6μM. Data are consistent with ATP release relying on the rise of intracellular Ca2+. Transepithelial potential also controls ATP release, also acting via an A1 receptor-dependent pathway. To test the hypothesis that distension-induced ATP release from the bladder urothelium is regulated by adenosine as well as changes to transurothelial potential (TEP). To examine the role of changes to intracellular [Ca(2+) ] in ATP release. Rabbit urothelium/suburothelium membranes were used in an Ussing chamber system. Distension was induced by fluid removal from the chamber bathing the serosal (basolateral) membrane face. The TEP and short-circuit current were measured. ATP was measured in samples aspirated from the serosal chamber by a luciferin-luciferase assay. Intracellular [Ca(2+) ] was measured in isolated urothelial cells using the fluorochrome Fura-2. All experiments were performed at 37°C. Distension-induced ATP release was decreased by adenosine (1-10 μm) and enhanced by adenosine deaminase and A1- (but not A2-) receptor antagonists. Distension-induced ATP release was reduced by 2-APB, nifedipine and capsazepine; capsaicin induced ATP release in the absence of distension. ATP and capsaicin, but not adenosine, generated intracellular Ca(2+) transients; adenosine did not affect the ATP-generated Ca(2+) transient. ATP release was dependent on a finite transepithelial potential. Changes to TEP, in the absence of distension, generated ATP release that was in turn reduced by adenosine

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.

One-step synthesis of magnetic chitosan for controlled release of 5-hydroxytryptophan

NASA Astrophysics Data System (ADS)

Santos Menegucci, Jucély dos; Santos, Mac-Kedson Medeiros Salviano; Dias, Diego Juscelino Santos; Chaker, Juliano Alexandre; Sousa, Marcelo Henrique

2015-04-01

In this work, nanoparticles of chitosan embedded with 25% (w/w) of iron oxide magnetic nanoparticles (magnetite/maghemite) with narrow size-distribution and with a loading efficiency of about 80% for 5-hydroxytryptophan (5-HTP), which is a chemical precursor in the biosynthesis of important neurotransmitters as serotonin, were synthesized with an initial mass ratio of 5-HTP/magnetic chitosan=1.2, using homogeneous precipitation by urea decomposition, in an efficient one-step procedure. Characterization of morphology, structure and surface were performed by XRD, TEM, FTIR, TGA, magnetization and zeta potential measurements, while drug loading and drug releasing were investigated using UV-vis spectroscopy. Kinetic drug release experiments under different pH conditions revealed a pH-sensitivecontrolled-release system, ruled by polymer swelling and/or particle dissolution.

Lignin content in natural Populus variants affects sugar release

PubMed Central

Studer, Michael H.; DeMartini, Jaclyn D.; Davis, Mark F.; Sykes, Robert W.; Davison, Brian; Keller, Martin; Tuskan, Gerald A.; Wyman, Charles E.

2011-01-01

The primary obstacle to producing renewable fuels from lignocellulosic biomass is a plant's recalcitrance to releasing sugars bound in the cell wall. From a sample set of wood cores representing 1,100 individual undomesticated Populus trichocarpa trees, 47 extreme phenotypes were selected across measured lignin content and ratio of syringyl and guaiacyl units (S/G ratio). This subset was tested for total sugar release through enzymatic hydrolysis alone as well as through combined hot-water pretreatment and enzymatic hydrolysis using a high-throughput screening method. The total amount of glucan and xylan released varied widely among samples, with total sugar yields of up to 92% of the theoretical maximum. A strong negative correlation between sugar release and lignin content was only found for pretreated samples with an S/G ratio < 2.0. For higher S/G ratios, sugar release was generally higher, and the negative influence of lignin was less pronounced. When examined separately, only glucose release was correlated with lignin content and S/G ratio in this manner, whereas xylose release depended on the S/G ratio alone. For enzymatic hydrolysis without pretreatment, sugar release increased significantly with decreasing lignin content below 20%, irrespective of the S/G ratio. Furthermore, certain samples featuring average lignin content and S/G ratios exhibited exceptional sugar release. These facts suggest that factors beyond lignin and S/G ratio influence recalcitrance to sugar release and point to a critical need for deeper understanding of cell-wall structure before plants can be rationally engineered for reduced recalcitrance and efficient biofuels production. PMID:21444820

Role of different types of Ca2+ channels and a reticulum-like Ca2+ pump in neurotransmitter release.

PubMed

Fossier, P; Baux, G; Tauc, L

1993-01-01

The factors controlling the Ca2+ concentration directly responsible for triggering acetylcholine (ACh) release were investigated at an identified neuro-neuronal synapse of the Aplysia buccal ganglion. The types of presynaptic voltage-gated Ca2+ channels associated with transmitter release were determined by using selective blockers such as nifedipine, omega-conotoxin and a partially purified extract from the venom of a funnel web spider (FTx). L-type, N-type and P-type Ca2+ channels are present in the presynaptic neuron. The influx of Ca2+ through both N- and P-types induces the release of ACh whereas Ca2+ flowing through L-type channels modulates the duration of the presynaptic action potential by controlling the Ca(2+)-dependent K+ current. tBuBHQ, a blocker of the reticulum Ca2+ pump, induces a potentiation of evoked release without modifying the presynaptic Ca2+ influx. This seems to indicate that a part of the Ca2+ entering the presynaptic terminal through N- and P-type Ca2+ channels is sequestered in a presynaptic reticulum-like Ca2+ buffer preventing these ions from contributing to ACh release. To exert its control, this Ca2+ buffer must be located close to both the presynaptic Ca2+ channels and the transmitter release mechanism.

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.

Caffeine and Cannabis Effects on Vital Neurotransmitters and Enzymes in the Brain Tissue of Juvenile Experimental Rats.

PubMed

Owolabi, J O; Olatunji, S Y; Olanrewaju, A J

2017-05-01

Caffeine and cannabis are globally consumed and abused psychoactive substances. While caffeine is legally used in various forms, including in tea and coffee as beverages, it is also consumed in soda and energy drinks as additives. Cannabis, on the other hand, is considered illegal in most countries; albeit, it is being consumed globally particularly by adolescents. The adolescent stage marks a critical stage of brain development and maturation. Influences of agents on the brain at this stage may affect neuronal structural and functional attributes. To this end, the current experiment considered the effects of cannabis and caffeine on selected key neurotransmitters and enzymes in the brain tissues after regimented caffeine and cannabis treatment for 21 days. A total of 72 juvenile Wistar rats that were approximately 40 days old were divided into 6 groups A-F. The group A served as the control. Other groups were administered various dosages of caffeine or cannabis in distilled water, using oral gavages as follows: group B animals received 100 mg/kg body weight of caffeine, group C animals received 50 mg/kg body weight of caffeine, group D animals received 500 mg/kg body weight of cannabis, group E animals received 200 mg/kg body weight of cannabis, and group F received a low dose of cannabis (200 mg/kg body weight) plus a low dose of caffeine (50 mg/kg body weight). The animals were killed by cervical dislocation 24 h after the last administration. The brain tissues were excised and homogenized. The enzymes cytochrome C oxidase and glucose-6-phosphate dehydrogenase were assayed to observe tissue energy metabolism while the neurotransmitters gamma-amino butyric acid (GABA), glutamate, and dopamine were assayed to observe the effects of the psychoactive substances on their activities relative to mental activities. GABA, glutamate, and dopamine were generally higher in the treated groups of animals. The levels of G-6-PDH were higher in all treated animals' brains

Octopamine: Presence in Single Neurons of Aplysia Suggests Neurotransmitter Function

DTIC Science & Technology

1974-10-01

responsive to octopamine than 2 any other phenylethylamine . All of these observations indicate that octopamine may function as a neurotransmitter...B., Landsberg, L. and Axelrod, J. An enzymatic assay for octop- amine and other g-hydroxylated phenylethylamines . J. Pharmacol. Exptl. Ther

Neurotransmitter modulation of extracellular H+ fluxes from isolated retinal horizontal cells of the skate

PubMed Central

Molina, Anthony J A; Verzi, Michael P; Birnbaum, Andrea D; Yamoah, Ebenezer N; Hammar, Katherine; Smith, Peter J S; Malchow, Robert Paul

2004-01-01

Self-referencing H+-selective microelectrodes were used to measure extracellular H+ fluxes from horizontal cells isolated from the skate retina. A standing H+ flux was detected from quiescent cells, indicating a higher concentration of free hydrogen ions near the extracellular surface of the cell as compared to the surrounding solution. The standing H+ flux was reduced by removal of extracellular sodium or application of 5-(N-ethyl-N-isopropyl) amiloride (EIPA), suggesting activity of a Na+–H+ exchanger. Glutamate decreased H+ flux, lowering the concentration of free hydrogen ions around the cell. AMPA/kainate receptor agonists mimicked the response, and the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) eliminated the effects of glutamate and kainate. Metabotropic glutamate agonists were without effect. Glutamate-induced alterations in H+ flux required extracellular calcium, and were abolished when cells were bathed in an alkaline Ringer solution. Increasing intracellular calcium by photolysis of the caged calcium compound NP-EGTA also altered extracellular H+ flux. Immunocytochemical localization of the plasmalemma Ca2+–H+-ATPase (PMCA pump) revealed intense labelling within the outer plexiform layer and on isolated horizontal cells. Our results suggest that glutamate modulation of H+ flux arises from calcium entry into cells with subsequent activation of the plasmalemma Ca2+–H+-ATPase. These neurotransmitter-induced changes in extracellular pH have the potential to play a modulatory role in synaptic processing in the outer retina. However, our findings argue against the hypothesis that hydrogen ions released by horizontal cells normally act as the inhibitory feedback neurotransmitter onto photoreceptor synaptic terminals to create the surround portion of the centre-surround receptive fields of retinal neurones. PMID:15272044

Kinetics, Ca2+ dependence, and biophysical properties of integrin-mediated mechanical modulation of transmitter release from frog motor nerve terminals

NASA Technical Reports Server (NTRS)

Chen, B. M.; Grinnell, A. D.

1997-01-01

Neurotransmitter release from frog motor nerve terminals is strongly modulated by change in muscle length. Over the physiological range, there is an approximately 10% increase in spontaneous and evoked release per 1% muscle stretch. Because many muscle fibers do not receive suprathreshold synaptic inputs at rest length, this stretch-induced enhancement of release constitutes a strong peripheral amplifier of the spinal stretch reflex. The stretch modulation of release is inhibited by peptides that block integrin binding of natural ligands. The modulation varies linearly with length, with a delay of no more than approximately 1-2 msec and is maintained constant at the new length. Moreover, the stretch modulation persists in a zero Ca2+ Ringer and, hence, is not dependent on Ca2+ influx through stretch activated channels. Eliminating transmembrane Ca2+ gradients and buffering intraterminal Ca2+ to approximately normal resting levels does not eliminate the modulation, suggesting that it is not the result of release of Ca2+ from internal stores. Finally, changes in temperature have no detectable effect on the kinetics of stretch-induced changes in endplate potential (EPP) amplitude or miniature EPP (mEPP) frequency. We conclude, therefore, that stretch does not act via second messenger pathways or a chemical modification of molecules involved in the release pathway. Instead, there is direct mechanical modulation of release. We postulate that tension on integrins in the presynaptic membrane is transduced mechanically into changes in the position or conformation of one or more molecules involved in neurotransmitter release, altering sensitivity to Ca2+ or the equilibrium for a critical reaction leading to vesicle fusion.

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.

Direct Visualization of Neurotransmitters in Rat Brain Slices by Desorption Electrospray Ionization Mass Spectrometry Imaging (DESI - MS)

NASA Astrophysics Data System (ADS)

Fernandes, Anna Maria A. P.; Vendramini, Pedro H.; Galaverna, Renan; Schwab, Nicolas V.; Alberici, Luciane C.; Augusti, Rodinei; Castilho, Roger F.; Eberlin, Marcos N.

2016-12-01

Mass spectrometry imaging (MSI) of neurotransmitters has so far been mainly performed by matrix-assisted laser desorption/ionization (MALDI) where derivatization reagents, deuterated matrix and/or high resolution, or tandem MS have been applied to circumvent problems with interfering ion peaks from matrix and from isobaric species. We herein describe the application of desorption electrospray ionization mass spectrometry imaging (DESI)-MSI in rat brain coronal and sagittal slices for direct spatial monitoring of neurotransmitters and choline with no need of derivatization reagents and/or deuterated materials. The amino acids γ-aminobutyric (GABA), glutamate, aspartate, serine, as well as acetylcholine, dopamine, and choline were successfully imaged using a commercial DESI source coupled to a hybrid quadrupole-Orbitrap mass spectrometer. The spatial distribution of the analyzed compounds in different brain regions was determined. We conclude that the ambient matrix-free DESI-MSI is suitable for neurotransmitter imaging and could be applied in studies that involve evaluation of imbalances in neurotransmitters levels.

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.

Effect of antiparkinson drug HP-200 (Mucuna pruriens) on the central monoaminergic neurotransmitters.

PubMed

Manyam, Bala V; Dhanasekaran, Muralikrishnan; Hare, Theodore A

2004-02-01

HP-200, which contains Mucuna pruriens endocarp, has been shown to be effective in the treatment of Parkinson's disease. Mucuna pruriens endocarp has also been shown to be more effective compared to synthetic levodopa in an animal model of Parkinson's disease. The present study was designed to elucidate the long-term effect of Mucuna pruriens endocarp in HP-200 on monoaminergic neurotransmitters and its metabolite in various regions of the rat brain. HP-200 at a dose of 2.5, 5.0 or 10.0 g/kg/day was mixed with rat chow and fed daily ad lib to Sprague-Dawley rats (n = 6 for each group) for 52 weeks. Controls (n = 6) received no drug. Random assignment was made for doses and control. The rats were sacrificed at the end of 52 weeks and the neurotransmitters were analyzed in the cortex, hippocampus, substantia nigra and striatum. Oral administration of Mucuna pruriens endocarp in the form of HP-200 had a significant effect on dopamine content in the cortex with no significant effect on levodopa, norepinephrine or dopamine, serotonin, and their metabolites- HVA, DOPAC and 5-HIAA in the nigrostriatal tract. The failure of Mucuna pruriens endocarp to significantly affect dopamine metabolism in the striatonigral tract along with its ability to improve Parkinsonian symptoms in the 6-hydorxydopamine animal model and humans may suggest that its antiparkinson effect may be due to components other than levodopa or that it has an levodopa enhancing effect. Copyright 2004 John Wiley & Sons, Ltd. Copyright 2004 John Wiley & Sons, Ltd.

The essential oil of bergamot enhances the levels of amino acid neurotransmitters in the hippocampus of rat: implication of monoterpene hydrocarbons.

PubMed

Morrone, Luigi A; Rombolà, Laura; Pelle, Cinzia; Corasaniti, Maria T; Zappettini, Simona; Paudice, Paolo; Bonanno, Giambattista; Bagetta, Giacinto

2007-04-01

The effects of bergamot essential oil (BEO) on the release of amino acid neurotransmitters in rat hippocampus have been studied by in vivo microdialysis and by in vitro superfusion of isolated nerve terminals. Intraperitoneal administration of BEO (100microl/kg) significantly elevated the extracellular concentration of aspartate, glycine and taurine in a Ca(2+)-dependent manner. A dose-relation study generated a bell-shaped curve. When perfused into the hippocampus via the dialysis probe (20microl/20min), BEO produced a significant increase of extracellular aspartate, glycine, taurine as well as of GABA and glutamate. The augmentation of all amino acids was Ca(2+)-independent. Focally injected 1:1 diluted BEO preferentially caused extracellular increase of glutamate. Interestingly, this release appeared to be strictly Ca(2+)-dependent. BEO concentration-dependently enhanced the release of [(3)H]D-aspartate from superfused hippocampal synaptosomes. Similar results were obtained by monitoring the BEO-evoked release of endogenous glutamate. At relatively high concentrations, the BEO-induced [(3)H]d-aspartate release was almost entirely prevented by the glutamate transporter blocker dl-threo-beta-benzyloxyaspartic acid (DL-TBOA) and was Ca(2+)-independent. At relatively low concentrations the release of [(3)H]D-aspartate was only in part ( approximately 50%) DL-TBOA-sensitive and Ca(2+)-independent; the remaining portion of release was dependent on extracellular Ca(2+). Interestingly, the monoterpene hydrocarbon-free fraction of the essential oil appeared to be inactive while the bergapten-free fraction superimposed the releasing effect of BEO supporting the deduction that psoralens may not be implicated. To conclude, BEO contains into its volatile fraction still unidentified monoterpene hydrocarbons able to stimulate glutamate release by transporter reversal and/or by exocytosis, depending on the dose administered.

Introduction to the Special Issue “Pharmacotherapies for the Treatment of Alcohol Abuse and Dependence” and a Summary of Patents Targeting other Neurotransmitter Systems

PubMed Central

Bell, Richard L.; Franklin, Kelle M.; Hauser, Sheketha R.; Zhou, Feng C.

2013-01-01

This paper introduces the Special Section: Pharmacotherapies for the Treatment of Alcohol Abuse and Dependence and provides a summary of patents targeting neurotransmitter systems not covered in the other four chapters. The World Health Organization notes that alcoholic-type drinking results in 2.5 million deaths per year, and these deaths occur to a disproportionately greater extent among adolescents and young adults. Developing a pharmacological treatment targeting alcohol abuse and dependence is complicated by (a) the heterogeneous nature of the disease(s), (b) alcohol affecting multiple neurotransmitter and neuromodulator systems, and (c) alcohol affecting multiple organ systems which in turn influence the function of the central nervous system. Presently, the USA Federal Drug Administration has approved three pharmacotherapies for alcoholism: disulfiram, naltrexone, and acamprosate. This chapter provides a summary of the following systems, which are not covered in the accompanying chapters; alcohol and acetaldehyde metabolism, opioid, glycinergic, GABA-A, neurosteroid, dopaminergic, serotonergic, and endocannabinoid, as well as patents targeting these systems for the treatment of alcoholism. Finally, an overview is presented on the use of pharmacogenetics and pharmacogenomics in tailoring treatments for certain subpopulations of alcoholics, which is expected to continue in the future. PMID:22574678

LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou,Z.; Zhen, J.; Karpowich, N.

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 bindingmore » 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.« less

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

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'. © 2017 The Author(s).

Evidence for a possible neurotransmitter/neuromodulator role of tyramine on the locust oviducts.

PubMed

Donini, Andrew; Lange, Angela B

2004-04-01

Visualization of the tyraminergic innervation of the oviducts was demonstrated by immunohistochemistry, and the presence of tyramine was confirmed using high-performance liquid chromatography coupled to electrochemical detection. Oviducts incubated in high-potassium saline released tyramine in a calcium-dependent manner. Stimulation of the oviducal nerves also resulted in tyramine release, suggesting that tyramine might function as a neurotransmitter/neuromodulator at the locust oviducts. Tyramine decreased the basal tension, and also attenuated proctolin-induced contractions in a dose-dependent manner over a range of doses between 10(-7) and 10(-4) M. Low concentrations of tyramine attenuated forskolin-stimulated cyclic AMP levels in a dose-dependent manner. This effect was not blocked by yohimbine. High concentrations of tyramine increased basal cyclic AMP levels of locust oviducts in a dose-dependent manner; however, the increases in cyclic AMP were only evident at the highest concentrations tested, 5 x 10(-5) and 10(-4) M tyramine. The tyramine-induced increase in cyclic AMP shared a similar pharmacological profile with the octopamine-induced increase in cyclic AMP. Tyramine increased the amplitude of excitatory junction potentials at low concentrations while hyperpolarizing the membrane potential by 2-5 mV. A further increase in the amplitude of the excitatory junction potentials and the occurrence of an active response was seen upon washing tyramine from the preparation. These results suggest that tyramine can activate at least three different endogenous receptors on the locust oviducts a putative tyramine receptor at low concentrations, a different tyramine receptor to inhibit muscle contraction, and an octopamine receptor at high concentrations.

Simultaneous monitoring of presynaptic transmitter release and postsynaptic receptor trafficking reveals an enhancement of presynaptic activity in metabotropic glutamate receptor-mediated long-term depression.

PubMed

Xu, Wei; Tse, Yiu Chung; Dobie, Frederick A; Baudry, Michel; Craig, Ann Marie; Wong, Tak Pan; Wang, Yu Tian

2013-03-27

Although the contribution of postsynaptic mechanisms to long-term synaptic plasticity has been studied extensively, understanding the contribution of presynaptic modifications to this process lags behind, primarily because of a lack of techniques with which to directly and quantifiably measure neurotransmitter release from synaptic terminals. Here, we developed a method to measure presynaptic activity through the biotinylation of vesicular transporters in vesicles fused with presynaptic membranes during neurotransmitter release. This method allowed us for the first time to selectively quantify the spontaneous or evoked release of glutamate or GABA at their respective synapses. Using this method to investigate presynaptic changes during the expression of group I metabotropic glutamate receptor (mGluR1/5)-mediated long-term depression (LTD) in cultured rat hippocampal neurons, we discovered that this form of LTD was associated with increased presynaptic release of glutamate, despite reduced miniature EPSCs measured with whole-cell recording. Moreover, we found that specific blockade of AMPA receptor (AMPAR) endocytosis with a membrane-permeable GluR2-derived peptide not only prevented the expression of LTD but also eliminated LTD-associated increase in presynaptic release. Thus, our work not only demonstrates that mGluR1/5-mediated LTD is associated with increased endocytosis of postsynaptic AMPARs but also reveals an unexpected homeostatic/compensatory increase in presynaptic release. In addition, this study indicates that biotinylation of vesicular transporters in live cultured neurons is a valuable tool for studying presynaptic function.

Cerebral taurine release mechanisms in vivo: pharmacological investigations in rats using microdialysis for proof of principle.

PubMed

Scheller, D; Korte, M; Szathmary, S; Tegtmeier, F

2000-06-01

Cerebral taurine acts as neurotransmitter, as neuromodulator, or as osmoregulator. To investigate its release mechanisms in vivo, we combined the microdialysis technique with a variety of experimental paradigms. Taurine release was stimulated by either NMDA, NO or a hypotonic solution locally with or without the addition of the NMDA antagonists APV or Ketamine, or the NO synthase inhibitor L-NAME. Alternatively, the neuroprotective drug lubeluzole was applied i.v. NMDA, NO or the hypotonic solution stimulated the release of taurine. NMDA-mediated taurine release was inhibited by either APV, Ketamine or the NO synthase inhibitor L-NAME. Lubeluzole had no effect. Under the hypotonic conditions only lubeluzole was effective. These data confirm in vivo that the NMDA-induced taurine release is mediated via the NO cascade. By contrast, the release after a hypotonic stimulus is not related to the NO cascade. Instead, Na(+)- and/or Ca(2+)-mediated events might have been attenuated by lubeluzole.

Caffeine and Cannabis Effects on Vital Neurotransmitters and Enzymes in the Brain Tissue of Juvenile Experimental Rats

PubMed Central

Owolabi, J.O.; Olatunji, S.Y.; Olanrewaju, A.J.

2017-01-01

Background Caffeine and cannabis are globally consumed and abused psychoactive substances. While caffeine is legally used in various forms, including in tea and coffee as beverages, it is also consumed in soda and energy drinks as additives. Cannabis, on the other hand, is considered illegal in most countries; albeit, it is being consumed globally particularly by adolescents. Purpose The adolescent stage marks a critical stage of brain development and maturation. Influences of agents on the brain at this stage may affect neuronal structural and functional attributes. To this end, the current experiment considered the effects of cannabis and caffeine on selected key neurotransmitters and enzymes in the brain tissues after regimented caffeine and cannabis treatment for 21 days. Methods A total of 72 juvenile Wistar rats that were approximately 40 days old were divided into 6 groups A-F. The group A served as the control. Other groups were administered various dosages of caffeine or cannabis in distilled water, using oral gavages as follows: group B animals received 100 mg/kg body weight of caffeine, group C animals received 50 mg/kg body weight of caffeine, group D animals received 500 mg/kg body weight of cannabis, group E animals received 200 mg/kg body weight of cannabis, and group F received a low dose of cannabis (200 mg/kg body weight) plus a low dose of caffeine (50 mg/kg body weight). The animals were killed by cervical dislocation 24 h after the last administration. The brain tissues were excised and homogenized. The enzymes cytochrome C oxidase and glucose-6-phosphate dehydrogenase were assayed to observe tissue energy metabolism while the neurotransmitters gamma-amino butyric acid (GABA), glutamate, and dopamine were assayed to observe the effects of the psychoactive substances on their activities relative to mental activities. Results GABA, glutamate, and dopamine were generally higher in the treated groups of animals. The levels of G-6-PDH were higher in

Acetylcholine released by endothelial cells facilitates flow‐mediated dilatation

PubMed Central

Wilson, Calum; Lee, Matthew D.

2016-01-01

Key points The endothelium plays a pivotal role in the vascular response to chemical and mechanical stimuli.The endothelium is exquisitely sensitive to ACh, although the physiological significance of ACh‐induced activation of the endothelium is unknown.In the present study, we investigated the mechanisms of flow‐mediated endothelial calcium signalling.Our data establish that flow‐mediated endothelial calcium responses arise from the autocrine action of non‐neuronal ACh released by the endothelium. Abstract Circulating blood generates frictional forces (shear stress) on the walls of blood vessels. These frictional forces critically regulate vascular function. The endothelium senses these frictional forces and, in response, releases various vasodilators that relax smooth muscle cells in a process termed flow‐mediated dilatation. Although some elements of the signalling mechanisms have been identified, precisely how flow is sensed and transduced to cause the release of relaxing factors is poorly understood. By imaging signalling in large areas of the endothelium of intact arteries, we show that the endothelium responds to flow by releasing ACh. Once liberated, ACh acts to trigger calcium release from the internal store in endothelial cells, nitric oxide production and artery relaxation. Flow‐activated release of ACh from the endothelium is non‐vesicular and occurs via organic cation transporters. ACh is generated following mitochondrial production of acetylCoA. Thus, we show ACh is an autocrine signalling molecule released from endothelial cells, and identify a new role for the classical neurotransmitter in endothelial mechanotransduction. PMID:27730645

Ca2+ Entry is Required for Mechanical Stimulation-induced ATP Release from Astrocyte

PubMed Central

Lee, Jaekwang; Chun, Ye-Eun; Han, Kyung-Seok; Lee, Jungmoo; Woo, Dong Ho

2015-01-01

Astrocytes and neurons are inseparable partners in the brain. Neurotransmitters released from neurons activate corresponding G protein-coupled receptors (GPCR) expressed in astrocytes, resulting in release of gliotransmitters such as glutamate, D-serine, and ATP. These gliotransmitters in turn influence neuronal excitability and synaptic activities. Among these gliotransmitters, ATP regulates the level of network excitability and is critically involved in sleep homeostasis and astrocytic Ca2+ oscillations. ATP is known to be released from astrocytes by Ca2+-dependent manner. However, the precise source of Ca2+, whether it is Ca2+ entry from outside of cell or from the intracellular store, is still not clear yet. Here, we performed sniffer patch to detect ATP release from astrocyte by using various stimulation. We found that ATP was not released from astrocyte when Ca2+ was released from intracellular stores by activation of Gαq-coupled GPCR including PAR1, P2YR, and B2R. More importantly, mechanical stimulation (MS)-induced ATP release from astrocyte was eliminated when external Ca2+ was omitted. Our results suggest that Ca2+ entry, but not release from intracellular Ca2+ store, is critical for MS-induced ATP release from astrocyte. PMID:25792866

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

[The association between plasma neurotransmitters levels and depression in acute hemorrhagic stroke].

PubMed

Yuan, Huai-wu; Zhang, Ning; Wang, Chun-xue; Shi, Yu-zhi; Qi, Dong; Luo, Ben-yan; Wang, Yong-jun

2013-08-01

To explore the relation between plasma neurotransmitters (Glutamic acid, GAA; γ-aminobutyric acid, GABA; 5-hydroxytryptamine, 5-HT; and noradrenaline, NE) and depression in acute hemorrhagic stroke. Objectives were screened from consecutive hospitalized patients with acute stroke. Fasting blood samples were taken on the day next to hospital admission, and neurotransmitters were examined by the liquid chromatography-high resolution mass spectrometry (LC-HRMS). The fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) was used to diagnose depression at two weeks after onset of stroke. The modified Ranking Scale (mRS) was followed up at 1 year. Pearson test was used to analyse the correlation between serum concentration of neurotransmitters and the Hamilton Depression scale-17-items (HAMD-17) score. Logistic regression was used to analyse the relation of serum concentration of neurotransmitters and depression and outcome of stroke. One hundred and eighty-one patients were included in this study. GABA significantly decreased [6.1(5.0-8.2) µg/L vs 8.1(6.3-14.7) µg/L, P < 0.05] in patients with depression in hemorrhagic stroke, and there was no significant difference in GAA, 5-HT, or NE. GABA concentration was negatively correlated with HAMD-17 score (r = -0.131, P < 0.05); while concentration of serum GABA rose by 1 µg/L, risk of depression in acute phase of hemorrhagic stroke was reduced by 5.6% (OR 0.944, 95%CI 0.893-0.997). While concentration of serum GAA rose by 1 µg/L, risk of worse outcome at 1 year was raised by 0.1%, although a statistic level was on marginal status (OR 1.001, 95%CI 1.000-1.002). In patients with depression in the acute phase of hemorrhagic stroke, there was a significant reduction in plasma GABA concentration. GABA may have a protective effect on depression in acute phase of hemorrhagic stroke. Increased concentrations of serum GAA may increase the risk of worse outcomes at 1 year after stroke.

Mechanisms of multiple neurotransmitters in the effects of Lycopene on brain injury induced by Hyperlipidemia.

PubMed

Yang, Weichun; Shen, Ziyi; Wen, Sixian; Wang, Wei; Hu, Minyu

2018-02-07

levels of LDLR, NGF, GABA, 5-HT, GABA A , 5-HT 1 , and neuron quantities in the hippocampal CA1 and CA3 areas were lower than those in the control group (P<0.05). Compared to the CCT group, levels of TC, TG, LDL-C, IL-1, TNF-α, and ox-LDL in the serum and brain, as well as the content of Glu, DA and the expression of pro-apoptotic Caspase3 in the brain decreased in the rats with lycopene (25 mg to 85 mg) added to the diet (P<0.05); the levels of LDLR, NGF, GABA, 5-HT, GABA A , and 5-HT 1 as well as the expression of anti-apoptotic bcl-2 and the neuron quantity in hippocampal CA1 and CA3 areas increased (P<0.05); further, the hippocampal cells were closely arranged. Lycopene dose was negatively correlated with the levels of TC, TG, and LDL-C in the serum and brain as well as levels of IL-1, TNF-α, ox-LDL, Glu/GABA, NMDA1R, and Caspase3 (P<0.05); it was positively correlated with the levels of LDLR, NGF, 5-HT, 5-HT 1 , GABA A , bcl-2, and the neuron quantity in hippocampal CA1 and CA3 areas (P<0.05). Lycopene exerts anti-injury effects in the brain as-induced by hyperlipidemia. It can inhibit the elevation of serum TC, TG, and LDL-C in rats with hyperlipidemia while indirectly affecting the levels of TC, TG, and LDL-C in the brain, leading to a reduction in ox-LDL, IL-1, and TNF-α in the brain. This inhibits the release of Glu, which weakens nerve toxicity and downregulates pro-apoptotic Caspase3. Lycopene also plays an anti-injury role by promoting the release of the inhibitory neurotransmitter GABA and 5-HT, which enhances the protective effect, and by upregulating the anti-apoptotic bcl-2.

Conditions affecting the release of phosphorus from surface lake sediments.

PubMed

Christophoridis, Christophoros; Fytianos, Konstantinos

2006-01-01

Laboratory studies were conducted to determine the effect of pH and redox conditions, as well as the effect of Fe, Mn, Ca, Al, and organic matter, on the release of ortho-phosphates in lake sediments taken from Lakes Koronia and Volvi (Northern Greece). Results were evaluated in combination with experiments to determine P fractionation in the sediment. The study revealed the major effect of redox potential and pH on the release of P from lake sediments. Both lakes showed increased release rates under reductive conditions and high pH values. The fractionation experiments revealed increased mobility of the reductive P fraction as well as of the NaOH-P fraction, indicating participation of both fractions in the overall release of sediment-bound P, depending on the prevailing environmental conditions. The results were assessed in combination with the release patterns of Fe, Mn, Ca, Al, and organic matter, enabling the identification of more specific processes of P release for each lake. The basic release patterns included the redox induced reductive dissolution of P-bearing metal oxides and the competitive exchange of phosphate anions with OH- at high pH values. The formation of an oxidized surface microlayer under oxic conditions acted as a protective film, preventing further P release from the sediments of Lake Volvi, while sediments from Lake Koronia exhibited a continuous and increased tendency to release P under various physicochemical conditions, acting as a constant source of internal P loading.

Laser R2PI spectroscopic and mass spectrometric studies of chiral neurotransmitters

NASA Astrophysics Data System (ADS)

Giardini, A.; Marotta, V.; Paladini, A.; Piccirillo, S.; Rondino, F.; Satta, M.; Speranza, M.

2007-07-01

One color, mass selected resonant two-photon ionization (1cR2PI) spectra of supersonically expanded bare neurotransmitter, (1 S,2 S)-(+)- N-methyl pseudoephedrine (MPE), and its complexes with chiral and achiral molecules have been investigated. The excitation spectrum of bare MPE has been analyzed and discussed on the basis of theoretical predictions at the B3LYP/6-31G** level of theory. The results allowed to get information on the possible conformers of MPE molecule and on the intermolecular forces on its cluster formed with a variety of solvent molecules, including chiral alcohols, lactates and water. Further information on intermolecular interactions have been obtained with ESI-CID-MS 2 technique, applied to chiral biomolecules linked through a metal ion to the neurotransmitter. The experimental results are compared with theoretical predictions.

Involvement of P-type Ca2+ channels in the K(+)- and d-fenfluramine-induced [3H]5-HT release from rat hippocampal synaptosomes.

PubMed

Frittoli, E; Gobbi, M; Mennini, T

1994-06-01

The Ca2(+)-dependent [3H]5-HT release induced by depolarization or by 0.5 microM d-fenfluramine in rat hippocampal synaptosomes, was significantly reduced (35-42%) by three different P-type Ca2+ channels blockers (omega-Agatoxin-IVA, 100 nM, funnel-web spider toxin, FTX, 0.05 microliters/ml, and its synthetic analogue, sFTX, 1 mM), indicating the major role of these channels in the Ca2+ influx preceding neurotransmitter release.

Seasonal Affective Disorder

PubMed Central

Rohan, Kelly J.

2005-01-01

Seasonal affective disorder (SAD), characterized by fall/winter major depression with spring/summer remission, is a prevalent mental health problem. SAD etiology is not certain, but available models focus on neurotransmitters, hormones, circadian rhythm dysregulation, genetic polymorphisms, and psychological factors. Light therapy is established as the best available treatment for SAD. Alternative and/or supplementary approaches involving medications, cognitive-behavioral therapy, and exercise are currently being developed and evaluated. Given the complexity of the disorder, interdisciplinary research stands to make a significant contribution to advancing our understanding of SAD conceptualization and treatment. PMID:21179639

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. Published by Elsevier Inc.

Nonsynaptic glycine release is involved in the early KCC2 expression.

PubMed

Allain, Anne-Emilie; Cazenave, William; Delpy, Alain; Exertier, Prisca; Barthe, Christophe; Meyrand, Pierre; Cattaert, Daniel; Branchereau, Pascal

2016-07-01

The cation-chloride co-transporters are important regulators of the cellular Cl(-) homeostasis. Among them the Na(+) -K(+) -2Cl(-) co-transporter (NKCC1) is responsible for intracellular chloride accumulation in most immature brain structures, whereas the K(+) -Cl(-) co-transporter (KCC2) extrudes chloride from mature neurons, ensuring chloride-mediated inhibitory effects of GABA/glycine. We have shown that both KCC2 and NKCC1 are expressed at early embryonic stages (E11.5) in the ventral spinal cord (SC). The mechanisms by which KCC2 is prematurely expressed are unknown. In this study, we found that chronically blocking glycine receptors (GlyR) by strychnine led to a loss of KCC2 expression, without affecting NKCC1 level. This effect was not dependent on the firing of Na(+) action potentials but was mimicked by a Ca(2+) -dependent PKC blocker. Blocking the vesicular release of neurotransmitters did not impinge on strychnine effect whereas blocking volume-sensitive outwardly rectifying (VSOR) chloride channels reproduced the GlyR blockade, suggesting that KCC2 is controlled by a glycine release from progenitor radial cells in immature ventral spinal networks. Finally, we showed that the strychnine treatment prevented the maturation of rhythmic spontaneous activity. Thereby, the GlyR-activation is a necessary developmental process for the expression of functional spinal motor networks. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 764-779, 2016. © 2015 Wiley Periodicals, Inc.

Reduced signal crosstalk multi neurotransmitter image sensor by microhole array structure

NASA Astrophysics Data System (ADS)

Ogaeri, Yuta; Lee, You-Na; Mitsudome, Masato; Iwata, Tatsuya; Takahashi, Kazuhiro; Sawada, Kazuaki

2018-06-01

A microhole array structure combined with an enzyme immobilization method using magnetic beads can enhance the target discernment capability of a multi neurotransmitter image sensor. Here we report the fabrication and evaluation of the H+-diffusion-preventing capability of the sensor with the array structure. The structure with an SU-8 photoresist has holes with a size of 24.5 × 31.6 µm2. Sensors were prepared with the array structure of three different heights: 0, 15, and 60 µm. When the sensor has the structure of 60 µm height, 48% reduced output voltage is measured at a H+-sensitive null pixel that is located 75 µm from the acetylcholinesterase (AChE)-immobilized pixel, which is the starting point of H+ diffusion. The suppressed H+ immigration is shown in a two-dimensional (2D) image in real time. The sensor parameters, such as height of the array structure and measuring time, are optimized experimentally. The sensor is expected to effectively distinguish various neurotransmitters in biological samples.

Characterization of noradrenaline release in the locus coeruleus of freely moving awake rats by in vivo microdialysis.

PubMed

Fernández-Pastor, Begoña; Mateo, Yolanda; Gómez-Urquijo, Sonia; Javier Meana, J

2005-07-01

The origin and regulation of noradrenaline (NA) in the locus coeruleus (LC) is unknown. The neurochemical features of NA overflow (nerve impulse dependence, neurotransmitter synthesis, vesicle storage, reuptake, alpha2-adrenoceptor-mediated regulation) were characterized in the LC. Brain microdialysis was performed in awake rats. Dialysates were analyzed for NA. NA in the LC decreased via local infusion of Ca2+-free medium (-42+/-5%) or the sodium channel blocker tetrodotoxine (TTX) (-47+/-8%) but increased (333+/-40%) via KCl-induced depolarization. The tyrosine hydroxylase (TH) inhibitor alpha-methyl-p-tyrosine (250 mg kg(-1), i.p.) and the vesicle depletory drug reserpine (5 mg kg(-1), i.p.) decreased NA. Therefore, extracellular NA in the LC satisfies the criteria for an impulse flow-dependent vesicular exocytosis of neuronal origin. Local perfusion of the alpha2-adrenoceptor agonist clonidine (0.1-100 microM) decreased NA (E(max)=-79+/-5%) in the LC, whereas the opposite effect (E(max)=268+/-53%) was observed with the alpha2A-adrenoceptor antagonist BRL44408 (0.1-100 microM). This suggests a tonic modulation of NA release through local alpha2A-adrenoceptors. The selective NA reuptake inhibitor desipramine (DMI) (0.1-100 microM) administered into the LC increased NA in the LC (E(max)=223+/-40%) and simultaneously decreased NA in the cingulate cortex, confirming the modulation exerted by NA in the LC on firing activity of noradrenergic cells and on the subsequent NA release in noradrenergic terminals. Synaptic processes underlying NA release in the LC are similar to those in noradrenergic terminal areas. NA in the LC could represent local somatodendritic release, but also the presence of neurotransmitter release from collateral axon terminals.

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).

Growth hormone-releasing peptides.

PubMed

Ghigo, E; Arvat, E; Muccioli, G; Camanni, F

1997-05-01

decreases thereafter. By the sixth decade of life, the activity of GHRPs is reduced but it is still marked and higher than that of GHRH. The GH-releasing activity of GHRPs is synergistic with that of GHRH, is not affected by opioid receptor antagonists, such as naloxone, and is only blunted by inhibitory influences, including neurotransmitters, glucose, free fatty acids, gluco corticoids, recombinant human GH and even exogenous somatostatin, which are known to almost abolish the effect of GHRH. GHRPs maintain their GH-releasing effect in somatotrope hypersecretory states such as in acromegaly, anorexia nervosa and hyperthyroidism. On the other hand, their good GH-releasing activity has been shown in some but not in other somatotrope hyposecretory states. In fact, reduced GH responses after GHRP administration have been reported in idiopathic GH deficiency as well as in idiopathic short stature, in obesity and in hypothyroidism, while in patients with pituitary stalk disconnection or Cushing's syndrome the somatotrope responsiveness to GHRPs is almost absent. In short children an increase in height velocity has also been reported during chronic GHRP treatment. Thus, based on their marked GH-releasing effect even after oral administration, GHRPs offer their own clinical usefulness for treatment of some GH hyposecretory states.

Dual-Functionalization Device for Therapy through Dopamine Release and Monitoring.

PubMed

Fabregat, Georgina; Giménez, Alessia; Díaz, Angélica; Puiggalí, Jordi; Alemán, Carlos

2018-05-01

A dual-functional device is fabricated to release progressively dopamine (DA) from a biohydrogel under real-time monitoring via electrochemical detection. For this purpose, a poly-γ-glutamic acid biohydrogel is assembled with a poly(3,4-ethylenedioxythiophene) (PEDOT) layer, previously deposited onto a screen printed electrode. The biohydrogel is formulated to achieve dimensional stability and maximum DA-loading capacity. Conditions for DA-loading are influenced by the oxidation of the neurotransmitter in acid environments and the poor resistance of PEDOT to the lyophilization. The performance of the device is proved in a medium with the physiological pH of blood and the cerebrospinal fluid. The progressive release of DA is successfully monitored by the device, the limit of detection and sensitivity of the integrated sensor being 450 × 10 -9 m and 8 × 10 -5 mA µm -1 , respectively. The effect of electrochemical stimulation in the kinetics of the DA release is also investigated applying potential ramps in cyclic phase to alter the biohydrogel morphology. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The release of acetylcholine from post-ganglionic cell bodies in response to depolarization.

PubMed Central

Johnson, D A; Pilar, G

1980-01-01

1. Acetylcholine (Ach) release from parasympathetic ganglia cell somata was investigated in denervated avian ciliary ganglia. Three days after the input to the ganglion (the oculomotor nerve) was sectioned, all presynaptic nerve terminals had degenerated. 2. Denervated ganglia were shown to contain endogenous ACh and to be capable of synthesizing [3H]ACh from [3H]choline added to the incubation medium. 3. In response to depolarization induced by incubation in 50 mM-[K+]o, denervated ganglia released [3H]ACh into bath effluents in amounts approximately 15% of the non-denervated contralateral control. This release was shown to be Ca2+ dependent in both intact and denervated ganglia. 4. Antidromic electrical stimulation of ciliary nerves also elicited [3H]ACh release. Nicotine (1 microgram/microliter.) depolarized denervated ciliary ganglion cells and evoked release of the transmitter and this release was antagonized by curare. 5. It is concluded that the ganglionic cell bodies sysnthesized ACh and released the transmitter in response to K+ depolarization, antidromic stimulation and cholinergic agonists, despite the lack of morphological specializations usually associated with stimulus-induced release of neurotransmitter. The evidence suggests the existence of a mechanism of transmitter release which is Ca2+ dependent, probably from a cytoplasmic pool and therefore distinct from the usual vesicular release at the nerve terminal. Images Plate 1 Plate 2 PMID:6247485

Modulating dopamine release by optogenetics in transgenic mice reveals terminal dopaminergic dynamics

PubMed Central

Lu, Yao; Driscoll, Nicolette; Ozden, Ilker; Yu, Zeyang; Nurmikko, Arto V.

2015-01-01

Abstract. Dopamine (DA) release and uptake dynamics in the nucleus accumbens (NAc) have important implications for neurological diseases and mammalian animal behaviors. We demonstrate here the use of cell-type-specific optogenetic targeting in conjunction with fast-scan cyclic voltammetry applied to brain slices prepared from specifically tailored transgenic mice, which conditionally express channelrhodopsin-2 (ChR2) through dopamine transporter (DAT)-Cre. Terminal dopaminergic dynamics and the direct manipulation of induced DA release level by controlling light intensity, pulse width, and the shape of stimulation waveforms were studied. Effective cell terminal-targeting optogenetic induction of DA release at physiological levels in NAc is demonstrated and discussed. It was found that delivering more light energy by increasing stimulation intensity and length is not the only way to control DA release; the temporal shape of the stimulus waveform at light onset is also critically related to induced DA concentrations. In addition, DA uptake dynamics as well as the recovery of the presynaptic releasable DA pool are studied and modeled. More broadly, our experimental findings provide important further evidence for effectively applying optogenetics to induce neurotransmitter release in the behaviorally relevant region of the brain in a highly cell-type selective context. PMID:26171413

Immunoglobulin Fc gamma receptor promotes immunoglobulin uptake, immunoglobulin-mediated calcium increase, and neurotransmitter release in motor neurons

NASA Technical Reports Server (NTRS)

Mohamed, Habib A.; Mosier, Dennis R.; Zou, Ling L.; Siklos, Laszlo; Alexianu, Maria E.; Engelhardt, Jozsef I.; Beers, David R.; Le, Wei-dong; Appel, Stanley H.

2002-01-01

Receptors for the Fc portion of immunoglobulin G (IgG; FcgammaRs) facilitate IgG uptake by effector cells as well as cellular responses initiated by IgG binding. In earlier studies, we demonstrated that amyotrophic lateral sclerosis (ALS) patient IgG can be taken up by motor neuron terminals and transported retrogradely to the cell body and can alter the function of neuromuscular synapses, such as increasing intracellular calcium and spontaneous transmitter release from motor axon terminals after passive transfer. In the present study, we examined whether FcgammaR-mediated processes can contribute to these effects of ALS patient immunoglobulins. F(ab')(2) fragments (which lack the Fc portion) of ALS patient IgG were not taken up by motor axon terminals and were not retrogradely transported. Furthermore, in a genetically modified mouse lacking the gamma subunit of the FcR, the uptake of whole ALS IgG and its ability to enhance intracellular calcium and acetylcholine release were markedly attenuated. These data suggest that FcgammaRs appear to participate in IgG uptake into motor neurons as well as IgG-mediated increases in intracellular calcium and acetylcholine release from motor axon terminals. Copyright 2002 Wiley-Liss, Inc.

Stress modulation of cognitive and affective processes

PubMed Central

CAMPEAU, SERGE; LIBERZON, ISRAEL; MORILAK, DAVID; RESSLER, KERRY

2012-01-01

This review summarizes the major discussion points of a symposium on stress modulation of cognitive and affective processes, which was held during the 2010 workshop on the neurobiology of stress (Boulder, CO, USA). The four discussants addressed a number of specific cognitive and affective factors that are modulated by exposure to acute or repeated stress. Dr David Morilak discussed the effects of various repeated stress situations on cognitive flexibility, as assessed with a rodent model of attentional set-shifting task, and how performance on slightly different aspects of this test is modulated by different prefrontal regions through monoaminergic neurotransmission. Dr Serge Campeau summarized the findings of several studies exploring a number of factors and brain regions that regulate habituation of various autonomic and neuroendocrine responses to repeated audiogenic stress exposures. Dr Kerry Ressler discussed a body of work exploring the modulation and extinction of fear memories in rodents and humans, especially focusing on the role of key neurotransmitter systems including excitatory amino acids and brain-derived neurotrophic factor. Dr Israel Liberzon presented recent results on human decision-making processes in response to exogenous glucocorticoid hormone administration. Overall, these discussions are casting a wider framework on the cognitive/affective processes that are distinctly regulated by the experience of stress and some of the brain regions and neurotransmitter systems associated with these effects. PMID:21790481

Benzo[a]pyrene-induced neurobehavioral function and neurotransmitter alterations in coke oven workers.

PubMed

Niu, Qiao; Zhang, Hongmei; Li, Xin; Li, Meiqin

2010-07-01

To study alterations in neurobehavioral function and neurotransmitter levels in coke oven workers occupationally exposed to benzo[a]pyrene (B[a]P) and explore possible biomarkers of B[a]P neurotoxicity. 176 coke oven workers occupationally exposed to B[a]P and 48 warehouse workers (controls) were investigated by questionnaire. Emotional and cognitive function was investigated using the WHO/NCTB. B[a]P concentrations in the working environment, concentrations of monoamine and amino acid neurotransmitters, and levels of urinary 1-hydroxypyrene (1-OH-Py) were assayed by HPLC. Spectrophotometry was used to determine choline neurotransmitter concentrations. Airborne B[a]P concentrations were higher in the coke oven plant than in the controls' workplace, and 1-OH-Py levels were significantly increased in coke workers compared to controls (p=0.000). Digital span and order digital span scores indicated that learning and memory were significantly decreased in coke oven workers (p=0.006). Concentrations of norepinephrine (NE), dopamine, 5-hydroxytryptamine and homovanillic acid were lower, while levels of 5-hydroxyindoleacetic acid were higher in the exposed group compared to controls; the difference in NE was significant (p=0.000). Aspartic acid and gamma-aminobutyric acid levels were significantly decreased in coke oven workers compared to controls (p=0.004 and p=0.004). Acetylcholine (Ach) concentration was four- to fivefold greater in coke oven workers than in controls, while acetylcholine esterase (AchE) activity was significantly decreased (p=0.000 and p=0.012). Statistical analysis showed that digital span and order digital span scores were negatively correlated to Ach and positively correlated to AchE. Occupational B[a]P exposure may reduce coke oven workers' neurobehavioral function and monoamine, amino acid and choline neurotransmitter levels. Moreover, Ach and AchE correlated with neurobehavioral function; AchE has poor specificity, but Ach is a potential

Valine but not leucine or isoleucine supports neurotransmitter glutamate synthesis during synaptic activity in cultured cerebellar neurons.

PubMed

Bak, Lasse K; Johansen, Maja L; Schousboe, Arne; Waagepetersen, Helle S

2012-09-01

Synthesis of neuronal glutamate from α-ketoglutarate for neurotransmission necessitates an amino group nitrogen donor; however, it is not clear which amino acid(s) serves this role. Thus, the ability of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine, to act as amino group nitrogen donors for synthesis of vesicular neurotransmitter glutamate was investigated in cultured mouse cerebellar (primarily glutamatergic) neurons. The cultures were superfused in the presence of (15) N-labeled BCAAs, and synaptic activity was induced by pulses of N-methyl-D-aspartate (300 μM), which results in release of vesicular glutamate. At the end of the superfusion experiment, the vesicular pool of glutamate was released by treatment with α-latrotoxin (3 nM, 5 min). This experimental paradigm allows a separate analysis of the cytoplasmic and vesicular pools of glutamate. Amount and extent of (15) N labeling of intracellular amino acids plus vesicular glutamate were analyzed employing HPLC and LC-MS analysis. Only when [(15) N]valine served as precursor did the labeling of both cytoplasmic and vesicular glutamate increase after synaptic activity. In addition, only [(15) N]valine was able to maintain the amount of vesicular glutamate during synaptic activity. This indicates that, among the BCAAs, only valine supports the increased need for synthesis of vesicular glutamate. Copyright © 2012 Wiley Periodicals, Inc.

Serotonin and dopamine differentially affect appetitive and aversive general Pavlovian-to-instrumental transfer.

PubMed

Hebart, Martin N; Gläscher, Jan

2015-01-01

Human motivation and decision-making is influenced by the interaction of Pavlovian and instrumental systems. The neurotransmitters dopamine and serotonin have been suggested to play a major role in motivation and decision-making, but how they affect this interaction in humans is largely unknown. We investigated the effect of these neurotransmitters in a general Pavlovian-to-instrumental transfer (PIT) task which measured the nonspecific effect of appetitive and aversive Pavlovian cues on instrumental responses. For that purpose, we used selective dietary depletion of the amino acid precursors of serotonin and dopamine: tryptophan (n = 34) and tyrosine/phenylalanine (n = 35), respectively, and compared the performance of these groups to a control group (n = 34) receiving a nondepleted (balanced) amino acid drink. We found that PIT differed between groups: Relative to the control group that exhibited only appetitive PIT, we found reduced appetitive PIT in the tyrosine/phenylalanine-depleted group and enhanced aversive PIT in the tryptophan-depleted group. These results demonstrate a differential involvement of serotonin and dopamine in motivated behavior. They suggest that reductions in serotonin enhance the motivational influence of aversive stimuli on instrumental behavior and do not affect the influence of appetitive stimuli, while reductions in dopamine diminish the influence of appetitive stimuli. No conclusions could be drawn about how dopamine affects the influence of aversive stimuli. The interplay of both neurotransmitter systems allows for flexible and adaptive responses depending on the behavioral context.

Physiological Concentrations of Amyloid Beta Regulate Recycling of Synaptic Vesicles via Alpha7 Acetylcholine Receptor and CDK5/Calcineurin Signaling

PubMed Central

Lazarevic, Vesna; Fieńko, Sandra; Andres-Alonso, Maria; Anni, Daniela; Ivanova, Daniela; Montenegro-Venegas, Carolina; Gundelfinger, Eckart D.; Cousin, Michael A.; Fejtova, Anna

2017-01-01

Despite the central role of amyloid β (Aβ) peptide in the etiopathogenesis of Alzheimer’s disease (AD), its physiological function in healthy brain is still debated. It is well established that elevated levels of Aβ induce synaptic depression and dismantling, connected with neurotoxicity and neuronal loss. Growing evidence suggests a positive regulatory effect of Aβ on synaptic function and cognition; however the exact cellular and molecular correlates are still unclear. In this work, we tested the effect of physiological concentrations of Aβ species of endogenous origin on neurotransmitter release in rat cortical and hippocampal neurons grown in dissociated cultures. Modulation of production and degradation of the endogenous Aβ species as well as applications of the synthetic rodent Aβ40 and Aβ42 affected efficacy of neurotransmitter release from individual presynapses. Low picomolar Aβ40 and Aβ42 increased, while Aβ depletion or application of low micromolar concentration decreased synaptic vesicle recycling, showing a hormetic effect of Aβ on neurotransmitter release. These Aβ-mediated modulations required functional alpha7 acetylcholine receptors as well as extracellular and intracellular calcium, involved regulation of CDK5 and calcineurin signaling and increased recycling of synaptic vesicles. These data indicate that Aβ regulates neurotransmitter release from presynapse and suggest that failure of the normal physiological function of Aβ in the fine-tuning of SV cycling could disrupt synaptic function and homeostasis, which would, eventually, lead to cognitive decline and neurodegeneration. PMID:28785201

BDE99 (2,2',4,4',5-pentabromodiphenyl ether) suppresses differentiation into neurotransmitter phenotypes in PC12 cells.

PubMed

Slotkin, Theodore A; Card, Jennifer; Infante, Alice; Seidler, Frederic J

2013-01-01

Early-life exposures to brominated diphenyl ethers (BDEs) lead to neurobehavioral abnormalities later in life. Although these agents are thyroid disruptors, it is not clear whether this mechanism alone accounts for the adverse effects. We evaluated the impact of 2,2',4,4',5-pentabromodiphenyl ether (BDE99) on PC12 cells undergoing neurodifferentiation, contrasting the effects with chlorpyrifos, a known developmental neurotoxicant. BDE99 elicited decrements in the number of cells, evidenced by a reduction in DNA levels, to a lesser extent than did chlorpyrifos. This did not reflect cytotoxicity from oxidative stress, since cell enlargement, monitored by the total protein/DNA ratio, was not only unimpaired by BDE99, but was actually enhanced. Importantly, BDE99 impaired neurodifferentiation into both the dopamine and acetylcholine neurotransmitter phenotypes. The cholinergic phenotype was affected to a greater extent, so that neurotransmitter fate was diverted away from acetylcholine and toward dopamine. Chlorpyrifos produced the same imbalance, but through a different underlying mechanism, promoting dopaminergic development at the expense of cholinergic development. In our earlier work, we did not find these effects with BDE47, a BDE that has greater endocrine disrupting and cytotoxic effects than BDE99. Thus, our results point to interference with neurodifferentiation by specific BDE congeners, distinct from cytotoxic or endocrine mechanisms. Copyright © 2013 Elsevier Inc. All rights reserved.

Trans-synaptic (GABA-dopamine) modulation of cocaine induced dopamine release: A potential therapeutic strategy for cocaine abuse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dewey, S.L.; Straughter-Moore, R.; Chen, R.

We recently developed a new experimental strategy for measuring interactions between functionally-linked neurotransmitter systems in the primate and human brain with PET. As part of this research, we demonstrated that increases in endogenous GABA concentrations significantly reduced striatal dopamine concentrations in the primate brain. We report here the application of the neurotransmitter interaction paradigm with PET and with microdialysis to the investigation of a novel therapeutic strategy for treating cocaine abuse based on the ability of GABA to inhibit cocaine induced increases in striatal dopamine. Using gamma-vinyl GABA (GVG, a suicide inhibitor of GABA transaminase), we performed a series ofmore » PET studies where animals received a baseline PET scan with labeled raclopride injection, animals received cocaine (2.0 mg/kg). Normally, a cocaine challenge significantly reduces the striatal binding of {sup 11}C-raclopride. However, in animals pretreated with GVG, {sup 11}C-raclopride binding was less affected by a cocaine challenge compared to control studies. Furthermore, microdialysis studies in freely moving rats demonstrate that GVG (300 mg/kg) significantly inhibited cocaine-induced increases in extracellular dopamine release. GVG also attenuated cocaine-induced increases in locomotor activity. However, at a dose of 100 mg/kg, GVG had no effect. Similar findings were obtained with alcohol. Alcohol pretreatment dose dependantly (1-4 g/kg) inhibited cocaine-induced increases in extracellular dopamine concentrations in freely moving rats. Taken together, these studies suggest that therapeutic strategies targeted at increasing central GABA concentrations may be beneficial for the treatment of cocaine abuse.« less

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.

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.

Do soft drinks affect metal ions release from orthodontic appliances?

PubMed

Mikulewicz, Marcin; Wołowiec, Paulina; Loster, Bartłomiej W; Chojnacka, Katarzyna

2015-01-01

The effect of orange juice and Coca Cola(®) on the release of metal ions from fixed orthodontic appliances. A continuous flow system designed for in vitro testing of orthodontic appliances was used. Orange juice/Coca Cola(®) was flowing through the system alternately with artificial saliva for 5.5 and 18.5h, respectively. The collected samples underwent a multielemental ICP-OES analysis in order to determine the metal ions release pattern in time. The total mass of ions released from the appliance into orange juice and Coca Cola(®) (respectively) during the experiment was calculated (μg): Ni (15.33; 37.75), Cr (3.604; 1.052), Fe (48.42; ≥ 156.1), Cu (57.87, 32.91), Mn (9.164; 41.16), Mo (9.999; 30.12), and Cd (0.5967; 2.173). It was found that orange juice did not intensify the release of metal ions from orthodontic appliances, whereas Coca Cola(®) caused increased release of Ni ions. Copyright © 2015 Elsevier GmbH. All rights reserved.

Detection of neurotransmitters by a light scattering technique based on seed-mediated growth of gold nanoparticles

NASA Astrophysics Data System (ADS)

Shang, Li; Dong, Shaojun

2008-03-01

A simple light scattering detection method for neurotransmitters has been developed, based on the growth of gold nanoparticles. Neurotransmitters (dopamine, L-dopa, noradrenaline and adrenaline) can effectively function as active reducing agents for generating gold nanoparticles, which result in enhanced light scattering signals. The strong light scattering of gold nanoparticles then allows the quantitative detection of the neurotransmitters simply by using a common spectrofluorometer. In particular, Au-nanoparticle seeds were added to facilitate the growth of nanoparticles, which was found to enhance the sensing performance greatly. Using this light scattering technique based on the seed-mediated growth of gold nanoparticles, detection limits of 4.4 × 10-7 M, 3.5 × 10-7 M, 4.1 × 10-7 M, and 7.7 × 10-7 M were achieved for dopamine, L-dopa, noradrenaline and adrenaline, respectively. The present strategy can be extended to detect other biologically important molecules in a very fast, simple and sensitive way, and may have potential applications in a wide range of fields.

Detection of amino acid neurotransmitters by surface enhanced Raman scattering and hollow core photonic crystal fiber

NASA Astrophysics Data System (ADS)

Tiwari, Vidhu S.; Khetani, Altaf; Monfared, Ali Momenpour T.; Smith, Brett; Anis, Hanan; Trudeau, Vance L.

2012-03-01

The present work explores the feasibility of using surface enhanced Raman scattering (SERS) for detecting the neurotransmitters such as glutamate (GLU) and gamma-amino butyric acid (GABA). These amino acid neurotransmitters that respectively mediate fast excitatory and inhibitory neurotransmission in the brain, are important for neuroendocrine control, and upsets in their synthesis are also linked to epilepsy. Our SERS-based detection scheme enabled the detection of low amounts of GLU (10-7 M) and GABA (10-4 M). It may complement existing techniques for characterizing such kinds of neurotransmitters that include high-performance liquid chromatography (HPLC) or mass spectrography (MS). This is mainly because SERS has other advantages such as ease of sample preparation, molecular specificity and sensitivity, thus making it potentially applicable to characterization of experimental brain extracts or clinical diagnostic samples of cerebrospinal fluid and saliva. Using hollow core photonic crystal fiber (HC-PCF) further enhanced the Raman signal relative to that in a standard cuvette providing sensitive detection of GLU and GABA in micro-litre volume of aqueous solutions.

Regional Differential Effects of the Novel Histamine H3 Receptor Antagonist 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) on Histamine Release in the Central Nervous System of Freely Moving Rats

PubMed Central

Giannoni, Patrizia; Medhurst, Andrew D.; Passani, Maria Beatrice; Giovannini, Maria Grazia; Ballini, Chiara; Corte, Laura Della

2010-01-01

After oral administration, the nonimidazole histamine H3 receptor antagonist, 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254), increased histamine release from the tuberomammillary nucleus, where all histaminergic somata are localized, and from where their axons project to the entire brain. To further understand functional histaminergic circuitry in the brain, dual-probe microdialysis was used to pharmacologically block H3 receptors in the tuberomammillary nucleus, and monitor histamine release in projection areas. Perfusion of the tuberomammillary nucleus with GSK189254 increased histamine release from the tuberomammillary nucleus, nucleus basalis magnocellularis, and cortex, but not from the striatum or nucleus accumbens. Cortical acetylcholine (ACh) release was also increased, but striatal dopamine release was not affected. When administered locally, GSK189254 increased histamine release from the nucleus basalis magnocellularis, but not from the striatum. Thus, defined by their sensitivity to GSK189254, histaminergic neurons establish distinct pathways according to their terminal projections, and can differentially modulate neurotransmitter release in a brain region-specific manner. Consistent with its effects on cortical ACh release, systemic administration of GSK189254 antagonized the amnesic effects of scopolamine in the rat object recognition test, a cognition paradigm with important cortical components. PMID:19815811

[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.

Nerve growth factor alters microtubule targeting agent-induced neurotransmitter release but not MTA-induced neurite retraction in sensory neurons.

PubMed

Pittman, Sherry K; Gracias, Neilia G; Fehrenbacher, Jill C

2016-05-01

Peripheral neuropathy is a dose-limiting side effect of anticancer treatment with the microtubule-targeted agents (MTAs), paclitaxel and epothilone B (EpoB); however, the mechanisms by which the MTAs alter neuronal function and morphology are unknown. We previously demonstrated that paclitaxel alters neuronal sensitivity, in vitro, in the presence of nerve growth factor (NGF). Evidence in the literature suggests that NGF may modulate the neurotoxic effects of paclitaxel. Here, we examine whether NGF modulates changes in neuronal sensitivity and morphology induced by paclitaxel and EpoB. Neuronal sensitivity was assessed using the stimulated release of calcitonin gene-related peptide (CGRP), whereas morphology of established neurites was evaluated using a high content screening system. Dorsal root ganglion cultures, maintained in the absence or presence of NGF, were treated from day 7 to day 12 in culture with paclitaxel (300nM) or EpoB (30nM). Following treatment, the release of CGRP was stimulated using capsaicin or high extracellular potassium. In the presence of NGF, EpoB mimicked the effects of paclitaxel: capsaicin-stimulated release was attenuated, potassium-stimulated release was slightly enhanced and the total peptide content was unchanged. In the absence of NGF, both paclitaxel and EpoB decreased capsaicin- and potassium-stimulated release and the total peptide content, suggesting that NGF may reverse MTA-induced hyposensitivity. Paclitaxel and EpoB both decreased neurite length and branching, and this attenuation was unaffected by NGF in the growth media. These differential effects of NGF on neuronal sensitivity and morphology suggest that neurite retraction is not a causative factor to alter neuronal sensitivity. Copyright © 2016 Elsevier Inc. All rights reserved.

The spontaneous and evoked release of spermine from rat brain in vitro.

PubMed Central

Harman, R. J.; Shaw, G. G.

1981-01-01

1 The efflux of previously accumulated [3H]-spermine from brain slices was measured using a continuous perfusion system. The spontaneous efflux was biphasic, consisting of an initial rapid efflux followed by a much slower release. 2 The slices were depolarized by the addition to the medium of high potassium concentrations, ouabain or veratrine. 3 At concentrations greater than 30 mM, potassium evoked a striking increase in the release of [3H]-spermine. Following uptake in the presence of 5.7 x 10(-9)M [3H]-spermine, K+-evoked release was dependent on the presence of calcium ions. Release of spermine after uptake at 5.6 x 10(-8)M or 5.0 x 10(-7)M was not calcium-dependent. 4 The calcium-dependent, K+-stimulated release of spermine was inhibited in the presence of diphenylhydantoin (5 x 10(-5)M) or ruthenium red (10(-5)M). 5 Following uptake of 5.7 x 10(-9)M [3H]-spermine in a sodium-free medium, the calcium-dependent, K+-stimulated release was significantly inhibited. 5 Ouabain (10(-4)M) caused a large but calcium-independent increase in the efflux of [3H]-spermine. 7 Veratrine-induced release was less substantial but was increased in a calcium-free medium. Release evoked by veratrine was abolished in the absence of sodium. 8 These results are discussed with respect to a possible 'neurotransmitter' or 'neuromodulator' role for spermine. PMID:6169383

Variables that affect the mechanism of drug release from osmotic pumps coated with acrylate/methacrylate copolymer latexes.

PubMed

Jensen, J L; Appel, L E; Clair, J H; Zentner, G M

1995-05-01

The feasibility of using modified Eudragit acrylic latexes as microporous coatings for osmotic devices was investigated. Potassium chloride tablets were coated with mixtures of Eudragit RS30D and RL30D acrylic latexes that also contained a plasticizer (triethyl citrate or acetyl tributyl citrate) and a pore-forming agent (urea). A 2(5-1) fractional factorial experimental design was employed to determine the effect of five formulation variables (RS30D:RL30D polymer ratio plasticizer type, plasticizer level, urea level, and cure) on the in vitro release rate of KCl in deionized water (di water), lag time, and coat burst strength. The RS30D:RL30D polymer ratio had the greatest effect on the release rate, and both lag time and burst strength were most affected by the urea level. Statistical optimization was performed, and a coat formulation with predicted desirable in vitro performance was prepared and tested. The in vitro release rate (di water), lag time, and coat burst strength agreed well with the prediction. Dissolutions were also performed in phosphate buffered saline (PBS; pH 7.4); several formulations released markedly slower in PBS than in di water. This discrepancy was dependent on the type of plasticizer and the amount of pore former. Only those coat formulations containing acetyl tributyl citrate as the plasticizer and a 100% urea [(g urea/g polymer solids) x 100] level exhibited similar release rates in di water and PBS. The mechanism of release from these devices was primarily osmotic, whereas the release from devices coated with a formulation containing triethyl citrate and 50% urea was not dependent on the osmotic pressure difference. Devices with an osmotic release mechanism behaved similarly in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Compact microelectrode array system: tool for in situ monitoring of drug effects on neurotransmitter release from neural cells.

PubMed

Chen, Yu; Guo, Chunxian; Lim, Layhar; Cheong, Serchoong; Zhang, Qingxin; Tang, Kumcheong; Reboud, Julien

2008-02-15

This paper presents a compact microelectrode array (MEA) system, to study potassium ion-induced dopamine release from PC12 neural cells, without relying on a micromanipulator and a microscope. The MEA chip was integrated with a custom-made "test jig", which provides a robust electrical interfacing tool between the microchip and the macroenvironment, together with a potentiostat and a microfluidic syringe pump. This integrated system significantly simplifies the operation procedures, enhances sensing performance, and reduces fabrication costs. The achieved detection limit for dopamine is 3.8 x 10-2 muM (signal/noise, S/N = 3) and the dopamine linear calibration range is up to 7.39 +/- 0.06 muM (mean +/- SE). The effects of the extracelluar matrix collagen coating of the microelectrodes on dopamine sensing behaviors, as well as the influences of K+ and l-3,4-digydroxyphenylalanine concentrations and incubation times on dopamine release, were extensively studied. The results show that our system is well suited for biologists to study chemical release from living cells as well as drug effects on secreting cells. The current system also shows a potential for further improvements toward a multichip array system for drug screening applications.

Serotonergic neurosecretory synapse targeting is controlled by Netrin-releasing guidepost neurons in C. elegans

PubMed Central

Nelson, Jessica C.; Colón-Ramos, Daniel A.

2013-01-01

Neurosecretory release sites lack distinct post-synaptic partners, yet target to specific circuits. This targeting specificity regulates local release of neurotransmitters and modulation of adjacent circuits. How neurosecretory release sites target to specific regions is not understood. Here we identify a molecular mechanism that governs the spatial specificity of extrasynaptic neurosecretory terminal formation in the serotonergic NSM neurons of C. elegans. We show that post-embryonic arborization and neurosecretory terminal targeting of the C. elegans NSM neuron is dependent on the Netrin receptor UNC-40/DCC. We observe that UNC-40 localizes to specific neurosecretory terminals at the time of axon arbor formation. This localization is dependent on UNC-6/Netrin, which is expressed by nerve ring neurons that act as guideposts to instruct local arbor and release site formation. We find that both UNC-34/Enabled and MIG-10/Lamellipodin are required downstream of UNC-40 to link the sites of ENT formation to nascent axon arbor extensions. Our findings provide a molecular link between release site development and axon arborization, and introduce a novel mechanism that governs the spatial specificity of serotonergic extrasynaptic neurosecretory terminals in vivo. PMID:23345213

α7 Nicotinic Acetylcholine Receptor Signaling Inhibits Inflammasome Activation by Preventing Mitochondrial DNA Release

PubMed Central

Lu, Ben; Kwan, Kevin; Levine, Yaakov A; Olofsson, Peder S; Yang, Huan; Li, Jianhua; Joshi, Sonia; Wang, Haichao; Andersson, Ulf; Chavan, Sangeeta S; Tracey, Kevin J

2014-01-01

The mammalian immune system and the nervous system coevolved under the influence of cellular and environmental stress. Cellular stress is associated with changes in immunity and activation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, a key component of innate immunity. Here we show that α7 nicotinic acetylcholine receptor (α7 nAchR)-signaling inhibits inflammasome activation and prevents release of mitochondrial DNA, an NLRP3 ligand. Cholinergic receptor agonists or vagus nerve stimulation significantly inhibits inflammasome activation, whereas genetic deletion of α7 nAchR significantly enhances inflammasome activation. Acetylcholine accumulates in macrophage cytoplasm after adenosine triphosphate (ATP) stimulation in an α7 nAchR-independent manner. Acetylcholine significantly attenuated calcium or hydrogen oxide–induced mitochondrial damage and mitochondrial DNA release. Together, these findings reveal a novel neurotransmitter-mediated signaling pathway: acetylcholine translocates into the cytoplasm of immune cells during inflammation and inhibits NLRP3 inflammasome activation by preventing mitochondrial DNA release. PMID:24849809

P301L tau expression affects glutamate release and clearance in the hippocampal trisynaptic pathway.

PubMed

Hunsberger, Holly C; Rudy, Carolyn C; Batten, Seth R; Gerhardt, Greg A; Reed, Miranda N

2015-01-01

Individuals at risk of developing Alzheimer's disease (AD) often exhibit hippocampal hyperexcitability. A growing body of evidence suggests that perturbations in the glutamatergic tripartite synapse may underlie this hyperexcitability. Here, we used a tau mouse model of AD (rTg(TauP301L)4510) to examine the effects of tau pathology on hippocampal glutamate regulation. We found a 40% increase in hippocampal vesicular glutamate transporter, which packages glutamate into vesicles, and has previously been shown to influence glutamate release, and a 40% decrease in hippocampal glutamate transporter 1, the major glutamate transporter responsible for removing glutamate from the extracellular space. To determine whether these alterations affected glutamate regulation in vivo, we measured tonic glutamate levels, potassium-evoked glutamate release, and glutamate uptake/clearance in the dentate gyrus, cornu ammonis 3(CA3), and cornu ammonis 1(CA1) regions of the hippocampus. P301L tau expression resulted in a 4- and 7-fold increase in potassium-evoked glutamate release in the dentate gyrus and CA3, respectively, and significantly decreased glutamate clearance in all three regions. Both release and clearance correlated with memory performance in the hippocampal-dependent Barnes maze task. Alterations in mice expressing P301L were observed at a time when tau pathology was subtle and before readily detectable neuron loss. These data suggest novel mechanisms by which tau may mediate hyperexcitability. Pre-synaptic vesicular glutamate transporters (vGLUTs) package glutamate into vesicles before exocytosis into the synaptic cleft. Once in the extracellular space, glutamate acts on glutamate receptors. Glutamate is removed from the extracellular space by excitatory amino acid transporters, including GLT-1, predominantly localized to glia. P301L tau expression increases vGLUT expression and glutamate release, while also decreasing GLT-1 expression and glutamate clearance. © 2014

Substance P provoked gamma-aminobutyric acid release from the myenteric plexus of the guinea-pig small intestine.

PubMed Central

Tanaka, C; Taniyama, K

1985-01-01

The release of [3H]gamma-aminobutyric acid (GABA) from the isolated small intestine of the guinea-pig pre-loaded with [3H]GABA was measured in the presence of substance P and vasoactive intestinal polypeptide (VIP). Substance P (10(-10)-10(-7) M) produced a dose-dependent increase in the fractional rate of [3H]GABA release. VIP, even at 10(-7) M, did not affect the spontaneous [3H]GABA release nor the release of [3H]GABA evoked by electrical transmural stimulation (0.5 ms, 15 V, 10 Hz for 30 s). The release of endogenous GABA from the isolated small intestine was measured in the presence of substance P (10(-9) M). After 60 min superfusion, the spontaneous release of GABA was 4.61 +/- 0.14 pmol min-1 g-1 wet wt. (n = 20). Substance P (10(-9) M) produced an approximate 2-fold spontaneous release of endogeneous GABA (8.74 +/- 0.21 pmol min-1 g-1 wet wt. (n = 10)). Perfusion with Ca-free medium containing 1 mM-EGTA and tetrodotoxin (3 X 10(-7) M) inhibited the release of endogenous GABA evoked by substance P (10(-9) M). (D-Pro2, D-Trp7,9) substance P (10(-6) M) antagonized the release of endogenous GABA evoked by substance P (10(-9) M). These results indicate that substance P induces a neuronal release of GABA through its receptor located in the guinea-pig small intestine. Substance P (10(-11)-10(-7) M) produced a dose-dependent increase in the fractional rate of [3H]acetylcholine (ACh) release from the isolated small intestine pre-loaded with [3H]choline. The release of [3H]ACh evoked by substance P (10(-9) M) was inhibited by perfusion with Ca-free medium containing 1 mM-EGTA, tetrodotoxin (3 X 10(-7) M) and (D-Pro2, D-Trp7,9)substance P (10(-6) M). Bicuculline (10(-6) M) inhibited the release of [3H]ACh evoked by substance P (10(-9) M) by 68.1 +/- 4.6% (n = 5), thereby suggesting that the substance P-evoked ACh release is partly mediated through the endogenous GABA released by substance P. These results provide evidence for the neurotransmitter role of GABA and a

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. Copyright 2012, SLACK Incorporated.

Structure-Activity Relationships of Substituted Cathinones, with Transporter Binding, Uptake, and Release

PubMed Central

Wolfrum, Katherine M.; Reed, John F.; Kim, Sunyoung O.; Swanson, Tracy; Johnson, Robert A.; Janowsky, Aaron

2017-01-01

Synthetic cathinones are components of “bath salts” and have physical and psychologic side effects, including hypertension, paranoia, and hallucinations. Here, we report interactions of 20 “bath salt” components with human dopamine, serotonin, and norepinephrine transporters [human dopamine transporter (hDAT), human serotonin transporter (hSERT), and human norepinephrine transporter (hNET), respectively] heterologously expressed in human embryonic kidney 293 cells. Transporter inhibitors had nanomolar to micromolar affinities (Ki values) at radioligand binding sites, with relative affinities of hDAT>hNET>hSERT for α-pyrrolidinopropiophenone (α-PPP), α-pyrrolidinobutiophenone, α-pyrrolidinohexiophenone, 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone, 3,4-methylenedioxy-α-pyrrolidinopropiophenone, 3,4-methylenedioxy-α-pyrrolidinobutiophenone, 4-methyl-α-pyrrolidinopropiophenone, α-pyrrolidinovalerophenone, 4-methoxy-α-pyrrolidinovalerophenone, α-pyrrolidinopentiothiophenone (alpha-PVT), and α-methylaminovalerophenone, and hDAT>hSERT>hNET for methylenedioxypentedrone. Increasing the α-carbon chain length increased the affinity and potency of the α-pyrrolidinophenones. Uptake inhibitors had relative potencies of hDAT>hNET>hSERT except α-PPP and α-PVT, which had highest potencies at hNET. They did not induce [3H]neurotransmitter release. Substrates can enter presynaptic neurons via transporters, and the substrates methamphetamine and 3,4-methylenedioxymethylamphetamine are neurotoxic. We determined that 3-fluoro-, 4-bromo-, 4-chloro-methcathinone, and 4-fluoroamphetamine were substrates at all three transporters; 5,6-methylenedioxy-2-aminoindane (MDAI) and 4-methylethcathinone (4-MEC) were substrates primarily at hSERT and hNET; and 3,4-methylenedioxy-N-ethylcathinone (ethylone) and 5-methoxy-methylone were substrates only at hSERT and induced [3H]neurotransmitter release. Significant correlations between potencies for inhibition of uptake and for

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.

Citrate Modulates the Regulation by Zn2+ of N-Methyl-D-Aspartate Receptor-Mediated Channel Current and Neurotransmitter Release

NASA Astrophysics Data System (ADS)

Westergaard, Niels; Banke, Tue; Wahl, Philip; Sonnewald, Ursula; Schousboe, Arne

1995-04-01

The effect of the two metal-ion chelators EDTA and citrate on the action of N-methyl-D-aspartate (NMDA) receptors was investigated by use of cultured mouse cerebellar granule neurons and Xenopus oocytes, respectively, to monitor either NMDA-evoked transmitter release or membrane currents. Transmitter release from the glutamatergic neurons was determined by superfusion of the cells after preloading with the glutamate analogue D-[^3H]aspartate. The oocytes were injected with mRNA isolated from mouse cerebellum and, after incubation to allow translation to occur, currents mediated by NMDA were recorded electrophysiologically by voltage clamp at a holding potential of -80 mV. It was found that citrate as well as EDTA could attenuate the inhibitory action of Zn2+ on NMDA receptor-mediated transmitter release from the neurons and membrane currents in the oocytes. These effects were specifically related to the NMDA receptor, since the NMDA receptor antagonist MK-801 abolished the action and no effects of Zn2+ and its chelators were observed when kainate was used to selectively activate non-NMDA receptors. Since it was additionally demonstrated that citrate (and EDTA) preferentially chelated Zn2+ rather than Ca2+, the present findings strongly suggest that endogenous citrate released specifically from astrocytes into the extracellular space in the brain may function as a modulator of NMDA receptor activity. This is yet another example of astrocytic influence on neuronal activity.

[The effects of lesions in the compact part of the substantia nigra on glutamate and GABA release in the pedunculopontine nucleus].

PubMed

Blanco-Lezcano, L; Rocha-Arrieta, L L; Alvarez-González, L; Martínez-Martí, L; Pavón-Fuentes, N; González-Fraguela, M E; Bauzá-Calderín, Y; Coro-Grave de Peralta, Y

The pedunculopontine nucleus (PPN), co-localized with the mesencephalic locomotor region, has been proposed as a key structure in the physiopathology of Parkinson's disease. The goal of the present study was to assess if the aminoacid neurotransmitter release in the PPN is modified by the degeneration of dopaminergic cells, from substantia nigra pars compacta in 6-hydroxidopamine (6-OHDA)-lesioned rats. In addition, it was studied the aminoacid neurotransmitter release in the PPN of rats with lesion of the subthalamic nucleus by quinolinic acid (QUIN) (100 nmol) intracerebral injection. Rats were assigned to five groups: untreated rats (I) (n = 13), 6-OHDA lesion (II) (n = 11), 6-OHDA + QUIN lesion (III) (n = 9), sham-operated (IV) (n = 10), QUIN, STN (V) lesioned (n = 9). The extracellular concentrations of glutamic acid (GLU) and gamma-aminobutyric acid (GABA) were determined by brain microdialysis and high performance liquid chromatography (HPLC). RESULTS. GLU released in PPN from 6-OHDA lesioned rats (group II), was significantly increased in comparison with the others groups (F(4, 47) = 18.21, p < 0.001). GABA released shows significant differences between experimental groups (F(4, 45) = 12.75, p < 0.001). It was detected a higher valour (p < 0.05) in-group II. The groups III and IV exhibited intermeddle valour (p < 0.001) and groups I and IV (p < 0.001) showed the lower GABA extracellular concentrations. The infusion of artificial cerebrospinal fluid with higher potassium (100 mmol) induced an increase in the GLU and GABA released in all groups, which confirm the neuronal origin of the extracellular content. These results are in agreement with the current model of basal ganglia functioning and suggest the role of STN-PPN projection in the physiopathology of Parkinson's disease.

Brain neurotransmitter transporter/receptor genomics and efavirenz central nervous system adverse events.

PubMed

Haas, David W; Bradford, Yuki; Verma, Anurag; Verma, Shefali S; Eron, Joseph J; Gulick, Roy M; Riddler, Sharon A; Sax, Paul E; Daar, Eric S; Morse, Gene D; Acosta, Edward P; Ritchie, Marylyn D

2018-05-29

We characterized associations between central nervous system (CNS) adverse events and brain neurotransmitter transporter/receptor genomics among participants randomized to efavirenz-containing regimens in AIDS Clinical Trials Group studies in the USA. Four clinical trials randomly assigned treatment-naive participants to efavirenz-containing regimens. Genome-wide genotype and PrediXcan were used to infer gene expression levels in tissues including 10 brain regions. Multivariable regression models stratified by race/ethnicity were adjusted for CYP2B6/CYP2A6 genotypes that predict plasma efavirenz exposure, age, and sex. Combined analyses also adjusted for genetic ancestry. Analyses included 167 cases with grade 2 or greater efavirenz-consistent CNS adverse events within 48 weeks of study entry, and 653 efavirenz-tolerant controls. CYP2B6/CYP2A6 genotype level was independently associated with CNS adverse events (odds ratio: 1.07; P=0.044). Predicted expression of six genes postulated to mediate efavirenz CNS side effects (SLC6A2, SLC6A3, PGR, HTR2A, HTR2B, HTR6) were not associated with CNS adverse events after correcting for multiple testing, the lowest P value being for PGR in hippocampus (P=0.012), nor were polymorphisms in these genes or AR and HTR2C, the lowest P value being for rs12393326 in HTR2C (P=6.7×10). As a positive control, baseline plasma bilirubin concentration was associated with predicted liver UGT1A1 expression level (P=1.9×10). Efavirenz-related CNS adverse events were not associated with predicted neurotransmitter transporter/receptor gene expression levels in brain or with polymorphisms in these genes. Variable susceptibility to efavirenz-related CNS adverse events may not be explained by brain neurotransmitter transporter/receptor genomics.

Unsupported platinum nanoparticles as effective sensors of neurotransmitters and possible drug curriers

NASA Astrophysics Data System (ADS)

Tąta, Agnieszka; Gralec, Barbara; Proniewicz, Edyta

2018-03-01

Herein, surface-enhanced Raman scattering (SERS) activity of positively charged unsupported platinum nanoparticles (PtNPs) with ∼12 nm size and narrow size distribution, in an aqueous solution, towards neurotransmitters was monitored at 785 nm excitation wavelength. The pure PtNPs were synthetized by polyol method. Their morphology and structure were checked by scanning electron microscopy (SEM) and X-ray diffraction spectroscopy (XRD) measurements. As a neurotransmitter bombesin (BN), which exhibits autocrine effect on the growth of normal and tumour tissues, and its fragments from the C-terminal end: BN13-14, BN12-14, BN11-14, BN10-14, BN9-14, and BN8-14 (X-14 fragments of the BN amino acid sequence) were chosen. The collected spectra were interpreted and discussed. This is to determine the adsorption mode of bombesin onto the PtNPs surface and changes in this mode as a result of the bombesin backbone shortening from the N-terminal end. This is important from the point of using PtNPs as potential BN carrier into the cancerous tissue and antitumor drug.

Regulation of embryonic neurotransmitter and tyrosine hydroxylase protein levels by ascorbic acid

PubMed Central

Meredith, M. Elizabeth; May, James M.

2013-01-01

Scope: Ascorbic acid (ascorbate) is required to recycle tetrahydrobiopterin, which is necessary for neurotransmitter synthesis by the rate-limiting enzymes tyrosine and tryptophan hydroxylases. We sought to determine whether ascorbate might regulate embryonic brain cortex monoamine synthesis utilizing transgenic mouse models with varying intracellular ascorbate levels. Methods and Results: In embryos lacking the sodium-dependent vitamin C transporter 2 (SVCT2), very low levels of brain ascorbate decreased cortex levels of norepinephrine and dopamine by approximately 33%, but had no effect on cortex serotonin or its metabolite, 5-hydroxyindole acetic acid. This decrease in ascorbate also led to a decrease in protein levels of tyrosine hydroxylase, but not of tryptophan hydroxylase. Increased cortex ascorbate in embryos carrying extra copies of the SVCT2 resulted in increased levels of dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), as well as serotonin and 5-hydroxyindole acetic acid. Conclusion: The dependence of embryonic brain cortex neurotransmitter synthesis and tyrosine hydroxylase expression on intracellular ascorbate emphasizes the importance of receiving adequate ascorbate during development. PMID:24095796

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

Miniaturized and Wireless Optical Neurotransmitter Sensor for Real-Time Monitoring of Dopamine in the Brain.

PubMed

Kim, Min H; Yoon, Hargsoon; Choi, Sang H; Zhao, Fei; Kim, Jongsung; Song, Kyo D; Lee, Uhn

2016-11-10

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).

Effects of atropine on refractive development, dopamine release, and slow retinal potentials in the chick.

PubMed

Schwahn, H N; Kaymak, H; Schaeffel, F

2000-01-01

Atropine has previously been found to suppress visually induced myopia both in animals and humans. The mechanism of its action is unclear. We have studied its retinal effects in an in vitro preparation, using the retina-pigment epithelium-choroid complex of the chick eye. In vivo, deprivation myopia was induced by translucent goggles. Atropine solution was injected into the vitreous at two-day intervals. Dopamine release from the retina following atropine injection in vivo and from the in vitro retina preparation was quantified by HPLC-EC. In vitro preparations of the isolated chick retina-pigment epithelium-choroid were superfused with atropine. Light-induced potentials (local ERG), slow standing potentials from the retinal pigment epithelium/neural retina, and extracellular potassium concentrations were recorded. In line with previous findings, intravitreal injections of atropine (25 microg, 250 microg) reduced deprivation myopia in a dose-dependent manner. Atropine increased the release of the neurotransmitter dopamine into the superfusate in vitro at 100-500 microM and into the vitreous in vivo at 250 microg. Before an increase was measured in the vitreous, the retinal dopamine content was elevated. In concentrations equivalent to the intravitreal concentration to suppress myopia in vivo (200-800 microM), atropine induced spreading depression (SD) in the in vitro preparation. In contrast, muscarinic agonists, acetylcholine and pilocarpine, did not induce SD. Atropine reduced the ERG b- and d-wave, led to damped oscillations of RPE potentials, and reversed the ERG c-wave. Atropine suppressed myopia only at doses at which severe nonspecific side effects were observed in the retina. Atropine seems to intrude massively into the vital functions of the retina as indicated by the occurrence of SD. We conclude that atropine, by inducing SD, boosts neurotransmitter release from cellular stores, which may cancel out a presumed retinal signal that controls eye growth and

Removal of urothelium affects bladder contractility and release of ATP but not release of NO in rat urinary bladder.

PubMed

Munoz, Alvaro; Gangitano, David A; Smith, Christopher P; Boone, Timothy B; Somogyi, George T

2010-05-24

The objective of our work was to investigate both the contractile function and the release of ATP and NO from strips of bladder tissue after removal of the urothelium. The method of removal was a gentle swabbing motion rather than a sharp surgical cutting to separate the urothelium from the smooth muscle. The contractile response and ATP and NO release were measured in intact as well as on swabbed preparations. The removal of the urothelial layer was affirmed microscopically. After the swabbing, the smaller contractions were evoked by electrical as well as by chemical stimulation (50 microM carbachol or 50 microM alpha, beta meATP). Electrical stimulation, carbachol and substance P (5 microM) evoked lower release of ATP in the swabbed strips than in intact strips. Although release of NO evoked by electrical stimulation or substance P was not changed, release of NO evoked by carbachol was significantly less in the swabbed preparations. Since swabbing removes only the urothelium, the presence of the suburothelial layer may explain the difference between our findings and those of others who found an increase in contractility. Evoked release of ATP is reduced in swabbed strips, indicating that ATP derives solely from the urothelium. On the other hand, electrical stimulation and substance P evoke identical degrees of NO release in both intact and swabbed preparations, suggesting that NO can be released from the suburothelium. Conversely, carbachol-induced release of NO is lower in swabbed strips, implying that the cholinergic receptors (muscarinic or nicotinic) are located in the upper layer of the urothelium.

Hypo-and hyperthyroidism affect the ATP, ADP and AMP hydrolysis in rat hippocampal and cortical slices.

PubMed

Bruno, Alessandra Nejar; Diniz, Gabriela Placoná; Ricachenevsky, Felipe Klein; Pochmann, Daniela; Bonan, Carla Denise; Barreto-Chaves, Maria Luiza M; Sarkis, João José Freitas

2005-05-01

The presence of severe neurological symptoms in thyroid diseases has highlighted the importance of thyroid hormones in the normal functioning of the mature brain. Since, ATP is an important excitatory neurotransmitter and adenosine acts as a neuromodulatory structure inhibiting neurotransmitters release in the central nervous system (CNS), the ectonucleotidase cascade that hydrolyzes ATP to adenosine, is also involved in the control of brain functions. Thus, we investigated the influence of hyper-and hypothyroidism on the ATP, ADP and AMP hydrolysis in hippocampal and cortical slices from adult rats. Hyperthyroidism was induced by daily injections of l-thyroxine (T4) 25 microg/100 g body weight, for 14 days. Hypothyroidism was induced by thyroidectomy and methimazole (0.05%) added to their drinking water for 14 days. Hypothyroid rats were hormonally replaced by daily injections of T4 (5 microg/100 g body weight, i.p.) for 5 days. Hyperthyroidism significantly inhibited the ATP, ADP and AMP hydrolysis in hippocampal slices. In brain cortical slices, hyperthyroidism inhibited the AMP hydrolysis. In contrast, hypothyroidism increased the ATP, ADP and AMP hydrolysis in both hippocampal and cortical slices and these effects were reverted by T4 replacement. Furthermore, hypothyroidism increased the expression of NTPDase1 and 5'-nucleotidase, whereas hyperthyroidism decreased the expression of 5'-nucleotidase in hippocampus of adult rats. These findings demonstrate that thyroid disorders may influence the enzymes involved in the complete degradation of ATP to adenosine and possibly affects the responses mediated by adenine nucleotides in the CNS of adult rats.

The novel protein kinase C epsilon isoform modulates acetylcholine release in the rat neuromuscular junction.

PubMed

Obis, Teresa; Hurtado, Erica; Nadal, Laura; Tomàs, Marta; Priego, Mercedes; Simon, Anna; Garcia, Neus; Santafe, Manel M; Lanuza, Maria A; Tomàs, Josep

2015-12-01

Various protein kinase C (PKC) isoforms contribute to the phosphorylating activity that modulates neurotransmitter release. In previous studies we showed that nPKCε is confined in the presynaptic site of the neuromuscular junction and its presynaptic function is activity-dependent. Furthermore, nPKCε regulates phorbol ester-induced acetylcholine release potentiation, which further indicates that nPKCε is involved in neurotransmission. The present study is designed to examine the nPKCε involvement in transmitter release at the neuromuscular junction. We use the specific nPKCε translocation inhibitor peptide εV1-2 and electrophysiological experiments to investigate the involvement of this isoform in acetylcholine release. We observed that nPKCε membrane translocation is key to the synaptic potentiation of NMJ, being involved in several conditions that upregulate PKC isoforms coupling to acetylcholine (ACh) release (incubation with high Ca(2+), stimulation with phorbol esters and protein kinase A, stimulation with adenosine 3',5'-cyclic monophosphorothioate, 8-Bromo-, Rp-isomer, sodium salt -Sp-8-BrcAMP-). In all these conditions, preincubation with the nPKCε translocation inhibitor peptide (εV1-2) impairs PKC coupling to acetylcholine release potentiation. In addition, the inhibition of nPKCε translocation and therefore its activity impedes that presynaptic muscarinic autoreceptors and adenosine autoreceptors modulate transmitter secretion. Together, these results point to the importance of nPKCε isoform in the control of acetylcholine release in the neuromuscular junction.

Inhalation of air polluted with gasoline vapours alters the levels of amino acid neurotransmitters in the cerebral cortex, hippocampus, and hypothalamus of the rat.

PubMed

Kinawy, Amal A; Ezzat, Ahmed R; Al-Suwaigh, Badryah R

2014-08-01

This study was designed to investigate the impact of exposure to the vapours of two kinds of gasoline, a widely used fuel for the internal combustion engines on the levels of the amino acid neurotransmitters of the rat brain. Recent studies provide strong evidence for a causative role for traffic-related air pollution on morbidity outcomes as well as premature death (Health Effects Institute, 2009; Levy et al., 2010; von Stackelberg et al., 2013). Exposure to the vapours of gasoline or its constituents may be accidental, occupational by workers at fuel stations and factories, or through abuse as a mean of mood alteration (Fortenberry, 1985; Mc Garvey et al., 1999). Two kinds of gasoline that are common in Egypt have been used in this study. The first contains octane enhancers in the form of lead derivatives (leaded gasoline; G1) and the other contains methyl-tertiary butyl ether (MTBE) as the octane enhancer (unleaded gasoline; G2). The levels of the major excitatory (aspartic acid and glutamic acid) and the inhibitory (GABA and glycine) amino acid neurotransmitters were determined in the cerebral cortex, hippocampus, and hypothalamus. The current study revealed that the acute inhalation of air polluted with the two types of gasoline vapours (1/2 LC50 for 30 min) induced elevation in the levels of aspartic and glutamic acids along with a decrease in glycine and GABA in most studied brain areas. Chronic inhalation of both types of gasoline (a single daily 30-min session of 1/5 LC50 for 60 days) caused a significant increase in the aspartic and glutamic acid concentrations of the hippocampus without affecting the levels of GABA or glycine. Acute and chronic inhalation of either one of G1 and G2 vapours induced a disturbance and fluctuation in the levels of the free amino acids that act as excitatory and inhibitory neurotransmitters in the brain areas under investigation. These neurotransmitters are fundamental for the communicative functioning of the neurons and such

Sympathetic nerves: How do they affect angiogenesis, particularly during wound healing of soft tissues?

PubMed

Pan, Liangli; Tang, Jianbing; Liu, Hongwei; Cheng, Biao

2016-01-01

Angiogenesis is essential for wound healing, and angiogenesis impairment can result in chronic ulcers. Studies have shown that the sympathetic nervous system has an important role in angiogenesis. In recent years, researchers have focused on the roles of sympathetic nerves in tumor angiogenesis. In fact, sympathetic nerves can affect angiogenesis in the wound healing of soft tissues, and may have a similar mechanism of action as that seen in tumorigenesis. Sympathetic nerves act primarily through interactions between the neurotransmitters released from nerve endings and receptors present in target organs. Among this, activation or inhibition of adrenergic receptors (mainly β-adrenergic receptors) influence formation of new blood vessels considerably. As sympathetic nerves locate near pericytes in microvessel, go along the capillaries and there are adrenergic receptors present in endothelial cells and pericytes, sympathetic nerves may participate in angiogenesis by influencing the endothelial cells and pericytes of new capillaries. Studying the roles of sympathetic nerves on the angiogenesis of wound healing can contribute to understanding the mechanisms of tissue repair, tissue regeneration, and tumorigenesis, thereby providing new therapeutic perspectives.

Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study.

PubMed

Blatt, G J; Fitzgerald, C M; Guptill, J T; Booker, A B; Kemper, T L; Bauman, M L

2001-12-01

Neuropathological studies in autistic brains have shown small neuronal size and increased cell packing density in a variety of limbic system structures including the hippocampus, a change consistent with curtailment of normal development. Based on these observations in the hippocampus, a series of quantitative receptor autoradiographic studies were undertaken to determine the density and distribution of eight types of neurotransmitter receptors from four neurotransmitter systems (GABAergic, serotoninergic [5-HT], cholinergic, and glutamatergic). Data from these single concentration ligand binding studies indicate that the GABAergic receptor system (3[H]-flunitrazepam labeled benzodiazepine binding sites and 3[H]-muscimol labeled GABA(A) receptors) is significantly reduced in high binding regions, marking for the first time an abnormality in the GABA system in autism. In contrast, the density and distribution of the other six receptors studied (3[H]-80H-DPAT labeled 5-HT1A receptors, 3[H]-ketanserin labeled 5-HT2 receptors, 3[H]-pirenzepine labled M1 receptors, 3[H]-hemicholinium labeled high affinity choline uptake sites, 3[H]-MK801 labeled NMDA receptors, and 3[H]-kainate labeled kainate receptors) in the hippocampus did not demonstrate any statistically significant differences in binding.

Spintronic characteristics of self-assembled neurotransmitter acetylcholine molecular complexes enable quantum information processing in neural networks and brain

NASA Astrophysics Data System (ADS)

Tamulis, Arvydas; Majauskaite, Kristina; Kairys, Visvaldas; Zborowski, Krzysztof; Adhikari, Kapil; Krisciukaitis, Sarunas

2016-09-01

Implementation of liquid state quantum information processing based on spatially localized electronic spin in the neurotransmitter stable acetylcholine (ACh) neutral molecular radical is discussed. Using DFT quantum calculations we proved that this molecule possesses stable localized electron spin, which may represent a qubit in quantum information processing. The necessary operating conditions for ACh molecule are formulated in self-assembled dimer and more complex systems. The main quantum mechanical research result of this paper is that the neurotransmitter ACh systems, which were proposed, include the use of quantum molecular spintronics arrays to control the neurotransmission in neural networks.

A Conserved Asparagine Residue in Transmembrane Segment 1 (TM1) of Serotonin Transporter Dictates Chloride-coupled Neurotransmitter Transport*

PubMed Central

Henry, L. Keith; Iwamoto, Hideki; Field, Julie R.; Kaufmann, Kristian; Dawson, Eric S.; Jacobs, Miriam T.; Adams, Chelsea; Felts, Bruce; Zdravkovic, Igor; Armstrong, Vanessa; Combs, Steven; Solis, Ernesto; Rudnick, Gary; Noskov, Sergei Y.; DeFelice, Louis J.; Meiler, Jens; Blakely, Randy D.

2011-01-01

Na+- and Cl−-dependent uptake of neurotransmitters via transporters of the SLC6 family, including the human serotonin transporter (SLC6A4), is critical for efficient synaptic transmission. Although residues in the human serotonin transporter involved in direct Cl− coordination of human serotonin transport have been identified, the role of Cl− in the transport mechanism remains unclear. Through a combination of mutagenesis, chemical modification, substrate and charge flux measurements, and molecular modeling studies, we reveal an unexpected role for the highly conserved transmembrane segment 1 residue Asn-101 in coupling Cl− binding to concentrative neurotransmitter uptake. PMID:21730057

[Analysis on content of serum monoamine neurotransmitters in macaques with anger-in-induced premenstrual syndrome and liver-qi depression syndrome].

PubMed

Wei, Sheng; Hou, Jin-Liang; Chao, Yu-Bin; Du, Xi-Yang; Zong, Shao-Bo

2012-08-01

To observe the changes in content of monoamine neurotransmitters in the serum of rhesus macaques, and explore the role of serum monoamine neurotransmitters in premenstrual syndrome (PMS) and liver-qi depression induced by anger-in emotion. Social level pressure was applied on 24 female macaques to induce the angry emotional reaction, and then nine of the low-status macaques with anger-in emotional reaction were screened out and were divided into anger-in emotion group, PMS and liver-qi depression group (model group) and Jingqianshu Granule group. Macaques in the last two groups were suffered extruding in a pack cage for inducing PMS liver-qi depression. After 5 d of extruding, experimental animals were evaluated according to the emotional evaluation scale, meanwhile, macaque serum of follicular phase and middle-late luteal phase was collected to analyze the content of serum norepinephrine, dopamine, and 5-hydroxytryptamine. Compared with the normal control group, the scores of depression of the model group and the anger-in emotion group evaluated with emotional evaluation scale were significantly increased (P<0.01, P<0.05); while the score of the model group was significantly higher than that of the anger-in emotion group (P<0.05), and it returned to normal after Jingqianshu Granule treatment. As compared to the normal control group, serum monoamine neurotransmitter levels of the model group and the anger-in emotion group were increased (P<0.05, P<0.01), and the serum monoamine neurotransmitter levels of the model group were significantly higher than those of the anger-in emotion group (P<0.05), while there was no significant difference when compared with the normal control group after the treatment. Anger-in emotion can induce liver-qi depression syndrome which is related to the changes in monoamine neurotransmitters.

Increased glutamate-stimulated norepinephrine release from prefrontal cortex slices of spontaneously hypertensive rats.

PubMed

Russell, V A; Wiggins, T M

2000-12-01

Spontaneously hypertensive rats (SHR) have behavioral characteristics (hyperactivity, impulsiveness, poorly sustained attention) similar to the behavioral disturbances of children with attention-deficit hyperactivity disorder (ADHD). We have previously shown that dopaminergic and noradrenergic systems are disturbed in the prefrontal cortex of SHR compared to their normotensive Wistar-Kyoto (WKY) control rats. It was of interest to determine whether the underlying neural circuits that use glutamate as a neurotransmitter function normally in the prefrontal cortex of SHR. An in vitro superfusion technique was used to demonstrate that glutamate caused a concentration-dependent stimulation of [3H]norepinephrine release from rat prefrontal cortex slices. Glutamate (100 microM and 1 mM) caused significantly greater release of norepinephrine from prefrontal cortex slices of SHR than from control slices. The effect of glutamate was not mediated by NMDA receptors, since NMDA (10 and 100 microM) did not exert any effect on norepinephrine release and MK-801 (10 microM) did not antagonize the effect of 100 microM glutamate. These results demonstrate that glutamate stimulates norepinephrine release from rat prefrontal cortex slices and that this increase is enhanced in SHR. The results are consistent with the suggestion that the noradrenergic system is overactive in prefrontal cortex of SHR, the animal model for ADHD.

Involvement of enzymatic degradation in the inactivation of tachykinin neurotransmitters in neonatal rat spinal cord.

PubMed Central

Suzuki, H; Yoshioka, K; Yanagisawa, M; Urayama, O; Kurihara, T; Hosoki, R; Saito, K; Otsuka, M

1994-01-01

1. The possible involvement of enzymatic degradation in the inactivation of tachykinin neurotransmitters was examined in the spinal cord of the neonatal rat. 2. The magnitude of substance P (SP)- or neurokinin A (NKA)-evoked depolarization of a lumbar ventral root in the isolated spinal cord preparation was increased by a mixture of peptidase inhibitors, consisting of actinonin (6 microM), arphamenine B (6 microM), bestatin (10 microM), captopril (10 microM) and thiorphan (0.3 microM). The mixture augmented the response to NKA more markedly than that to SP. 3. In the isolated spinal cord-cutaneous nerve preparation, the saphenous nerve-evoked slow depolarization of the L3 ventral root was augmented by the mixture of peptidase inhibitors in the presence of naloxone (0.5 microM) but not in the presence of both naloxone and a tachykinin receptor antagonist, GR71251 (5 microM). 4. Application of capsaicin (0.5 microM) for 6 min to the spinal cord evoked an increase in the release of SP from the spinal cord. The amount of SP released was significantly augmented by the mixture of peptidase inhibitors. 5. Synaptic membrane fractions were prepared from neonatal rat spinal cords. These fractions showed degrading activities for SP and NKA and the activities were inhibited by the mixture of peptidase inhibitors. The degrading activity for NKA was higher than that for SP and the inhibitory effect of the mixture for NKA was more marked than that for SP. Although some other fractions obtained from homogenates of spinal cords showed higher degrading activities for SP, these activities were insensitive to the mixture of peptidase inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7529113

Transient receptor potential ankyrin 1 channels are involved in spontaneous peptide hormone release from astrocytes.

PubMed

Takizawa, Mai; Harada, Kazuki; Nakamura, Kazuaki; Tsuboi, Takashi

2018-07-02

Astrocytes, a large population of glial cells, detect neurotransmitters and respond by increasing intracellular Ca 2+ concentration ([Ca 2+ ] i ) and releasing chemical molecules called gliotransmitters. Recently discovered Ca 2+ influx through transient receptor potential ankyrin 1 (TRPA1) channels is reported to cause spontaneous [Ca 2+ ] i increase in astrocytes. While several physiological functions of TRPA1-mediated spontaneous Ca 2+ signal have been revealed, relation with gliotransmitter release, especially peptide hormone exocytosis is largely unknown. We therefore explored the [Ca 2+ ] i and exocytosis dynamics in rat astrocyte cell line C6 cells and primary astrocytes. TRPA1-mediated spontaneous [Ca 2+ ] i transients were observed in both C6 cells and primary astrocytes. Total internal reflection fluorescence microscopy revealed that Venus-tagged brain-derived neurotrophic factor and neuropeptide Y were released spontaneously from astrocytes. Activation of TRPA1 channels enhanced the frequency of peptide hormone exocytosis, and inhibition of TRPA1 channels decreased the number of peptide hormone exocytosis. These results suggest that TRPA1-mediated spontaneous [Ca 2+ ] i increase modulates the spontaneous release of peptide hormones from astrocytes. Copyright © 2018 Elsevier Inc. All rights reserved.

Dopamine Modulates Delta-Gamma Phase-Amplitude Coupling in the Prefrontal Cortex of Behaving Rats.

PubMed

Andino-Pavlovsky, Victoria; Souza, Annie C; Scheffer-Teixeira, Robson; Tort, Adriano B L; Etchenique, Roberto; Ribeiro, Sidarta

2017-01-01

Dopamine release and phase-amplitude cross-frequency coupling (CFC) have independently been implicated in prefrontal cortex (PFC) functioning. To causally investigate whether dopamine release affects phase-amplitude comodulation between different frequencies in local field potentials (LFP) recorded from the medial PFC (mPFC) of behaving rats, we used RuBiDopa, a light-sensitive caged compound that releases the neurotransmitter dopamine when irradiated with visible light. LFP power did not change in any frequency band after the application of light-uncaged dopamine, but significantly strengthened phase-amplitude comodulation between delta and gamma oscillations. Saline did not exert significant changes, while injections of dopamine and RuBiDopa produced a slow increase in comodulation for several minutes after the injection. The results show that dopamine release in the medial PFC shifts phase-amplitude comodulation from theta-gamma to delta-gamma. Although being preliminary results due to the limitation of the low number of animals present in this study, our findings suggest that dopamine-mediated modification of the frequencies involved in comodulation could be a mechanism by which this neurotransmitter regulates functioning in mPFC.

Gamma-vinyl GABA increases nonvesicular release of GABA and glutamate in the nucleus accumbens in rats via action on anion channels and GABA transporters

PubMed Central

Peng, Xiao-Qing; Gardner, Eliot L.

2013-01-01

Rationale γ-Amino butyric acid (GABA) is a well-characterized inhibitory neurotransmitter in the central nervous system, which may also stimulate nonvesicular release of other neurotransmitters under certain conditions. We have recently reported that γ-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, elevates extracellular GABA but fails to alter dopamine release in the nucleus accumbens (NAc). Objectives Here, we investigated the mechanism(s) by which GVG elevates extracellular GABA levels and whether GVG also alters glutamate release in the NAc. Materials and methods In vivo microdialysis was used to simultaneously measure extracellular NAc GABA and glutamate before and after GVG administration in freely moving rats. Results Systemic administration of GVG or intra-NAc local perfusion of GVG significantly increased extracellular NAc GABA and glutamate. GVG-enhanced GABA was completely blocked by intra-NAc local perfusion of 5-nitro-2, 3-(phenylpropylamino)-benzoic acid (NPPB), a selective anion channel blocker and partially blocked by SKF89976A, a type 1 GABA transporter inhibitor. GVG-enhanced glutamate was completely blocked by NPPB or SKF89976A. Tetrodotoxin, a voltage-dependent Na+-channel blocker, failed to alter GVG-enhanced GABA and glutamate. Conclusions These data suggest that GVG-enhanced extracellular GABA and glutamate are mediated predominantly by the opening of anion channels and partially by the reversal of GABA transporters. Enhanced extracellular glutamate may functionally attenuate the pharmacological action of GABA and prevent enhanced GABA-induced excess inhibition. PMID:20033132

Cerebellar level of neurotransmitters in rats exposed to paracetamol during development.

PubMed

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

2016-12-01

The present study was designed to clarify the effect of prenatal and postnatal paracetamol administration on the neurotransmitter level and balance of amino acids in the cerebellum. Biochemical analysis to determine the concentration of neurotransmitters in this brain structure was performed on two-month-old Wistar male rats previously exposed to paracetamol in doses of 5 (P5, n=10) or 15mg/kg (P15, n=10) throughout the entire prenatal period, lactation and until the completion of the second month of life, when the experiment was terminated. Control animals were given tapped water (Con, n=10). The cerebellar concentration of monoamines, their metabolites and amino acids were assayed using High Performance Liquid Chromatography (HPLC). The present experiment demonstrates that prenatal and postnatal paracetamol exposure results in modulation of cerebellar neurotransmission with changes concerning mainly 5-HIAA and MHPG levels. The effect of paracetamol on monoaminergic neurotransmission in the cerebellum is reflected by changes in the level of catabolic end-products of serotonin (5-HIAA) and noradrenaline (MHPG) degradation. Further work is required to define the mechanism of action and impact of prenatal and postnatal exposure to paracetamol in the cerebellum and other structures of the central nervous system (CNS). Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Inhibition by spinal mu- and delta-opioid agonists of afferent-evoked substance P release.

PubMed

Kondo, Ichiro; Marvizon, Juan Carlos G; Song, Bingbing; Salgado, Frances; Codeluppi, Simone; Hua, Xiao-Ying; Yaksh, Tony L

2005-04-06

Opioid mu- and delta-receptors are present on the central terminals of primary afferents, where they are thought to inhibit neurotransmitter release. This mechanism may mediate analgesia produced by spinal opiates; however, when they used neurokinin 1 receptor (NK1R) internalization as an indicator of substance P release, Trafton et al. (1999) noted that this evoked internalization was altered only modestly by morphine delivered intrathecally at spinal cord segment S1-S2. We reexamined this issue by studying the effect of opiates on NK1R internalization in spinal cord slices and in vivo. In slices, NK1R internalization evoked by dorsal root stimulation at C-fiber intensity was abolished by the mu agonist [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO) (1 microM) and decreased by the delta agonist [D-Phe2,5]-enkephalin (DPDPE) (1 microM). In vivo, hindpaw compression induced NK1R internalization in ipsilateral laminas I-II. This evoked internalization was significantly reduced by morphine (60 nmol), DAMGO (1 nmol), and DPDPE (100 nmol), but not by the kappa agonist trans-(1S,2S)-3,4-dichloro-N-mathyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride (200 nmol), delivered at spinal cord segment L2 using intrathecal catheters. These doses of the mu and delta agonists were equi-analgesic as measured by a thermal escape test. Lower doses neither produced analgesia nor inhibited NK1R internalization. In contrast, morphine delivered by percutaneous injections at S1-S2 had only a modest effect on thermal escape, even at higher doses. Morphine decreased NK1R internalization after systemic delivery, but at a dose greater than that necessary to produce equivalent analgesia. All effects were reversed by naloxone. These results indicate that lumbar opiates inhibit noxious stimuli-induced neurotransmitter release from primary afferents at doses that are confirmed behaviorally as analgesic.

Electrochemically triggered release of acetylcholine from scCO2 impregnated conductive polymer films evokes intracellular Ca2+ signaling in neurotypic SH-SY5Y cells.

PubMed

Löffler, Susanne; Seyock, Silke; Nybom, Rolf; Jacobson, Gunilla B; Richter-Dahlfors, Agneta

2016-12-10

Implantable devices for electronically triggered drug release are attractive to achieve spatial and temporal control over drug concentrations in patients. Realization of such devices is, however, associated with technical and biological challenges. Among these are containment of drug reservoirs, lack of precise control cues, as well as the charge and size of the drug. Here, we present a method for electronically triggered release of the quaternary ammonium cation acetylcholine (ACh) from an impregnated conductive polymer film. Using supercritical carbon dioxide (scCO 2 ), a film of PEDOT/PSS (poly(3,4)-ethylenedioxythiophene doped with poly(styrenesulfonate)) is impregnated with the neurotransmitter acetylcholine. The gentle scCO 2 process generated a dry, drug-impregnated surface, well suited for interaction with biological material, while maintaining normal electrochemical properties of the polymer. Electrochemical switching of impregnated PEDOT/PSS films stimulated release of ACh from the polymer matrix, likely due to swelling mediated by the influx and efflux of charged and solvated ions. Triggered release of ACh did not affect the biological activity of the drug. This was shown by real-time monitoring of intracellular Ca 2+ signaling in neurotypic cells growing on the impregnated polymer surface. Collectively, scCO 2 impregnation of conducting polymers offers the first one-step, dopant-independent drug impregnation process, potentially facilitating loading of both anionic and cationic drugs that can be dissolved in scCO2 on its own or by using a co-solvent. We foresee that scCO 2 -loaded devices for electronically triggered drug release will create novel opportunities when generating active bio-coatings, tunable for specific needs, in a variety of medical settings. Copyright © 2016 Elsevier B.V. All rights reserved.

Histamine H3 Receptors Decrease Dopamine Release in the Ventral Striatum by Reducing the Activity of Striatal Cholinergic Interneurons.

PubMed

Varaschin, Rafael Koerich; Osterstock, Guillaume; Ducrot, Charles; Leino, Sakari; Bourque, Marie-Josée; Prado, Marco A M; Prado, Vania Ferreira; Salminen, Outi; Rannanpää Née Nuutinen, Saara; Trudeau, Louis-Eric

2018-04-15

Histamine H 3 receptors are widely distributed G i -coupled receptors whose activation reduces neuronal activity and inhibits release of numerous neurotransmitters. Although these receptors are abundantly expressed in the striatum, their modulatory role on activity-dependent dopamine release is not well understood. Here, we observed that histamine H 3 receptor activation indirectly diminishes dopamine overflow in the ventral striatum by reducing cholinergic interneuron activity. Acute brain slices from C57BL/6 or channelrhodopsin-2-transfected DAT-cre mice were obtained, and dopamine transients evoked either electrically or optogenetically were measured by fast-scan cyclic voltammetry. The H 3 agonist α-methylhistamine significantly reduced electrically- evoked dopamine overflow, an effect blocked by the nicotinic acetylcholine receptor antagonist dihydro-β-erythroidine, suggesting involvement of cholinergic interneurons. None of the drug treatments targeting H 3 receptors affected optogenetically evoked dopamine overflow, indicating that direct H 3 -modulation of dopaminergic axons is unlikely. Next, we used qPCR and confirmed the expression of histamine H 3 receptor mRNA in cholinergic interneurons, both in ventral and dorsal striatum. Activation of H 3 receptors by α-methylhistamine reduced spontaneous firing of cholinergic interneurons in the ventral, but not in the dorsal striatum. Resting membrane potential and number of spontaneous action potentials in ventral-striatal cholinergic interneurons were significantly reduced by α-methylhistamine. Acetylcholine release from isolated striatal synaptosomes, however, was not altered by α-methylhistamine. Together, these results indicate that histamine H 3 receptors are important modulators of dopamine release, specifically in the ventral striatum, and that they do so by decreasing the firing rate of cholinergic neurons and, consequently, reducing cholinergic tone on dopaminergic axons. Copyright © 2018 IBRO

[Glucagon-like peptide 2, a neurotransmitter with a newly discovered role in the regulation of food ingestion].

PubMed

Tang-Christensen, M; Larsen, P J; Thulesen, J; Nielsen, J R; Vrang, N

2001-01-15

We report here that glucagon-like peptide 2(GLP-2) and its receptor constitute a distinct projection system connecting the nucleus of the solitary tract with the dorsomedial hypothalamic nucleus (DMH). The DMH contains a dense plexus of GLP-2 immunoreactive fibres and is the only hypothalamic nucleus expressing GLP-2 receptor mRNA. Consistent with this, central application of GLP-2 activates the expression of neurones solely in the DMH. Furthermore, central administration of GLP-2 causes a dose-related, a pharmacologically and behaviourally specific inhibition of food intake in rats. Surprisingly, the alleged GLP-1 receptor antagonist, Exending (9-39), proved a functional antagonist of centrally applied GLP-2. These data implicate GLP-2 as an important neurotransmitter in the regulation of food intake and likely bodyweight. Our data therefore point to the DMH as a crossroad for endocrine and visceral information affecting feeding behaviour.

The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal.

PubMed

Contarino, Angelo; Papaleo, Francesco

2005-12-20

The negative affective symptoms of opiate withdrawal powerfully motivate drug-seeking behavior and may trigger relapse to heroin abuse. To date, no medications exist that effectively relieve the negative affective symptoms of opiate withdrawal. The corticotropin-releasing factor (CRF) system has been hypothesized to mediate the motivational effects of drug dependence. The CRF signal is transmitted by two distinct receptors named CRF receptor-1 (CRF1) and CRF2. Here we report that genetic disruption of CRF1 receptor pathways in mice eliminates the negative affective states of opiate withdrawal. In particular, neither CRF1 receptor heterozygous (CRF1+/-) nor homozygous (CRF1-/-) null mutant mice avoided environmental cues repeatedly paired with the early phase of opiate withdrawal. These results were not due to altered associative learning processes because CRF1+/- and CRF1-/- mice displayed reliable, conditioned place aversions to environmental cues paired with the kappa-opioid receptor agonist U-50,488H. We also examined the impact of CRF1 receptor-deficiency upon opiate withdrawal-induced dynorphin activity in the nucleus accumbens, a brain molecular mechanism thought to underlie the negative affective states of drug withdrawal. Consistent with the behavioral indices, we found that, during the early phase of opiate withdrawal, neither CRF1+/- nor CRF1-/- showed increased dynorphin mRNA levels in the nucleus accumbens. This study reveals a cardinal role for CRF/CRF1 receptor pathways in the negative affective states of opiate withdrawal and suggests therapeutic strategies for the treatment of opiate addiction.

Role of GABA Release From Leptin Receptor-Expressing Neurons in Body Weight Regulation

PubMed Central

Xu, Yuanzhong; O'Brien, William G.; Lee, Cheng-Chi; Myers, Martin G.

2012-01-01

It is well established that leptin regulates energy balance largely through isoform B leptin receptor-expressing neurons (LepR neurons) in the brain and that leptin activates one subset of LepR neurons (leptin-excited neurons) while inhibiting the other (leptin-inhibited neurons). However, the neurotransmitters released from LepR neurons that mediate leptin action in the brain are not well understood. Previous results demonstrate that leptin mainly acts on γ-aminobutyric acid (GABA)ergic neurons to reduce body weight, and that leptin activates proopiomelanocortin neuron activity by reducing GABA release onto these neurons, suggesting a body weight-promoting role for GABA released from leptin-inhibited neurons. To directly examine the role of GABA release from LepR neurons in body weight regulation, mice with disruption of GABA release specifically from LepR neurons were generated by deletion of vesicular GABA transporter in LepR neurons. Interestingly, these mice developed mild obesity on chow diet and were sensitive to diet-induced obesity, which were associated with higher food intake and lower energy expenditure. Moreover, these mice showed blunted responses in both food intake and body weight to acute leptin administration. These results demonstrate that GABA plays an important role in mediating leptin action. In combination with the previous studies that leptin reduces GABA release onto proopiomelanocortin neurons through leptin-inhibited neurons and that disruption of GABA release from agouti gene-related protein neurons, one subset of LepR-inhibited neurons, leads to a lean phenotype, our results suggest that, under our experimental conditions, GABA release from leptin-excited neuron dominates over leptin-inhibited ones. PMID:22334723

Leaky synapses: Regulation of spontaneous neurotransmission in central synapses

PubMed Central

Wasser, Catherine R.; Kavalali, Ege T.

2009-01-01

The mechanisms underlying spontaneous neurotransmitter release are not well understood. Under physiological as well as pathophysiological circumstances, spontaneous fusion events can set the concentration of ambient levels of neurotransmitter within the synaptic cleft and in the extracellular milieu. In the brain, unregulated release of excitatory neurotransmitters, exacerbated during pathological conditions such as stroke, can lead to neuronal damage and death. In addition, recent findings suggest that under physiological circumstances spontaneous release events can trigger postsynaptic signaling events independent of evoked neurotransmitter release. Therefore, elucidation of mechanisms underlying spontaneous neurotransmission may help us better understand the functional significance of this form of release and provide tools for its selective manipulation. For instance, our recent investigations indicate that the level of cholesterol in the synapse plays a critical role in limiting spontaneous synaptic vesicle fusion. Therefore, alterations in synaptic cholesterol metabolism can be a critical determinant of glutamatergic neurotransmission at rest. This article aims to provide a closer look into our current understanding of the mechanisms underlying spontaneous neurotransmission and the signaling triggered by these unitary release events. PMID:18434032

Initial substrate moisture content and storage temperature affects chemical properties of bagged substrates containing controlled release fertilizer at two different temperatures

USDA-ARS?s Scientific Manuscript database

Bagged potting mixes can be stored for weeks or months before being used by consumers. Some bagged potting mixes are amended with controlled release fertilizers (CRF). The objective of this research was to observe how initial substrate moisture content and storage temperature affect the chemical p...

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

Drug release through liposome pores.

PubMed

Dan, Nily

2015-02-01

Electrical, ultrasound and other types of external fields are known to induce the formation of pores in cellular and model membranes. This paper examines drug release through field induced liposome pores using Monte Carlo simulations. We find that drug release rates vary as a function of pore size and spacing, as well as the overall fraction of surface area covered by pores: The rate of release from liposomes is found to increase rapidly with pore surface coverage, approaching that of the fully ruptured liposome at fractional pore areas. For a given pore surface coverage, the pore size affects the release rate in the limit of low coverage, but not when the pores cover a relatively high fraction of the liposome surface area. On the other hand, for a given pore size and surface coverage, the distribution of pores significantly affects the release in the limit of high surface coverage: The rate of release from a liposome covered with a regularly spaced array of pores is, in this limit, higher than the release rate from (most) systems where the pores are distributed randomly on the liposome surface. In contrast, there is little effect of the pore distribution on release when the pore surface coverage is low. The simulation results are in good agreement with the predictions of detailed diffusion models. Copyright © 2014 Elsevier B.V. All rights reserved.

Effects of chronic delta-9-tetrahydrocannabinol (THC) administration on neurotransmitter concentrations and receptor binding in the rat brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ali, S.F.; Newport, G.D.; Scallet, A.C.

THC is the major psychoactive constituent of marijuana and is also known as an hallucinogenic compound. Numerous reports have shown that large doses of THC produce significant alterations in various neurotransmitter systems. The present study was designed to determine whether chronic exposure to THC produces significant alterations in selected neurotransmitter systems (dopamine, serotonin, acetylcholine, GABAergic, benzodiazepine, and opiate) in the rat brain. In Experiment 1, male Sprague-Dawley rats were gavaged with vehicle, 10 or 20 mg THC/kg body weight daily, 5 days/week for 90 days. Animals were killed either 24 hours or two months after the last dose. Brains weremore » dissected into different regions for neurochemical analyses. Two months after the cessation of chronic administration, there was a significant decrease in GABA receptor binding in the hippocampus of animals in the high dose group. However, no other significant changes were found in neurotransmitter receptor binding characteristics in the hippocampus or in neurotransmitter concentrations in the caudate nucleus, hypothalamus or septum after chronic THC administration. In an attempt to replicate the GABA receptor binding changes and also to determine the (35S)TBPS binding in hippocampus, we designed Experiment 2. In this experiment, we dosed the animals by gavage with 0, 5, 10 or 20 mg THC/kg daily, 5 days/week or with 20 mg THC/kg Monday through Thursday and 60 mg/kg on Friday for 90 days. Results from this experiment failed to replicate the dose-dependent effect of THC on GABA receptor binding in hippocampus. Modulation of (35S)TBPS binding by GABA or 3 alpha-OH-DHP or inhibition by cold TBPS in frontal cortex did not show any significant dose-related effects.« less

Effect of Gestational Exposure of Cypermethrin on Postnatal Development of Brain Cytochrome P450 2D1 and 3A1 and Neurotransmitter Receptors.

PubMed

Singh, Anshuman; Mudawal, Anubha; Shukla, Rajendra K; Yadav, Sanjay; Khanna, Vinay K; Sethumadhavan, Rao; Parmar, Devendra

2015-08-01

Oral administration of low doses (1.25, 2.5, or 5 mg/kg) of cypermethrin to pregnant Wistar rats from gestation days 5 to 21 led to dose-dependent differences in the induction of cytochrome P450 2D1 (CYP2D1) and 3A1 messenger RNA (mRNA) and protein in brain regions isolated from the offsprings postnatally at 3 weeks that persisted up to adulthood (12 weeks). Similar alterations were observed in the expression of GABAergic, muscarinic, dopaminergic, and serotonergic neurotransmitter receptors in brain regions of rat offsprings. Rechallenge of the prenatally exposed offsprings at adulthood (12 weeks old) with cypermethrin (p.o., 10 mg/kg for 6 days) led to a greater magnitude of alterations in the expression of CYPs, neurotransmitter receptors, and neurotransmitter receptor binding in the brain regions when compared to the control offsprings treated at adulthood with cypermethrin or prenatally exposed offsprings. A greater magnitude of decrease was also observed in the spontaneous locomotor activity (SLA) in prenatally exposed offsprings rechallenged with cypermethrin. The present data indicating similarities in the alterations in the expression of CYPs (2D1 and 3A1) and neurotransmitter receptors in brain has led us to suggest that endogenous function regulating CYPs is possibly associated with neurotransmission processes. A greater magnitude of alterations in CYP2D1, 3A1, neurotransmitter receptors, and SLA in rechallenged animals has further provided evidence that alterations in CYPs are possibly linked with neurotransmission processes.

Under stressful conditions activation of the ionotropic P2X7 receptor differentially regulates GABA and glutamate release from nerve terminals of the rat cerebral cortex.

PubMed

Barros-Barbosa, Aurora R; Oliveira, Ângela; Lobo, M Graça; Cordeiro, J Miguel; Correia-de-Sá, Paulo

2018-01-01

γ-Aminobutyric acid (GABA) and glutamate (Glu) are the main inhibitory and excitatory neurotransmitters in the central nervous system (CNS), respectively. Fine tuning regulation of extracellular levels of these amino acids is essential for normal brain activity. Recently, we showed that neocortical nerve terminals from patients with epilepsy express higher amounts of the non-desensitizing ionotropic P2X7 receptor. Once activated by ATP released from neuronal cells, the P2X7 receptor unbalances GABAergic vs. glutamatergic neurotransmission by differentially interfering with GABA and Glu uptake. Here, we investigated if activation of the P2X7 receptor also affects [ 3 H]GABA and [ 14 C]Glu release measured synchronously from isolated nerve terminals (synaptosomes) of the rat cerebral cortex. Data show that activation of the P2X7 receptor consistently increases [ 14 C]Glu over [ 3 H]GABA release from cortical nerve terminals, but the GABA/Glu ratio depends on extracellular Ca 2+ concentrations. While the P2X7-induced [ 3 H]GABA release is operated by a Ca 2+ -dependent pathway when external Ca 2+ is available, this mechanism shifts towards the reversal of the GAT1 transporter in low Ca 2+ conditions. A different scenario is verified regarding [ 14 C]Glu outflow triggered by the P2X7 receptor, since the amino acid seems to be consistently released through the recruitment of connexin-containing hemichannels upon P2X7 activation, both in the absence and in the presence of external Ca 2+ . Data from this study add valuable information suggesting that ATP, via P2X7 activation, not only interferes with the high-affinity uptake of GABA and Glu but actually favors the release of these amino acids through distinct molecular mechanisms amenable to differential therapeutic control. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cathepsin H Functions as an Aminopeptidase in Secretory Vesicles for Production of Enkephalin and Galanin Peptide Neurotransmitters

PubMed Central

Lu, W. Douglas; Funkelstein, Lydiane; Toneff, Thomas; Reinheckel, Thomas; Peters, Christoph; Hook, Vivian

2012-01-01

Peptide neurotransmitters function as key intercellular signaling molecules in the nervous system. These peptides are generated in secretory vesicles from proneuropeptides by proteolytic processing at dibasic residues, followed by removal of N- and/or C-terminal basic residues to form active peptides. Enkephalin biosynthesis from proenkephalin utilizes the cysteine protease cathepsin L and the subtilisin-like prohormone convertase 2 (PC2). Cathepsin L generates peptide intermediates with N-terminal basic residue extensions, which must be removed by an aminopeptidase. In this study, we identified cathepsin H as an aminopeptidase in secretory vesicles that produces (Met)enkephalin (ME) by sequential removal of basic residues from KR-ME and KK-ME, supported by in vivo knockout of the cathepsin H gene. Localization of cathepsin H in secretory vesicles was demonstrated by immunoelectron microscopy and confocal immunofluorescence microscopy. Purified human cathepsin H sequentially removes N-terminal basic residues to generate ME, with peptide products characterized by nano-LC-MS/MS tandem mass spectrometry. Cathepsin H shows highest activities for cleaving N-terminal basic residues (Arg and Lys) among amino acid fluorogenic substrates. Notably, knockout of the cathepsin H gene results in reduction of ME in mouse brain. Cathepsin H deficient mice also show a substantial decrease in galanin peptide neurotransmitter levels in brain. These results illustrate a role for cathepsin H as an aminopeptidase for enkephalin and galanin peptide neurotransmitter production. PMID:22582844

Affective Cognition and its Disruption in Mood Disorders

PubMed Central

Elliott, Rebecca; Zahn, Roland; Deakin, J F William; Anderson, Ian M

2011-01-01

In this review, we consider affective cognition, responses to emotional stimuli occurring in the context of cognitive evaluation. In particular, we discuss emotion categorization, biasing of memory and attention, as well as social/moral emotion. We discuss limited neuropsychological evidence suggesting that affective cognition depends critically on the amygdala, ventromedial frontal cortex, and the connections between them. We then consider neuroimaging studies of affective cognition in healthy volunteers, which have led to the development of more sophisticated neural models of these processes. Disturbances of affective cognition are a core and specific feature of mood disorders, and we discuss the evidence supporting this claim, both from behavioral and neuroimaging perspectives. Serotonin is considered to be a key neurotransmitter involved in depression, and there is a considerable body of research exploring whether serotonin may mediate disturbances of affective cognition. The final section presents an overview of this literature and considers implications for understanding the pathophysiology of mood disorder as well as developing and evaluating new treatment strategies. PMID:20571485

Adolescent binge drinking alters adult brain neurotransmitter gene expression, behavior, brain regional volumes, and neurochemistry in mice

PubMed Central

Coleman, Leon G.; He, Jun; Lee, Joohwi; Styner, Martin; Crews, Fulton T.

2013-01-01

Background Binge-drinking is common in human adolescents. The adolescent brain is undergoing structural maturation and has a unique sensitivity to alcohol neurotoxicity. Therefore, adolescent binge ethanol may have long-term effects on the adult brain that alter brain structure and behaviors that are relevant to alcohol use disorders. Methods In order to determine if adolescent ethanol binge drinking alters the adult brain, male C57BL/6 mice were treated with either water or ethanol during adolescence (5g/kg/day i.g., post-natal days P28-37) and assessed during adulthood (P60-P88). An array of neurotransmitter-specific genes, behavioral tests (i.e. reversal learning, prepulse inhibition, and open field), and post-mortem brain structure using MRI and immunohistochemistry, were employed to assess persistent alterations in adult brain. Results At P38, 24 hours after adolescent ethanol (AE) binge, many neurotransmitter genes, particularly cholinergic and dopaminergic, were reduced by ethanol treatment. Interestingly, dopamine receptor type 4 mRNA was reduced and confirmed using immunohistochemistry. Normal control maturation (P38-P88) resulted in decreased neurotransmitter mRNA, e.g. an average decrease of 56%. Following adolescent ethanol treatment, adults showed greater gene expression reductions than controls, averaging 73%. Adult spatial learning assessed in the Morris water maze was not changed by adolescent ethanol treatment, but reversal learning experiments revealed deficits. Assessment of adult brain region volumes using MRI indicated that the olfactory bulb and basal forebrain were smaller in adults following adolescent ethanol. Immunohistochemical analyses found reduced basal forebrain area and fewer basal forebrain cholinergic neurons. Conclusions Adolescent binge ethanol treatment reduces adult neurotransmitter gene expression, particularly cholinergic genes, reduces basal forebrain and olfactory bulb volumes, and causes a reduction in the density of basal

Neuromodulatory properties of fluorescent carbon dots: effect on exocytotic release, uptake and ambient level of glutamate and GABA in brain nerve terminals.

PubMed

Borisova, Tatiana; Nazarova, Anastasia; Dekaliuk, Mariia; Krisanova, Natalia; Pozdnyakova, Natalia; Borysov, Arsenii; Sivko, Roman; Demchenko, Alexander P

2015-02-01

Carbon dots (C-dots), a recently discovered class of fluorescent nano-sized particles with pure carbon core, have great bioanalytical potential. Neuroactive properties of fluorescent C-dots obtained from β-alanine by microwave heating were assessed based on the analysis of their effects on the key characteristics of GABA- and glutamatergic neurotransmission in isolated rat brain nerve terminals. It was found that C-dots (40-800 μg/ml) in dose-dependent manner: (1) decreased exocytotic release of [(3)H]GABA and L-[(14)C]glutamate; (2) reduced acidification of synaptic vesicles; (3) attenuated the initial velocity of Na(+)-dependent transporter-mediated uptake of [(3)H]GABA and L-[(14)C]glutamate; (4) increased the ambient level of the neurotransmitters, nevertheless (5) did not change significantly the potential of the plasma membrane of nerve terminals. Almost complete suppression of exocytotic release of the neurotransmitters was caused by C-dots at a concentration of 800 μg/ml. Fluorescent and neuromodulatory features combined in C-dots create base for their potential usage for labeling and visualization of key processes in nerve terminals, and also in theranostics. In addition, natural presence of carbon-containing nanoparticles in the human food chain and in the air may provoke the development of neurologic consequences. Copyright © 2014 Elsevier Ltd. All rights reserved.

Vinpocetine inhibits glutamate release induced by the convulsive agent 4-aminopyridine more potently than several antiepileptic drugs.

PubMed

Sitges, M; Sanchez-Tafolla, B M; Chiu, L M; Aldana, B I; Guarneros, A

2011-10-01

4-Aminopyridine (4-AP) is a convulsing agent that in vivo preferentially releases Glu, the most important excitatory amino acid neurotransmitter in the brain. Here the ionic dependence of 4-AP-induced Glu release and the effects of several of the most common antiepileptic drugs (AEDs) and of the new potential AED, vinpocetine on 4-AP-induced Glu release were characterized in hippocampus isolated nerve endings pre-loaded with labelled Glu ([3H]Glu). 4-AP-induced [3H]Glu release was composed by a tetrodotoxin (TTX) sensitive and external Ca2+ dependent fraction and a TTX insensitive fraction that was sensitive to the excitatory amino acid transporter inhibitor, TBOA. The AEDs: carbamazepine, phenytoin, lamotrigine and oxcarbazepine at the highest dose tested only reduced [3H]Glu release to 4-AP between 50-60%, and topiramate was ineffective. Vinpocetine at a much lower concentration than the above AEDs, abolished [3H]Glu release to 4-AP. We conclude that the decrease in [3H]Glu release linked to the direct blockade of presynaptic Na+ channels, may importantly contribute to the anticonvulsant actions of all the drugs tested here (except topiramate); and that the significantly greater vinpocetine effect in magnitude and potency on [3H]Glu release when excitability is exacerbated like during seizures, may involve the increase additionally exerted by vinpocetine in some K+ channels permeability. Copyright © 2011 Elsevier B.V. All rights reserved.

Hypertonic enhancement of transmitter release from frog motor nerve terminals: Ca2+ independence and role of integrins

NASA Technical Reports Server (NTRS)

Kashani, A. H.; Chen, B. M.; Grinnell, A. D.

2001-01-01

Hyperosmotic solutions cause markedly enhanced spontaneous quantal release of neurotransmitter from many nerve terminals. The mechanism of this enhancement is unknown. We have investigated this phenomenon at the frog neuromuscular junction with the aim of determining the degree to which it resembles the modulation of release by stretch, which has been shown to be mediated by mechanical tension on integrins.The hypertonicity enhancement, like the stretch effect, does not require Ca2+ influx or release from internal stores, although internal release may contribute to the effect. The hypertonicity effect is sharply reduced (but not eliminated) by peptides containing the RGD sequence, which compete with native ligands for integrin bonds.There is co-variance in the magnitude of the stretch and osmotic effects; that is, individual terminals exhibiting a large stretch effect also show strong enhancement by hypertonicity, and vice versa. The stretch and osmotic enhancements also can partially occlude each other.There remain some clear-cut differences between osmotic and stretch forms of modulation: the larger range of enhancement by hypertonic solutions, the relative lack of effect of osmolarity on evoked release, and the reported higher temperature sensitivity of osmotic enhancement. Nevertheless, our data strongly implicate integrins in a significant fraction of the osmotic enhancement, possibly acting via the same mechanism as stretch modulation.

The effects of ecstasy on neurotransmitter systems: a review on the findings of molecular imaging studies.

PubMed

Vegting, Yosta; Reneman, Liesbeth; Booij, Jan

2016-10-01

Ecstasy is a commonly used psychoactive drug with 3,4-methylenedioxymethamphetamine (MDMA) as the main content. Importantly, it has been suggested that use of MDMA may be neurotoxic particularly for serotonergic (5-hydroxytryptamine (5-HT)) neurons. In the past decades, several molecular imaging studies examined directly in vivo the effects of ecstasy/MDMA on neurotransmitter systems. The objective of the present study is to review the effects of ecstasy/MDMA on neurotransmitter systems as assessed by molecular imaging studies in small animals, non-human primates and humans. A search in PubMed was performed. Eighty-eight articles were found on which inclusion and exclusion criteria were applied. Thirty-three studies met the inclusion criteria; all were focused on the 5-HT or dopamine (DA) system. Importantly, 9 out of 11 of the animal studies that examined the effects of MDMA on 5-HT transporter (SERT) availability showed a significant loss of binding potential. In human studies, this was the case for 14 out of 16 studies, particularly in heavy users. In abstinent users, significant recovery of SERT binding was found over time. Most imaging studies in humans that focused on the DA system did not find any significant effect of ecstasy/MDMA use. Preclinical and clinical molecular imaging studies on the effects of ecstasy/MDMA use/administration on neurotransmitter systems show quite consistent alterations of the 5-HT system. Particularly, in human studies, loss of SERT binding was observed in heavy ecstasy users, which might reflect 5-HT neurotoxicity, although alternative explanations (e.g. down-regulation of the SERT) cannot be excluded.

Metabotropic GABAB receptors mediate GABA inhibition of acetylcholine release in the rat neuromuscular junction.

PubMed

Malomouzh, Artem I; Petrov, Konstantin A; Nurullin, Leniz F; Nikolsky, Evgeny E

2015-12-01

Gamma-aminobutyric acid (GABA) is an amino acid which acts as a neurotransmitter in the central nervous system. Here, we studied the effects of GABA on non-quantal, spontaneous, and evoked quantal acetylcholine (ACh) release from motor nerve endings. We found that while the application of 10 μM of GABA had no effect on spontaneous quantal ACh release, as detected by the frequency of miniature endplate potentials, GABA reduced the non-quantal ACh release by 57%, as determined by the H-effect value. Finally, the evoked quantal ACh release, estimated by calculating the quantal content of full-sized endplate potentials (EPPs), was reduced by 34%. GABA's inhibitory effect remained unchanged after pre-incubation with picrotoxin, an ionotropic GABAA receptor blocker, but was attenuated following application of the GABAB receptor blocker CGP 55845, which itself had no effect on ACh release. An inhibitor of phospholipase C, U73122, completely prevented the GABA-induced decrease in ACh release. Immunofluorescence demonstrated the presence of both subunits of the GABAB receptor (GABAB R1 and GABAB R2) in the neuromuscular junction. These findings suggest that metabotropic GABAB receptors are expressed in the mammalian neuromuscular synapse and their activation results in a phospholipase C-mediated reduction in the intensity of non-quantal and evoked quantal ACh release. We investigated the effect of gamma-aminobutyric acid (GABA) on neuromuscular transmission. GABA reduced the non-quantal and evoked quantal release of acetylcholine. These effects are mediated by GABAB receptors and are implemented via phospholipase C (PLC) activation. Our findings suggest that in the mammalian neuromuscular synapse, metabotropic GABAB receptors are expressed and their activation results in a reduction in the intensity of acetylcholine release. © 2015 International Society for Neurochemistry.

Evx1 and Evx2 specify excitatory neurotransmitter fates and suppress inhibitory fates through a Pax2-independent mechanism.

PubMed

Juárez-Morales, José L; Schulte, Claus J; Pezoa, Sofia A; Vallejo, Grace K; Hilinski, William C; England, Samantha J; de Jager, Sarah; Lewis, Katharine E

2016-02-19

For neurons to function correctly in neuronal circuitry they must utilize appropriate neurotransmitters. However, even though neurotransmitter specificity is one of the most important and defining properties of a neuron we still do not fully understand how neurotransmitter fates are specified during development. Most neuronal properties are determined by the transcription factors that neurons express as they start to differentiate. While we know a few transcription factors that specify the neurotransmitter fates of particular neurons, there are still many spinal neurons for which the transcription factors specifying this critical phenotype are unknown. Strikingly, all of the transcription factors that have been identified so far as specifying inhibitory fates in the spinal cord act through Pax2. Even Tlx1 and Tlx3, which specify the excitatory fates of dI3 and dI5 spinal neurons work at least in part by down-regulating Pax2. In this paper we use single and double mutant zebrafish embryos to identify the spinal cord functions of Evx1 and Evx2. We demonstrate that Evx1 and Evx2 are expressed by spinal cord V0v cells and we show that these cells develop into excitatory (glutamatergic) Commissural Ascending (CoSA) interneurons. In the absence of both Evx1 and Evx2, V0v cells still form and develop a CoSA morphology. However, they lose their excitatory fate and instead express markers of a glycinergic fate. Interestingly, they do not express Pax2, suggesting that they are acquiring their inhibitory fate through a novel Pax2-independent mechanism. Evx1 and Evx2 are required, partially redundantly, for spinal cord V0v cells to become excitatory (glutamatergic) interneurons. These results significantly increase our understanding of the mechanisms of neuronal specification and the genetic networks involved in these processes.

Near-future carbon dioxide levels alter fish behaviour by interfering with neurotransmitter function

NASA Astrophysics Data System (ADS)

Nilsson, Göran E.; Dixson, Danielle L.; Domenici, Paolo; McCormick, Mark I.; Sørensen, Christina; Watson, Sue-Ann; Munday, Philip L.

2012-03-01

Predicted future CO2 levels have been found to alter sensory responses and behaviour of marine fishes. Changes include increased boldness and activity, loss of behavioural lateralization, altered auditory preferences and impaired olfactory function. Impaired olfactory function makes larval fish attracted to odours they normally avoid, including ones from predators and unfavourable habitats. These behavioural alterations have significant effects on mortality that may have far-reaching implications for population replenishment, community structure and ecosystem function. However, the underlying mechanism linking high CO2 to these diverse responses has been unknown. Here we show that abnormal olfactory preferences and loss of behavioural lateralization exhibited by two species of larval coral reef fish exposed to high CO2 can be rapidly and effectively reversed by treatment with an antagonist of the GABA-A receptor. GABA-A is a major neurotransmitter receptor in the vertebrate brain. Thus, our results indicate that high CO2 interferes with neurotransmitter function, a hitherto unrecognized threat to marine populations and ecosystems. Given the ubiquity and conserved function of GABA-A receptors, we predict that rising CO2 levels could cause sensory and behavioural impairment in a wide range of marine species, especially those that tightly control their acid-base balance through regulatory changes in HCO3- and Cl- levels.

Short-Term Facilitation at a Detonator Synapse Requires the Distinct Contribution of Multiple Types of Voltage-Gated Calcium Channels.

PubMed

Chamberland, Simon; Evstratova, Alesya; Tóth, Katalin

2017-05-10

Neuronal calcium elevations are shaped by several key parameters, including the properties, density, and the spatial location of voltage-gated calcium channels (VGCCs). These features allow presynaptic terminals to translate complex firing frequencies and tune the amount of neurotransmitter released. Although synchronous neurotransmitter release relies on both P/Q- and N-type VGCCs at hippocampal mossy fiber-CA3 synapses, the specific contribution of VGCCs to calcium dynamics, neurotransmitter release, and short-term facilitation remains unknown. Here, we used random-access two-photon calcium imaging together with electrophysiology in acute mouse hippocampal slices to dissect the roles of P/Q- and N-type VGCCs. Our results show that N-type VGCCs control glutamate release at a limited number of release sites through highly localized Ca 2+ elevations and support short-term facilitation by enhancing multivesicular release. In contrast, Ca 2+ entry via P/Q-type VGCCs promotes the recruitment of additional release sites through spatially homogeneous Ca 2+ elevations. Altogether, our results highlight the specialized contribution of P/Q- and N-types VGCCs to neurotransmitter release. SIGNIFICANCE STATEMENT In presynaptic terminals, neurotransmitter release is dynamically regulated by the transient opening of different types of voltage-gated calcium channels. Hippocampal giant mossy fiber terminals display extensive short-term facilitation during repetitive activity, with a large several fold postsynaptic response increase. Though, how giant mossy fiber terminals leverage distinct types of voltage-gated calcium channels to mediate short-term facilitation remains unexplored. Here, we find that P/Q- and N-type VGCCs generate different spatial patterns of calcium elevations in giant mossy fiber terminals and support short-term facilitation through specific participation in two mechanisms. Whereas N-type VGCCs contribute only to the synchronization of multivesicular release

Integrated hybrid polystyrene-polydimethylsiloxane device for monitoring cellular release with microchip electrophoresis and electrochemical detection

PubMed Central

Johnson, Alicia S.; Mehl, Benjamin T.; Martin, R. Scott

2015-01-01

In this work, a polystyrene (PS)-polydimethylsiloxane (PDMS) hybrid device was developed to enable the integration of cell culture with analysis by microchip electrophoresis and electrochemical detection. It is shown that this approach combines the fundamental advantages of PDMS devices (the ability to integrate pumps and valves) and PS devices (the ability to permanently embed fluidic tubing and electrodes). The embedded fused-silica capillary enables high temporal resolution measurements from off-chip cell culture dishes and the embedded electrodes provide close to real-time analysis of small molecule neurotransmitters. A novel surface treatment for improved (reversible) adhesion between PS and PDMS is described using a chlorotrimethylsilane stamping method. It is demonstrated that a Pd decoupler is efficient at handling the high current (and cathodic hydrogen production) resulting from use of high ionic strength buffers needed for cellular analysis; thus allowing an electrophoretic separation and in-channel detection. The separation of norepinephrine (NE) and dopamine (DA) in highly conductive biological buffers was optimized using a mixed surfactant system. This PS-PDMS hybrid device integrates multiple processes including continuous sampling from a cell culture dish, on-chip pump and valving technologies, microchip electrophoresis, and electrochemical detection to monitor neurotransmitter release from PC 12 cells. PMID:25663849

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.

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

Ionic residues of human serum transferrin affect binding to the transferrin receptor and iron release.

PubMed

Steere, Ashley N; Miller, Brendan F; Roberts, Samantha E; Byrne, Shaina L; Chasteen, N Dennis; Smith, Valerie C; MacGillivray, Ross T A; Mason, Anne B

2012-01-17

Efficient delivery of iron is critically dependent on the binding of diferric human serum transferrin (hTF) to its specific receptor (TFR) on the surface of actively dividing cells. Internalization of the complex into an endosome precedes iron removal. The return of hTF to the blood to continue the iron delivery cycle relies on the maintenance of the interaction between apohTF and the TFR after exposure to endosomal pH (≤6.0). Identification of the specific residues accounting for the pH-sensitive nanomolar affinity with which hTF binds to TFR throughout the cycle is important to fully understand the iron delivery process. Alanine substitution of 11 charged hTF residues identified by available structures and modeling studies allowed evaluation of the role of each in (1) binding of hTF to the TFR and (2) TFR-mediated iron release. Six hTF mutants (R50A, R352A, D356A, E357A, E367A, and K511A) competed poorly with biotinylated diferric hTF for binding to TFR. In particular, we show that Asp356 in the C-lobe of hTF is essential to the formation of a stable hTF-TFR complex: mutation of Asp356 in the monoferric C-lobe hTF background prevented the formation of the stoichiometric 2:2 (hTF:TFR monomer) complex. Moreover, mutation of three residues (Asp356, Glu367, and Lys511), whether in the diferric or monoferric C-lobe hTF, significantly affected iron release when in complex with the TFR. Thus, mutagenesis of charged hTF residues has allowed identification of a number of residues that are critical to formation of and release of iron from the hTF-TFR complex.

Parvalbumin Interneurons of Central Amygdala Regulate the Negative Affective States and the Expression of Corticotrophin-Releasing Hormone During Morphine Withdrawal

PubMed Central

Wang, Li; Shen, Minjie; Jiang, Changyou

2016-01-01

Background: The central nucleus of the amygdala (CeA) is a crucial component of the neuronal circuitry mediating aversive emotion. Its role in the negative affective states during drug withdrawal includes changes in opioidergic, GABAergic, and corticotropin-releasing factor neurotransmission. However, the modulation of the neurobiological interconnectivity in the CeA and its effects in the negative reinforcement of drug dependents are poorly understood. Method: We performed electrophysiological recordings to assess the membrane excitability of parvalbumin (PV)+ interneurons in the CeA during chronic morphine withdrawal. We tested the morphine withdrawal–induced negative affective states, such as the aversive (assessed by conditioned place aversion), anxiety (assessed by elevated plus maze), and anhedonic-like (assessed by saccharin preference test) behaviors, as well as the mRNA level of corticotropin-releasing hormone (CRH) via optogenetic inhibition or activation of PV+ interneurons in the CeA. Result: Chronic morphine withdrawal increased the firing rate of CeA PV+ interneurons. Optogenetic inhibition of the activity of CeA PV+ interneurons attenuated the morphine withdrawal–induced negative affective states, such as the aversive, anxiety, and anhedonic-like behaviors, while direct activation of CeA PV+ interneurons could trigger those negative affective-like behaviors. Optogenetic inhibition of the CeA PV+ interneurons during the morphine withdrawal significantly attenuated the elevated CRH mRNA level in the CeA. Conclusion: The activity of PV+ interneurons in the CeA was up-regulated during chronic morphine withdrawal. The activation of PV+ interneurons during morphine withdrawal was crucial for the induction of the negative emotion and the up-regulation of CRH mRNA levels in the CeA. PMID:27385383

High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons

PubMed Central

Qiu, Jian; Nestor, Casey C; Zhang, Chunguang; Padilla, Stephanie L; Palmiter, Richard D

2016-01-01

Kisspeptin (Kiss1) and neurokinin B (NKB) neurocircuits are essential for pubertal development and fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (Kiss1ARH) co-express Kiss1, NKB, dynorphin and glutamate and are postulated to provide an episodic, excitatory drive to gonadotropin-releasing hormone 1 (GnRH) neurons, the synaptic mechanisms of which are unknown. We characterized the cellular basis for synchronized Kiss1ARH neuronal activity using optogenetics, whole-cell electrophysiology, molecular pharmacology and single cell RT-PCR in mice. High-frequency photostimulation of Kiss1ARH neurons evoked local release of excitatory (NKB) and inhibitory (dynorphin) neuropeptides, which were found to synchronize the Kiss1ARH neuronal firing. The light-evoked synchronous activity caused robust excitation of GnRH neurons by a synaptic mechanism that also involved glutamatergic input to preoptic Kiss1 neurons from Kiss1ARH neurons. We propose that Kiss1ARH neurons play a dual role of driving episodic secretion of GnRH through the differential release of peptide and amino acid neurotransmitters to coordinate reproductive function. DOI: http://dx.doi.org/10.7554/eLife.16246.001 PMID:27549338

Dopamine Modulates Delta-Gamma Phase-Amplitude Coupling in the Prefrontal Cortex of Behaving Rats

PubMed Central

Andino-Pavlovsky, Victoria; Souza, Annie C.; Scheffer-Teixeira, Robson; Tort, Adriano B. L.; Etchenique, Roberto; Ribeiro, Sidarta

2017-01-01

Dopamine release and phase-amplitude cross-frequency coupling (CFC) have independently been implicated in prefrontal cortex (PFC) functioning. To causally investigate whether dopamine release affects phase-amplitude comodulation between different frequencies in local field potentials (LFP) recorded from the medial PFC (mPFC) of behaving rats, we used RuBiDopa, a light-sensitive caged compound that releases the neurotransmitter dopamine when irradiated with visible light. LFP power did not change in any frequency band after the application of light-uncaged dopamine, but significantly strengthened phase-amplitude comodulation between delta and gamma oscillations. Saline did not exert significant changes, while injections of dopamine and RuBiDopa produced a slow increase in comodulation for several minutes after the injection. The results show that dopamine release in the medial PFC shifts phase-amplitude comodulation from theta-gamma to delta-gamma. Although being preliminary results due to the limitation of the low number of animals present in this study, our findings suggest that dopamine-mediated modification of the frequencies involved in comodulation could be a mechanism by which this neurotransmitter regulates functioning in mPFC. PMID:28536507

JIEYUANSHEN DECOCTION EXERTS ANTIDEPRESSANT EFFECTS ON DEPRESSIVE RAT MODEL VIA REGULATING HPA AXIS AND THE LEVEL OF AMINO ACIDS NEUROTRANSMITTER

PubMed Central

qiuxia, Zhang; xinlong, Ma; yilong, Yang; hui, Zhao; yali, Wang; xiaoquan, Yao; lei, Wang; jiahui, Chang; haiyan, Zou

2017-01-01

Background: Jieyuanshen decoction (JYAS-D) - a traditional Chinese medicine was invented by Professor Nie based on classic formulas, chaihu jia longgu muli decoction has been proved as having favorable curative effects on depression in clinical practices. The aim of this study was to investigate the antidepressant effects and its molecular mechanism of JYAS-D. Materials and Methods: The model of depression was established by Chronic Unpredictable Stress. Different doses (8.2 g/kg, 16.3 g/kg, 32.7 g/kg) of JYAS-D was orally administered; Fluoxetine was orally administered with 10mg/kg. All treatments lasted for 28 days. Sucrose preference and open-field tests were adopted to observe the behavior of rats. OPA (ortho-phthalaldehyde) derivatization method was used to detect the contents of amino acid neurotransmitter. RIA (Radiation immunity analysis) method was used to measure the serum concentrations of CORT (Corticosterone), ACTH (Adrenocorticotropic hormone) and CRH (Corticotropin-releasing hormone). ELISA (Enzyme linked immunosorbent assay) method was adopted to examine the contents of Glucocorticoid receptor (GR) and Mineralocorticoid receptor (MR) in hippocampus. Results: Compared with the model group, sucrose preference was increased in all treatment groups. The concentration of serum CORT was reduced in the middle dose of JYAS-D and control groups; the concentration of serum ACTH was reduced in the low and high-dose of JYAS-D; the concentration of serum CRH was reduced in the middle and high-dose of JYAS-D. The content of hippocampus GR was increased in the middle and high-dose of JYAS-D; the content of hippocampus Glu (Glutamic acid) was reduced among the low, middle and high-dose of JYAS-D and fluoxetine group, the ratio of Glu/γ-GABA (y-aminobutyric acid was reduced in the low and high-dose of JYAS-D. Conclusion: JYAS-D had a significant antidepressant-like effect on rat model through regulating serum concentration of CORT, ACTH and CRH, increasing the

JIEYUANSHEN DECOCTION EXERTS ANTIDEPRESSANT EFFECTS ON DEPRESSIVE RAT MODEL VIA REGULATING HPA AXIS AND THE LEVEL OF AMINO ACIDS NEUROTRANSMITTER.

PubMed

Qiuxia, Zhang; Xinlong, Ma; Yilong, Yang; Hui, Zhao; Yali, Wang; Xiaoquan, Yao; Lei, Wang; Jiahui, Chang; Haiyan, Zou

2017-01-01

Jieyuanshen decoction (JYAS-D) - a traditional Chinese medicine was invented by Professor Nie based on classic formulas, chaihu jia longgu muli decoction has been proved as having favorable curative effects on depression in clinical practices. The aim of this study was to investigate the antidepressant effects and its molecular mechanism of JYAS-D. The model of depression was established by Chronic Unpredictable Stress. Different doses (8.2 g/kg, 16.3 g/kg, 32.7 g/kg) of JYAS-D was orally administered; Fluoxetine was orally administered with 10mg/kg. All treatments lasted for 28 days. Sucrose preference and open-field tests were adopted to observe the behavior of rats. OPA (ortho-phthalaldehyde) derivatization method was used to detect the contents of amino acid neurotransmitter. RIA (Radiation immunity analysis) method was used to measure the serum concentrations of CORT (Corticosterone), ACTH (Adrenocorticotropic hormone) and CRH (Corticotropin-releasing hormone). ELISA (Enzyme linked immunosorbent assay) method was adopted to examine the contents of Glucocorticoid receptor (GR) and Mineralocorticoid receptor (MR) in hippocampus. Compared with the model group, sucrose preference was increased in all treatment groups. The concentration of serum CORT was reduced in the middle dose of JYAS-D and control groups; the concentration of serum ACTH was reduced in the low and high-dose of JYAS-D; the concentration of serum CRH was reduced in the middle and high-dose of JYAS-D. The content of hippocampus GR was increased in the middle and high-dose of JYAS-D; the content of hippocampus Glu (Glutamic acid) was reduced among the low, middle and high-dose of JYAS-D and fluoxetine group, the ratio of Glu/γ-GABA (y-aminobutyric acid was reduced in the low and high-dose of JYAS-D. JYAS-D had a significant antidepressant-like effect on rat model through regulating serum concentration of CORT, ACTH and CRH, increasing the content of hippocampus GR and regulating the equilibrium of

The Sea Urchin Embryo, an Invertebrate Model for Mammalian Developmental Neurotoxicity, Reveals Multiple Neurotransmitter Mechanisms for Effects of Chlorpyrifos: Therapeutic Interventions and a Comparison with the Monoamine Depleter, Reserpine

PubMed Central

Buznikov, Gennady A.; Nikitina, Lyudmila A.; Rakić, Ljubiša M.; Miloševi, Ivan; Bezuglov, Vladimir V.; Lauder, Jean M.; Slotkin, Theodore A.

2007-01-01

Lower organisms show promise for the screening of neurotoxicants that might target mammalian brain development. Sea urchins use neurotransmitters as embryonic growth regulatory signals, so that adverse effects on neural substrates for mammalian brain development can be studied in this simple organism. We compared the effects of the organophosphate insecticide, chlorpyrifos in sea urchin embryos with those of the monoamine depleter, reserpine, so as to investigate multiple neurotransmitter mechanisms involved in developmental toxicity and to evaluate different therapeutic interventions corresponding to each neurotransmitter system. Whereas reserpine interfered with all stages of embryonic development, the effects of chlorpyrifos did not emerge until the mid-blastula stage. After that point, the effects of the two agents were similar. Treatment with membrane permeable analogs of the monoamine neurotransmitters, serotonin and dopamine, prevented the adverse effects of either chlorpyrifos or reserpine, despite the fact that chlorpyrifos works simultaneously through actions on acetylcholine, monoamines and other neurotransmitter pathways. This suggests that different neurotransmitters, converging on the same downstream signaling events, could work together or in parallel to offset the developmental disruption caused by exposure to disparate agents. We tested this hypothesis by evaluating membrane permeable analogs of acetylcholine and cannabinoids, both of which proved effective against chlorpyrifos- or reserpine-induced teratogenesis. Invertebrate test systems can provide both a screening procedure for mammalian neuroteratogenesis and may uncover novel mechanisms underlying developmental vulnerability as well as possible therapeutic approaches to prevent teratogenesis. PMID:17720543

Interactions Between Bacteria and the Gut Mucosa: Do Enteric Neurotransmitters Acting on the Mucosal Epithelium Influence Intestinal Colonization or Infection?

PubMed

Green, Benedict T; Brown, David R

2016-01-01

The intestinal epithelium is a critical barrier between the internal and external milieux of the mammalian host. Epithelial interactions between these two host environments have been shown to be modulated by several different, cross-communicating cell types residing in the gut mucosa. These include enteric neurons, whose activity is influenced by bacterial pathogens, and their secreted products. Neurotransmitters appear to influence epithelial associations with bacteria in the intestinal lumen. For example, internalization of Salmonella enterica and Escherichia coli O157:H7 into the Peyer's patch mucosa of the small intestine is altered after the inhibition of neural activity with saxitoxin, a neuronal sodium channel blocker. Catecholamine neurotransmitters, such as dopamine and norepinephrine, also alter bacterial internalization in Peyer's patches. In the large intestine, norepinephrine increases the mucosal adherence of E. coli. These neurotransmitter actions are mediated by well-defined catecholamine receptors situated on the basolateral membranes of epithelial cells rather than through direct interactions with luminal bacteria. Investigations of the involvement of neuroepithelial communication in the regulation of interactions between the intestinal mucosa and luminal bacteria will provide novel insights into the mechanisms underlying bacterial colonization and pathogenesis at mucosal surfaces.

Rechargeable calcium phosphate orthodontic cement with sustained ion release and re-release

NASA Astrophysics Data System (ADS)

Zhang, Ling; Weir, Michael D.; Chow, Laurence C.; Reynolds, Mark A.; Xu, Hockin H. K.

2016-11-01

White spot lesions (WSL) due to enamel demineralization are major complications for orthodontic treatments. Calcium phosphate (CaP) dental resins with Ca and P ion releases are promising for remineralization. However, previous Ca and P releases lasted for only weeks. Experimental orthodontic cements were developed using pyromellitic glycerol dimethacrylate (PMGDM) and ethoxylated bisphenol A dimethacrylate (EBPADMA) at mass ratio of 1:1 (PE); and PE plus 10% of 2-hydroxyethyl methacrylate (HEMA) and 5% of bisphenol A glycidyl dimethacrylate (BisGMA) (PEHB). Particles of amorphous calcium phosphate (ACP) were incorporated into PE and PEHB at 40% filler level. Specimens were tested for bracket-enamel shear bond strength, water sorption, CaP release, and ion recharge and re-release. PEHB+40ACP had higher bracket-enamel bond strength and ion release and rechargeability than PE+40ACP. ACP incorporation into the novel orthodontic cement did not adversely affect the bracket-enamel bond strength. Ion release and re-release from the novel ACP orthodontic cement indicated favorable release and re-release patterns. The recharged orthodontic cement could release CaP ions continuously for four weeks without further recharge. Novel rechargeable orthodontic cement containing ACP was developed with a high bracket-enamel bond strength and the ability to be repeatedly recharged to maintain long-term high levels of CaP ion releases.

Rechargeable calcium phosphate orthodontic cement with sustained ion release and re-release

PubMed Central

Zhang, Ling; Weir, Michael D.; Chow, Laurence C.; Reynolds, Mark A.; Xu, Hockin H. K.

2016-01-01

White spot lesions (WSL) due to enamel demineralization are major complications for orthodontic treatments. Calcium phosphate (CaP) dental resins with Ca and P ion releases are promising for remineralization. However, previous Ca and P releases lasted for only weeks. Experimental orthodontic cements were developed using pyromellitic glycerol dimethacrylate (PMGDM) and ethoxylated bisphenol A dimethacrylate (EBPADMA) at mass ratio of 1:1 (PE); and PE plus 10% of 2-hydroxyethyl methacrylate (HEMA) and 5% of bisphenol A glycidyl dimethacrylate (BisGMA) (PEHB). Particles of amorphous calcium phosphate (ACP) were incorporated into PE and PEHB at 40% filler level. Specimens were tested for bracket-enamel shear bond strength, water sorption, CaP release, and ion recharge and re-release. PEHB+40ACP had higher bracket-enamel bond strength and ion release and rechargeability than PE+40ACP. ACP incorporation into the novel orthodontic cement did not adversely affect the bracket-enamel bond strength. Ion release and re-release from the novel ACP orthodontic cement indicated favorable release and re-release patterns. The recharged orthodontic cement could release CaP ions continuously for four weeks without further recharge. Novel rechargeable orthodontic cement containing ACP was developed with a high bracket-enamel bond strength and the ability to be repeatedly recharged to maintain long-term high levels of CaP ion releases. PMID:27808251

Spontaneous periodic hypothermia and hyperhidrosis: a possibly novel cerebral neurotransmitter disorder.

PubMed

Rodrigues Masruha, Marcelo; Lin, Jaime; Arita, Juliana Harumi; De Castro Neto, Eduardo Ferreira; Scerni, Débora Amado; Cavalheiro, Esper Abrão; Mazzacoratti, Maria Da Graça Naffah; Vilanova, Luiz Celso Pereira

2011-04-01

Spontaneous periodic episodes of hypothermia still defy medical knowledge. In 1969, Shapiro et al. described the first two cases of spontaneous periodic hypothermia associated with agenesis of the corpus callosum. Recently, Dundar et al. reported a case of spontaneous periodic hypothermia and hyperhidrosis without corpus callosum agenesis, suggesting that the periodic episodes of hypothermia might be of epileptiform origin. Here we describe two paediatric patients with spontaneous periodic hypothermia without corpus callosum agenesis and demonstrate, to our knowledge for the first time, altered levels of neurotransmitter metabolites within the cerebrospinal fluid. © The Authors. Journal compilation © Mac Keith Press 2010.

Comparative developmental neurotoxicity of organophosphates in vivo: transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems.

PubMed

Slotkin, Theodore A; Seidler, Frederic J

2007-05-30

Organophosphates affect mammalian brain development through a variety of mechanisms beyond their shared property of cholinesterase inhibition. We used microarrays to characterize similarities and differences in transcriptional responses to chlorpyrifos and diazinon, assessing defined gene groupings for the pathways known to be associated with the mechanisms and/or outcomes of chlorpyrifos-induced developmental neurotoxicity. We exposed neonatal rats to daily doses of chlorpyrifos (1mg/kg) or diazinon (1 or 2mg/kg) on postnatal days 1-4 and evaluated gene expression profiles in brainstem and forebrain on day 5; these doses produce little or no cholinesterase inhibition. We evaluated pathways for general neural cell development, cell signaling, cytotoxicity and neurotransmitter systems, and identified significant differences for >60% of 252 genes. Chlorpyrifos elicited major transcriptional changes in genes involved in neural cell growth, development of glia and myelin, transcriptional factors involved in neural cell differentiation, cAMP-related cell signaling, apoptosis, oxidative stress, excitotoxicity, and development of neurotransmitter synthesis, storage and receptors for acetylcholine, serotonin, norepinephrine and dopamine. Diazinon had similar effects on many of the same processes but also showed major differences from chlorpyrifos. Our results buttress the idea that different organophosphates target multiple pathways involved in neural cell development but also that they deviate in key aspects that may contribute to disparate neurodevelopmental outcomes. Equally important, these pathways are compromised at exposures that are unrelated to biologically significant cholinesterase inhibition and its associated signs of systemic toxicity. The approach used here demonstrates how planned comparisons with microarrays can be used to screen for developmental neurotoxicity.

Comparative Developmental Neurotoxicity of Organophosphates In Vivo: Transcriptional Responses of Pathways for Brain Cell Development, Cell Signaling, Cytotoxicity and Neurotransmitter Systems

PubMed Central

Slotkin, Theodore A.; Seidler, Frederic J.

2007-01-01

Organophosphates affect mammalian brain development through a variety of mechanisms beyond their shared property of cholinesterase inhibition. We used microarrays to characterize similarities and differences in transcriptional responses to chlorpyrifos and diazinon, assessing defined gene groupings for the pathways known to be associated with the mechanisms and/or outcomes of chlorpyrifos-induced developmental neurotoxicity. We exposed neonatal rats to daily doses of chlorpyrifos (1 mg/kg) or diazinon (1 or 2 mg/kg) on postnatal days 1-4 and evaluated gene expression profiles in brainstem and forebrain on day 5; these doses produce little or no cholinesterase inhibition. We evaluated pathways for general neural cell development, cell signaling, cytotoxicity and neurotransmitter systems, and identified significant differences for >60% of 252 genes. Chlorpyrifos elicited major transcriptional changes in genes involved in neural cell growth, development of glia and myelin, transcriptional factors involved in neural cell differentiation, cAMP-related cell signaling, apoptosis, oxidative stress, excitotoxicity, and development of neurotransmitter synthesis, storage and receptors for acetylcholine, serotonin, norepinephrine and dopamine. Diazinon had similar effects on many of the same processes but also showed major differences from chlorpyrifos. Our results buttress the idea that different organophosphates target multiple pathways involved in neural cell development but also that they deviate in key aspects that may contribute to disparate neurodevelopmental outcomes. Equally important, these pathways are compromised at exposures that are unrelated to biologically significant cholinesterase inhibition and its associated signs of systemic toxicity. The approach used here demonstrates how planned comparisons with microarrays can be used to screen for developmental neurotoxicity. PMID:17452286

Membrane Electromechanics at Hair-Cell Synapses

NASA Astrophysics Data System (ADS)

Brownell, W. E.; Farrell, B.; Raphael, R. M.

2003-02-01

Both outer hair cell electromotility and neurotransmission at the inner hair cell synapse are rapid mechanical events that are synchronized to the hair-cell receptor potential. We analyze whether the forces and potentials resulting from membrane flexoelectricity could affect synaptic vesicle fusion. The results suggest that the coupling of membrane curvature with membrane potential is of sufficient magnitude to influence neurotransmitter release.

Caffeine accelerates recovery from general anesthesia

PubMed Central

Wang, Qiang; Fong, Robert; Mason, Peggy; Fox, Aaron P.

2013-01-01

General anesthetics inhibit neurotransmitter release from both neurons and secretory cells. If inhibition of neurotransmitter release is part of an anesthetic mechanism of action, then drugs that facilitate neurotransmitter release may aid in reversing general anesthesia. Drugs that elevate intracellular cAMP levels are known to facilitate neurotransmitter release. Three cAMP elevating drugs (forskolin, theophylline, and caffeine) were tested; all three drugs reversed the inhibition of neurotransmitter release produced by isoflurane in PC12 cells in vitro. The drugs were tested in isoflurane-anesthetized rats. Animals were injected with either saline or saline containing drug. All three drugs dramatically accelerated recovery from isoflurane anesthesia, but caffeine was most effective. None of the drugs, at the concentrations tested, had significant effects on breathing rates, O2 saturation, heart rate, or blood pressure in anesthetized animals. Caffeine alone was tested on propofol-anesthetized rats where it dramatically accelerated recovery from anesthesia. The ability of caffeine to accelerate recovery from anesthesia for different chemical classes of anesthetics, isoflurane and propofol, opens the possibility that it will do so for all commonly used general anesthetics, although additional studies will be required to determine whether this is in fact the case. Because anesthesia in rodents is thought to be similar to that in humans, these results suggest that caffeine might allow for rapid and uniform emergence from general anesthesia in human patients. PMID:24375022

Remote modulation of neural activities via near-infrared triggered release of biomolecules.

PubMed

Li, Wei; Luo, Rongcong; Lin, Xudong; Jadhav, Amol D; Zhang, Zicong; Yan, Li; Chan, Chung-Yuan; Chen, Xianfeng; He, Jufang; Chen, Chia-Hung; Shi, Peng

2015-10-01

The capability to remotely control the release of biomolecules provides an unique opportunity to monitor and regulate neural signaling, which spans extraordinary spatial and temporal scales. While various strategies, including local perfusion, molecular "uncaging", or photosensitive polymeric materials, have been applied to achieve controlled releasing of neuro-active substances, it is still challenging to adopt these technologies in many experimental contexts that require a straightforward but versatile loading-releasing mechanism. Here, we develop a synthetic strategy for remotely controllable releasing of neuro-modulating molecules. This platform is based on microscale composite hydrogels that incorporate polypyrrole (PPy) nanoparticles as photo-thermal transducers and is triggered by near-infrared-light (NIR) irradiation. Specifically, we first demonstrate the utility of our technology by recapitulating the "turning assay" and "collapse assay", which involve localized treatment of chemotactic factors (e.g. Netrin or Semaphorin 3A) to subcellular neural elements and have been extensively used in studying axonal pathfinding. On a network scale, the photo-sensitive microgels are also validated for light-controlled releasing of neurotransmitters (e.g. glutamate). A single NIR-triggered release is sufficient to change the dynamics of a cultured hippocampal neuron network. Taking the advantage of NIR's capability to penetrate deep into live tissue, this technology is further shown to work similarly well in vivo, which is evidenced by synchronized spiking activity in response to NIR-triggered delivery of glutamate in rat auditory cortex, demonstrating remote control of brain activity without any genetic modifications. Notably, our nano-composite microgels are capable of delivering various molecules, ranging from small chemicals to large proteins, without involving any crosslinking chemistry. Such great versatility and ease-of-use will likely make our optically

Localization of multiple neurotransmitters in surgically derived specimens of human atrial ganglia.

PubMed

Hoover, D B; Isaacs, E R; Jacques, F; Hoard, J L; Pagé, P; Armour, J A

2009-12-15

Dysfunction of the intrinsic cardiac nervous system is implicated in the genesis of atrial and ventricular arrhythmias. While this system has been studied extensively in animal models, far less is known about the intrinsic cardiac nervous system of humans. This study was initiated to anatomically identify neurotransmitters associated with the right atrial ganglionated plexus (RAGP) of the human heart. Biopsies of epicardial fat containing a portion of the RAGP were collected from eight patients during cardiothoracic surgery and processed for immunofluorescent detection of specific neuronal markers. Colocalization of markers was evaluated by confocal microscopy. Most intrinsic cardiac neuronal somata displayed immunoreactivity for the cholinergic marker choline acetyltransferase and the nitrergic marker neuronal nitric oxide synthase. A subpopulation of intrinsic cardiac neurons also stained for noradrenergic markers. While most intrinsic cardiac neurons received cholinergic innervation evident as punctate immunostaining for the high affinity choline transporter, some lacked cholinergic inputs. Moreover, peptidergic, nitrergic, and noradrenergic nerves provided substantial innervation of intrinsic cardiac ganglia. These findings demonstrate that the human RAGP has a complex neurochemical anatomy, which includes the presence of a dual cholinergic/nitrergic phenotype for most of its neurons, the presence of noradrenergic markers in a subpopulation of neurons, and innervation by a host of neurochemically distinct nerves. The putative role of multiple neurotransmitters in controlling intrinsic cardiac neurons and mediating efferent signaling to the heart indicates the possibility of novel therapeutic targets for arrhythmia prevention.

Brain structures and neurotransmitters regulating aggression in cats: implications for human aggression.

PubMed

Gregg, T R; Siegel, A

2001-01-01

1. Violence and aggression are major public health problems. 2. The authors have used techniques of electrical brain stimulation, anatomical-immunohistochemical techniques, and behavioral pharmacology to investigate the neural systems and circuits underlying aggressive behavior in the cat. 3. The medial hypothalamus and midbrain periaqueductal gray are the most important structures mediating defensive rage behavior, and the perifornical lateral hypothalamus clearly mediates predatory attack behavior. The hippocampus, amygdala, bed nucleus of the stria terminalis, septal area, cingulate gyrus, and prefrontal cortex project to these structures directly or indirectly and thus can modulate the intensity of attack and rage. 4. Evidence suggests that several neurotransmitters facilitate defensive rage within the PAG and medial hypothalamus, including glutamate, Substance P, and cholecystokinin, and that opioid peptides suppress it; these effects usually depend on the subtype of receptor that is activated. 5. A key recent discovery was a GABAergic projection that may underlie the often-observed reciprocally inhibitory relationship between these two forms of aggression. 6. Recently, Substance P has come under scrutiny as a possible key neurotransmitter involved in defensive rage, and the mechanism by which it plays a role in aggression and rage is under investigation. 7. It is hoped that this line of research will provide a better understanding of the neural mechanisms and substrates regulating aggression and rage and thus establish a rational basis for treatment of disorders associated with these forms of aggression.

Sensory Processing and Integration at the Carotid Body Tripartite Synapse: Neurotransmitter Functions and Effects of Chronic Hypoxia.

PubMed

Leonard, Erin M; Salman, Shaima; Nurse, Colin A

2018-01-01

Maintenance of homeostasis in the respiratory and cardiovascular systems depends on reflexes that are initiated at specialized peripheral chemoreceptors that sense changes in the chemical composition of arterial blood. In mammals, the bilaterally-paired carotid bodies (CBs) are the main peripheral chemoreceptor organs that are richly vascularized and are strategically located at the carotid bifurcation. The CBs contribute to the maintenance of O 2 , CO 2 /H + , and glucose homeostasis and have attracted much clinical interest because hyperactivity in these organs is associated with several pathophysiological conditions including sleep apnea, obstructive lung disease, heart failure, hypertension, and diabetes. In response to a decrease in O 2 availability (hypoxia) and elevated CO 2 /H + (acid hypercapnia), CB receptor type I (glomus) cells depolarize and release neurotransmitters that stimulate apposed chemoafferent nerve fibers. The central projections of those fibers in turn activate cardiorespiratory centers in the brainstem, leading to an increase in ventilation and sympathetic drive that helps restore blood PO 2 and protect vital organs, e.g., the brain. Significant progress has been made in understanding how neurochemicals released from type I cells such as ATP, adenosine, dopamine, 5-HT, ACh, and angiotensin II help shape the CB afferent discharge during both normal and pathophysiological conditions. However, type I cells typically occur in clusters and in addition to their sensory innervation are ensheathed by the processes of neighboring glial-like, sustentacular type II cells. This morphological arrangement is reminiscent of a "tripartite synapse" and emerging evidence suggests that paracrine stimulation of type II cells by a variety of CB neurochemicals may trigger the release of "gliotransmitters" such as ATP via pannexin-1 channels. Further, recent data suggest novel mechanisms by which dopamine, acting via D2 receptors (D2R), may inhibit action

Sustained release of corticosterone in rats affects reactivity, but does not affect habituation to immobilization and acoustic stimuli.

PubMed

Tanke, Marit A C; Fokkema, Dirk S; Doornbos, Bennard; Postema, Folkert; Korf, Jakob

2008-07-18

Depression is often preceded by stressful life events and accompanied with elevated cortisol levels and glucocorticoid resistance. It has been suggested that a major depressive disorder may result from impaired coping with and adaptation to stress. The question is whether or not hypothalamus-pituitary-adrenal (HPA)-axis dysfunction influences the process of adaptation. We examined the effect of a dysregulated HPA-axis on the adaptation to acoustic stimuli in rats with or without preceding restraint stress. HPA-axis function was altered via slow release of corticosterone (CORT, 90 mg) from subcutaneously implanted pellets for 7 or 14 days. The rate of body temperature increases during restraint (10 min) and the response to acoustic stimuli (of 80+120 dB) were used to quantify daily stress reactivity. Rats habituated to either stress regardless of CORT treatment. CORT treatment combined with restraint decreased the initial reactivity and the variability in response, but the rate of habituation was not influenced. These results show that suppressing normal HPA-axis function by chronic exposure to CORT does affect the course of habituation, but not habituation per se. This implies that altered HPA-axis function in depressed patients may not be causally related to stress coping, but instead may influence the course of the disorder.

Do Proxies for the Neurotransmitter Cortisol Predict Adaptation to Life with Chronic Pain?

NASA Astrophysics Data System (ADS)

Deamond, Wade

Among the numerous difficulties encountered by chronic pain patients, impulsive and dysfunctional decision-making complicate their already difficult life situations yet remains relatively understudied. This study examined a recently published neurobiological decision making model that identifies eight specific neurotransmitters and hormones (Dopamine, Testosterone, Endogenous Opioids Glutamate, Serotonin, Norepinephrine, Cortisol, and GABA) linked to unsound decision making related to cognitive, motivational and emotional dysregulation (Nussbaum et al., 2011) (see Appendix 2). The Perceived Stress Scale (PSS), a proxy for the cortisol element in the pharmacological decision making model was analyzed for the neurotransmitter's relationship to functionality and quality of life in a group of 37 chronic pain patients. Participants were comprised of males and females ranging from 23 to 52 years of age and were classified with respect to levels of adjustment to living with chronic pain based on the Quality of Life Scale (QLS), the Dartmouth WONCA COOP Charts and the Global Assessment of Functioning (GAF). The Iowa Gambling Task (IGT) and Frontal System Behavioral Scale (FSBS) measured decision making related to immediate gratification and daily living respectively. Results suggest that emotional dysregulation, as measured by the PSS is a significant predictor for adaptation to life with chronic pain and the PSS is superior to predicting adaptation to life with chronic pain than reported levels of pain as measured by the McGill Pain Questionnaire.

Postnatal development of neurotransmitter systems and their relevance to extinction of conditioned fear.

PubMed

Kim, Jee Hyun; Perry, Christina J; Ganella, Despina E; Madsen, Heather B

2017-02-01

Remembering and forgetting are fundamental features of an organism. Extinction is a type of forgetting where there is a decrease in the significance and/or the meaning of an associative memory when elements of that memory no longer predict one another. The neural mechanisms underlying extinction of fear memories have been extensively studied in the laboratory because extinction processes are clinically relevant to exposure therapies that treat anxiety disorders. However, only in the last decade have we begun to unveil the similarities and differences in plasticity underlying extinction across development. So far it is clear that extinction is a developmentally dissociated process in behavior and in pharmacology, however there are many large gaps in the literature in understanding how the developmental trajectory of different neurotransmitters contribute to changes in the nature of extinction across development. We attempt to address these gaps in the present review. Major neurotransmitter systems including the glutamatergic and GABAergic systems, the monoamines, the endogenous opioid and cannabinoid systems, acetylcholines, and neuropeptides such as oxytocin have all been identified to play some role in extinction of fear memories and have been covered in this review. We hope to facilitate more research into mechanisms of extinction at different stages of life, especially noting that mental disorders are increasingly classified as neurodevelopmental disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

The effects of endomorphins and diprotin A on striatal dopamine release induced by electrical stimulation-an in vitro superfusion study in rats.

PubMed

Bagosi, Zsolt; Jászberényi, Miklós; Bujdosó, Erika; Szabó, Gyula; Telegdy, Gyula

2006-12-01

The endomorphins (EM1: Tyr-Pro-Trp-Phe-NH2, and EM2: Tyr-Pro-Phe-Phe-NH2) are recently discovered endogenous ligands for mu-opioid receptors (MORs) with role of neurotransmitters or neuromodulators in mammals. Cessation of their physiological action may be effected through rapid enzymatic degradation by the dipeptidyl-peptidase IV (DPPIV) found in the brain synaptic membranes. An in vitro superfusion system was utilized to investigate the actions of EM1, EM2 and specific DPPIV inhibitor diprotin A on the striatal release of dopamine (DA) induced by electrical stimulation in rats. The involvement of the different MORs (MOR1 and MOR2) in this process was studied by pretreatment with MOR antagonists beta-funaltrexamine (a MOR1 and MOR2 antagonist) and naloxonazine (a MOR1 antagonist). EM1 significantly increased the tritium-labelled dopamine DA release induced by electrical stimulation. EM2 was effective only when the slices were pretreated with diprotin A. beta-Funaltrexamine antagonized the stimulatory effects of both EM1 and EM2. The administration of naloxonazine did not appreciably influence the action of EM1, but blocked the action of EM2, at least when the slices were pretreated with diprotin A. These data suggest that both EM1 and EM2 increase DA release from the striatum and, though diprotin A does not affect the action of EM1, it inhibits the enzymatic degradation of EM2. The DA-stimulating action induced by EM1 seems to be mediated by MOR2, while that evoked by EM2 appears to be transmitted by MOR1.

Release of endogenous amino acids from the hippocampus and brain stem from developing and adult mice in ischemia.

PubMed

Oja, Simo S; Saransaari, Pirjo

2009-09-01

The release of neurotransmitters and modulators has been studied mostly using labeled preloaded compounds. For several reasons, however, the estimated release may not reliably reflect the release of endogenous compounds. The basal and K(+)-evoked release of the neuroactive endogenous amino acids GABA, glycine, taurine, L-glutamate and L-aspartate was now studied in slices from the hippocampus and brain stem from 7-day-old and 3-month-old mice under control and ischemic conditions. The release of synaptically not active L-glutamine, L-alanine, L-threonine and L-serine was assessed for comparison. The estimates for the hippocampus and brainstem were markedly different and also different in developing and adult mice. GABA release was much greater in 3-month-old than in 7-day-old mice, whereas with taurine the situation was the opposite, in the hippocampus in particular. K(+) stimulation enhanced glycine release more in the mature than immature brain stem while in the hippocampus the converse was observed. Ischemia enhanced the release of all neuroactive amino acids in both brain regions, the effects being relatively most pronounced in the case of GABA, aspartate and glutamate in the hippocampus in 3-month-old mice, and taurine in 7-day-old and glycine in 3-month-old mice in the brain stem. These results are qualitatively similar to those obtained on earlier experiments with labeled preloaded amino acids. However, the magnitudes of the release cannot be quite correctly estimated using radioactive labels. In developing mice only taurine release may counteract the harmful effects of excitatory amino acids in ischemia in both hippocampus and brain stem.

Expression of functional neurotransmitter receptors in Xenopus oocytes after injection of human brain membranes

NASA Astrophysics Data System (ADS)

Miledi, Ricardo; Eusebi, Fabrizio; Martínez-Torres, Ataúlfo; Palma, Eleonora; Trettel, Flavia

2002-10-01

The Xenopus oocyte is a very powerful tool for studies of the structure and function of membrane proteins, e.g., messenger RNA extracted from the brain and injected into oocytes leads to the synthesis and membrane incorporation of many types of functional receptors and ion channels, and membrane vesicles from Torpedo electroplaques injected into oocytes fuse with the oocyte membrane and cause the appearance of functional Torpedo acetylcholine receptors and Cl channels. This approach was developed further to transplant already assembled neurotransmitter receptors from human brain cells to the plasma membrane of Xenopus oocytes. Membranes isolated from the temporal neocortex of a patient, operated for intractable epilepsy, were injected into oocytes and, within a few hours, the oocyte membrane acquired functional neurotransmitter receptors to -aminobutyric acid, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and glycine. These receptors were also expressed in the plasma membrane of oocytes injected with mRNA extracted from the temporal neocortex of the same patient. All of this makes the Xenopus oocyte a more useful model than it already is for studies of the structure and function of many human membrane proteins and opens the way to novel pathophysiological investigations of some human brain disorders.

Tributyltin exposure influences predatory behavior, neurotransmitter content and receptor expression in Sebastiscus marmoratus.

PubMed

Yu, Ang; Wang, Xinli; Zuo, Zhenghong; Cai, Jiali; Wang, Chonggang

2013-03-15

Tributyltin (TBT) is a ubiquitous marine contaminant due to its extensive use as a biocide, fungicide and antifouling agent. However, the neurotoxic effect of TBT has not been extensively studied, especially in marine fish. This study was conducted to investigate the effects of TBT (10, 100 and 1000 ng/L) on the predatory behavior of Sebastiscus marmoratus and to look into the mechanism involved. The results showed that TBT exposure depressed predatory activity after 50 days exposure. Dopamine levels in the fish brains increased in a dose-dependent manner, while 5-hydroxytryptamine and norepinephrine levels decreased significantly in the TBT exposure group compared to the control. The mRNA levels of dopamine receptors, which have functions such as cognition, motor activity, motivation and reward, mood, attention and learning, were significantly down-regulated by TBT exposure. Although the levels of amino acid neurotransmitters, including glutamate, did not show marked alteration, the expression of the glutamatergic signaling pathway such as N-methyl-D-aspartate receptors, a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor, calmodulin, Ca(2+)/calmodulin-dependent protein kinases-II and cyclic adenosine monophosphate responsive element binding protein, was significantly reduced by TBT exposure, which indicated that central nerve activities were in a state of depression, thus affecting the predatory activities of the fish. Copyright © 2012 Elsevier B.V. All rights reserved.

[Effects of acrylonitrile in drinking water on monoamine neurotransmitters and its metabolites in male rat brains].

PubMed

Lu, Rong-zhu; Chen, Zi-qiang; Jin, Fu-sheng

2005-03-01

To elucidate the possible involvement of monoamine neurotransmitters in the development of neurobehavioral damage produced by acrylonitrile in drinking water in male rat brains. Totally 30 male SD rats were randomly divided into three groups, the control group (n = 10), low dosage group (n = 10), and high dosage group (n = 10), which were respectively administered 0 mg/L, 50 mg/L, 200 mg/L acrylonitrile (AN) in drinking water. The treatment was lasted for 12 weeks. Seven animals were randomly selected from each group for determination of monoamine neurotransmitters in striatum and cerebellum by high performance liquid chromatography with electrochemical detector and activities of monoamine oxidase in cortex. The contents of dopamine in the striatum of low and high dosage groups were decreased to (2.2 +/- 0.7) and (3.2 +/- 2.0) microg/g wet tissue, respectively, and compared with that of control group (9.0 +/- 4.2) microg/g wet tissue, the differences were statistically significant. There were no statistical differences among the contents of dopamine in the cerebellum of all rats, and the levels of 3,4-dihydroxyphenylacetic acid (DOPAC), the major metabolite of dopamine in the cerebellum were (186 +/- 41), (245 +/- 90) and (115 +/- 65) ng/g wet tissue in the control, low and high dosage groups, respectively and in low-dosage group they were significantly higher than those in other groups. There was dosage-dependently decreasing of the contents of serotonin of striatum in the control (249 +/- 34) ng/g wet tissue, low dosage (155 +/- 95) ng/g wet tissue and high dosage groups (128 +/- 101) ng/g wet tissue. This study underlines the importance of alterations in the monoamine neurotransmitters system as a possible causative mechanism behind the behavioural and functional changes produced by acrylonitrile.

Competing Insertion and External Binding Motifs in Hydrated Neurotransmitters: Infrared Spectra of Protonated Phenylethylamine Monohydrate.

PubMed

Bouchet, Aude; Schütz, Markus; Dopfer, Otto

2016-01-18

Hydration has a drastic impact on the structure and function of flexible biomolecules, such as aromatic ethylamino neurotransmitters. The structure of monohydrated protonated phenylethylamine (H(+) PEA-H2 O) is investigated by infrared photodissociation (IRPD) spectroscopy of cold cluster ions by using rare-gas (Rg=Ne and Ar) tagging and dispersion-corrected density functional theory calculations at the B3LYP-D3/aug-cc-pVTZ level. Monohydration of this prototypical neurotransmitter gives an insight into the first step of the formation of its solvation shell, especially regarding the competition between intra- and intermolecular interactions. The spectra of Rg-tagged H(+) PEA-H2 O reveal the presence of a stable insertion structure in which the water molecule is located between the positively charged ammonium group and the phenyl ring of H(+) PEA, acting both as a hydrogen bond acceptor (NH(+) ⋅⋅⋅O) and donor (OH⋅⋅⋅π). Two other nearly equivalent isomers, in which water is externally H bonded to one of the free NH groups, are also identified. The balance between insertion and external hydration strongly depends on temperature. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Immunohistochemical profile of various neurotransmitters, neurotrophins and MIB-1 in cholesteatomas of the petrous bone.

PubMed

Artico, Marco; Bronzetti, Elena; Lo Vasco, Vincenza Rita; Ionta, Brunella; Alicino, Valentina; D'Ambrosio, Anna; Magliulo, Giuseppe

2008-01-01

Compared to the normal epidermal epithelium, cholesteatomas have altered growth properties characterized by the excessive growth of keratinocytes leading to mucosal destruction. Either congenital or acquired, these lesions, which grow in the middle ear space, the petrous apex or the mastoid of temporal bones, are mostly considered benign skin tumoral lesions. However, many questions remain concerning their pathophysiology. Numerous studies have been proposed to identify those cholesteatoma lesions at risk of recurrence, a possible event that may cause hearing loss. We examined patients with petrous apex or mastoid cholesteatoma in order to analyze the expression of various neurotransmitters, neurotrophins and their receptors and the Ki-67 antigen for identification of a possible relationship between clinical outcome and histopathological behaviour in terms of the proliferative activity of cholesteatomas. Expression of the analyzed molecules was studied using immunohistochemical methods in seven adult patients with petrous apex cholesteatoma who underwent surgical removal of the lesion. Our results, in accordance with published data, confirm that Molecular Immunology Borstel-1 (MIB-1) and certain neurotransmitters could be useful in the prognostic evaluation of the risk of recurrence of aggressive forms of cholesteatoma.

Gamma-amino butyric acid (GABA) release in the ciliated protozoon Paramecium occurs by neuronal-like exocytosis.

PubMed

Ramoino, P; Milanese, M; Candiani, S; Diaspro, A; Fato, M; Usai, C; Bonanno, G

2010-04-01

Paramecium primaurelia expresses a significant amount of gamma-amino butyric acid (GABA). Paramecia possess both glutamate decarboxylase (GAD)-like and vesicular GABA transporter (vGAT)-like proteins, indicating the ability to synthesize GABA from glutamate and to transport GABA into vesicles. Using antibodies raised against mammalian GAD and vGAT, bands with an apparent molecular weight of about 67 kDa and 57 kDa were detected. The presence of these bands indicated a similarity between the proteins in Paramecium and in mammals. VAMP, syntaxin and SNAP, putative proteins of the release machinery that form the so-called SNARE complex, are present in Paramecium. Most VAMP, syntaxin and SNAP fluorescence is localized in spots that vary in size and density and are primarily distributed near the plasma membrane. Antibodies raised against mammal VAMP-3, sintaxin-1 or SNAP-25 revealed protein immunoblot bands having molecular weights consistent with those observed in mammals. Moreover, P. primaurelia spontaneously releases GABA into the environment, and this neurotransmitter release significantly increases after membrane depolarization. The depolarization-induced GABA release was strongly reduced not only in the absence of extracellular Ca(2+) but also by pre-incubation with bafilomycin A1 or with botulinum toxin C1 serotype. It can be concluded that GABA occurs in Paramecium, where it is probably stored in vesicles capable of fusion with the cell membrane; accordingly, GABA can be released from Paramecium by stimulus-induced, neuronal-like exocytotic mechanisms.

Metabotropic and ionotropic glutamate receptors mediate the modulation of acetylcholine release at the frog neuromuscular junction.

PubMed

Tsentsevitsky, Andrei; Nurullin, Leniz; Nikolsky, Evgeny; Malomouzh, Artem

2017-07-01

There is some evidence that glutamate (Glu) acts as a signaling molecule at vertebrate neuromuscular junctions where acetylcholine (ACh) serves as a neurotransmitter. In this study, performed on the cutaneous pectoris muscle of the frog Rana ridibunda, Glu receptor mechanisms that modulate ACh release processes were analyzed. Electrophysiological experiments showed that Glu reduces both spontaneous and evoked quantal secretion of ACh and synchronizes its release in response to electrical stimulation. Quisqualate, an agonist of ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors and metabotropic Group I mGlu receptors, also exerted Glu-like inhibitory effects on the secretion of ACh but had no effect on the kinetics of quantal release. Quisqualate's inhibitory effect did not occur when a blocker of Group I mGlu receptors (LY 367385) or an inhibitor of phospholipase C (U73122) was present. An increase in the degree of synchrony of ACh quantal release, such as that produced by Glu, was obtained after application of N-methyl-D-aspartic acid (NMDA). The presence of Group I mGlu and NMDA receptors in the neuromuscular synapse was confirmed by immunocytochemistry. Thus, the data suggest that both metabotropic Group I mGlu receptors and ionotropic NMDA receptors are present at the neuromuscular synapse of amphibians, and that the activation of these receptors initiates different mechanisms for the regulation of ACh release from motor nerve terminals. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Neurotransmitters behind pain relief with transcranial magnetic stimulation - positron emission tomography evidence for release of endogenous opioids.

PubMed

Lamusuo, S; Hirvonen, J; Lindholm, P; Martikainen, I K; Hagelberg, N; Parkkola, R; Taiminen, T; Hietala, J; Helin, S; Virtanen, A; Pertovaara, A; Jääskeläinen, S K

2017-10-01

Repetitive transcranial magnetic stimulation (rTMS) at M1/S1 cortex has been shown to alleviate neuropathic pain. To investigate the possible neurobiological correlates of cortical neurostimulation for the pain relief. We studied the effects of M1/S1 rTMS on nociception, brain dopamine D2 and μ-opioid receptors using a randomized, sham-controlled, double-blinded crossover study design and 3D-positron emission tomography (PET). Ten healthy subjects underwent active and sham rTMS treatments to the right M1/S1 cortex with E-field navigated device. Dopamine D2 and μ-receptor availabilities were assessed with PET radiotracers [ 11 C]raclopride and [ 11 C]carfentanil after each rTMS treatment. Thermal quantitative sensory testing (QST), contact heat evoked potential (CHEP) and blink reflex (BR) recordings were performed between the PET scans. μ-Opioid receptor availability was lower after active than sham rTMS (P ≤ 0.0001) suggested release of endogenous opioids in the right ventral striatum, medial orbitofrontal, prefrontal and anterior cingulate cortices, and left insula, superior temporal gyrus, dorsolateral prefrontal cortex and precentral gyrus. There were no differences in striatal dopamine D2 receptor availability between active and sham rTMS, consistent with lack of long-lasting measurable dopamine release. Active rTMS potentiated the dopamine-regulated habituation of the BR compared to sham (P = 0.02). Thermal QST and CHEP remained unchanged after active rTMS. rTMS given to M1/S1 activates the endogenous opioid system in a wide brain network associated with processing of pain and other salient stimuli. Direct enhancement of top-down opioid-mediated inhibition may partly explain the clinical analgesic effects of rTMS. Neurobiological correlates of rTMS for the pain relief are unclear. rTMS on M1/S1 with 11 C-carfentanyl-PET activates endogenous opioids. Thermal and heat pain thresholds remain unchanged. rTMS induces top-down opioid-mediated inhibition

Controls on Fe(II)-Activated Trace Element Release from Goethite and Hematite

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frierdich, Andrew J.; Catalano, Jeffrey G.

2012-03-26

Electron transfer and atom exchange (ETAE) between aqueous Fe(II) and Fe(III) oxides induces surface growth and dissolution that affects trace element fate and transport. We have recently demonstrated Ni(II) cycling through goethite and hematite (adsorbed Ni incorporates into the mineral structure and preincorporated Ni releases to solution) during Fe(II)-Fe(III) ETAE. However, the chemical parameters affecting net trace element release remain unknown. Here, we examine the chemical controls on Ni(II) and Zn(II) release from Ni- and Zn-substituted goethite and hematite during reaction with Fe(II). Release follows a rate law consistent with surface reaction limited mineral dissolution and suggests that release occursmore » near sites of Fe(III) reductive dissolution during Fe(II)-Fe(III) ETAE. Metal substituent type affects reactivity; Zn release is more pronounced from hematite than goethite, whereas the opposite trend occurs for Ni. Buildup of Ni or Zn in solution inhibits further release but this resumes upon fluid exchange, suggesting that sustained release is possible under flow conditions. Mineral and aqueous Fe(II) concentrations as well as pH strongly affect sorbed Fe(II) concentrations, which directly control the reaction rates and final metal concentrations. Our results demonstrate that structurally incorporated trace elements are mobilized from iron oxides into fluids without abiotic or microbial net iron reduction. Such release may affect micronutrient availability, contaminant transport, and the distribution of redox-inactive trace elements in natural and engineered systems.« less

Does release of antimicrobial agents from impregnated external ventricular drainage catheters affect the diagnosis of ventriculitis?

PubMed

Bayston, Roger; Ashraf, Waheed; Ortori, Catherine

2016-02-01

Recently concern has arisen over the effect of released antimicrobial agents from antibiotic-impregnated external ventricular drainage (EVD) catheters on the reliability of CSF culture for diagnosis of ventriculitis. The authors designed a laboratory study to investigate this possibility, and to determine whether there was also a risk of loss of bacterial viability when CSF samples were delayed in transport to the laboratory. Three types of commercially available antibiotic-impregnated EVD catheters were perfused with a suspension of bacteria (Staphylococcus epidermidis) over 21 days. Samples were analyzed for bacterial viability and for concentrations of antibiotics released from the catheters. The authors also investigated the effect on bacterial viability in samples stored at 18°C and 4°C to simulate delay in CSF samples reaching the laboratory for analysis. Bacterial viability was significantly reduced in all 3 catheter types when sampled on Day 1, but this effect was not observed in later samples. The results were reflected in stored samples, with significant loss of viability in Day 1 samples but with little further loss of viable bacteria in samples obtained after this time point. All samples stored for 18 hours showed significant loss of viable bacteria. While there were differences between the catheters, only samples taken on Day 1 showed a significant reduction in the numbers of viable bacteria after passing through the catheters. This reduction coincided with higher concentrations of antimicrobial agents in the first few hours after perfusion began. Similarly, bacterial viability declined significantly after storage of Day 1 samples, but only slightly in samples obtained thereafter. The results indicate that drugs released from these antimicrobial catheters are unlikely to affect the diagnosis of ventriculitis, as sampling for this purpose is not usually conducted in the first 24 hours of EVD.

The Role of Nutrients in Protecting Mitochondrial Function and Neurotransmitter Signaling: Implications for the Treatment of Depression, PTSD, and Suicidal Behaviors.

PubMed

Du, Jing; Zhu, Ming; Bao, Hongkun; Li, Bai; Dong, Yilong; Xiao, Chunjie; Zhang, Grace Y; Henter, Ioline; Rudorfer, Matthew; Vitiello, Benedetto

2016-11-17

Numerous studies have linked severe stress to the development of major depressive disorder (MDD) and suicidal behaviors. Furthermore, recent preclinical studies from our laboratory and others have demonstrated that in rodents, chronic stress and the stress hormone cortisol cause oxidative damage to mitochondrial function and membrane lipids in the brain. Mitochondria play a key role in synaptic neurotransmitter signaling by providing adenosine triphosphate (ATP), mediating lipid and protein synthesis, buffering intracellular calcium, and regulating apoptotic and resilience pathways. Membrane lipids are similarly essential to central nervous system (CNS) function because cholesterol, polyunsaturated fatty acids, and sphingolipids form a lipid raft region, a special lipid region on the membrane that mediates neurotransmitter signaling through G-protein-coupled receptors and ion channels. Low serum cholesterol levels, low antioxidant capacity, and abnormal early morning cortisol levels are biomarkers consistently associated with both depression and suicidal behaviors. In this review, we summarize the manner in which nutrients can protect against oxidative damage to mitochondria and lipids in the neuronal circuits associated with cognitive and affective behaviors. These nutrients include ω3 fatty acids, antioxidants (vitamin C and zinc), members of the vitamin B family (Vitamin B12 and folic acid), and magnesium. Accumulating data have shown that these nutrients can enhance neurocognitive function, and may have therapeutic benefits for depression and suicidal behaviors. A growing body of studies suggests the intriguing possibility that regular consumption of these nutrients may help prevent the onset of mood disorders and suicidal behaviors in vulnerable individuals, or significantly augment the therapeutic effect of available antidepressants. These findings have important implications for the health of both military and civilian populations.

The Role of Nutrients in Protecting Mitochondrial Function and Neurotransmitter Signaling: Implications for the Treatment of Depression, PTSD, and Suicidal Behaviors

PubMed Central

Du, Jing; Zhu, Ming; Bao, Hongkun; Li, Bai; Dong, Yilong; Xiao, Chunjie; Zhang, Grace Y.; Henter, Ioline; Rudorfer, Matthew; Vitiello, Benedetto

2015-01-01

Numerous studies have linked severe stress to the development of major depressive disorder (MDD), and suicidal behaviors. Furthermore, recent preclinical studies from our laboratory and others have demonstrated that in rodents, chronic stress and the stress hormone cortisol has caused oxidative damage to mitochondrial function and membrane lipids in the brain. Mitochondria play a key role in synaptic neurotransmitter signaling by providing adenosine triphosphate (ATP), mediating lipid and protein synthesis, buffering intracellular calcium, and regulating apoptotic and resilience pathways. Membrane lipids are similarly essential to central nervous system (CNS) function, because cholesterol, polyunsaturated fatty acids, and sphingolipids form a lipid raft region, a special lipid region on the membrane that mediates neurotransmitter signaling through G-protein coupled receptors and ion channels. Low serum cholesterol levels, low antioxidant capacity, and abnormal early morning cortisol levels are biomarkers consistently associated with both depression and suicidal behaviors. In this review, we summarize the manner in which nutrients can protect against oxidative damage to mitochondria and lipids in the neuronal circuits associated with cognitive and affective behaviors. These nutrients include ω3 fatty acids, antioxidants (vitamin C and zinc), members of the vitamin B family (Vitamin B12 and folic acid) and magnesium. Accumulating data have shown that these nutrients can enhance neurocognitive function, and may have therapeutic benefits for depression and suicidal behaviors. A growing body of studies suggests the intriguing possibility that regular consumption of these nutrients may help prevent the onset of mood disorders and suicidal behaviors in vulnerable individuals, or significantly augment the therapeutic effect of available antidepressants. These findings have important implications for the health of both military and civilian populations. PMID:25365455

Levels in neurotransmitter precursor amino acids correlate with mental health in patients with breast cancer.

PubMed

Hüfner, K; Oberguggenberger, A; Kohl, C; Geisler, S; Gamper, E; Meraner, V; Egeter, J; Hubalek, M; Beer, B; Fuchs, D; Sperner-Unterweger, B

2015-10-01

Breast cancer is the most common cancer among females. Approximately 30% of cancer patients develop depression or depressive adaptation disorder within 5 years post diagnosis. Low grade inflammation and subsequent changes in neurotransmitter levels could be the pathophysiological link. In the current study we investigated the association of neurotransmitter precursor amino acids with a diagnosis of depression or state anxiety in 154 subjects suffering from breast cancer (BCA(+)), depression (DPR(+)), both or neither. Sociodemographic parameters, severity of depressive symptoms, and state anxiety (ANX) were recorded. Neopterin, kynurenine/tryptophan and phenylalanine/tyrosine were analysed by HPLC or ELISA. Significantly higher serum neopterin values were found in DPR(+) patients (p = 0.034) and in ANX(+) subjects (p = 0.008), as a marker of Th1-related inflammation. The phenylalanine/tyrosine ratio (index of the catecholamine pathway) was associated with the factors "breast cancer" and "depression" and their interaction (all p < 0.001); it was highest in the DPR(+)BCA(+) group. The kynurenine/tryptophan ratio (index of the serotonin pathway) was significantly associated with the factors "breast cancer" and "state anxiety" and their interaction (p < 0.001, p = 0.026, p = 0.02, respectively); it was highest in the ANX(+)BCA(+) group. In BCA(+) patients kynurenine/tryptophan ratios correlated with severity of state anxiety (r = 0.226, p = 0.048, uncorrected) and phenylalanine/tyrosine ratios with severity of depressive symptoms (r = 0.376, p < 0.05, corrected). In conclusion, levels of neurotransmitter precursor amino acids correlate with mental health, an effect which was much more pronounced in BCA(+) patients than in BCA(-) subjects. Aside from identifying underlying pathophysiological mechanisms, these results could be the basis for future treatment studies: in BCA(+) patients with depression the use of serotonin-noradrenaline reuptake inhibitors might be

Safinamide Differentially Modulates In Vivo Glutamate and GABA Release in the Rat Hippocampus and Basal Ganglia.

PubMed

Morari, Michele; Brugnoli, Alberto; Pisanò, Clarissa Anna; Novello, Salvatore; Caccia, Carla; Melloni, Elsa; Padoani, Gloria; Vailati, Silvia; Sardina, Marco

2018-02-01

Safinamide has been recently approved as an add-on to levodopa therapy for Parkinson disease. In addition to inhibiting monoamine oxidase type B, it blocks sodium channels and modulates glutamate (Glu) release in vitro. Since this property might contribute to the therapeutic action of the drug, we undertook the present study to investigate whether safinamide inhibits Glu release also in vivo and whether this effect is consistent across different brain areas and is selective for glutamatergic neurons. To this aim, in vivo microdialysis was used to monitor the spontaneous and veratridine-induced Glu and GABA release in the hippocampus and basal ganglia of naive, awake rats. Brain levels of safinamide were measured as well. To shed light on the mechanisms underlying the effect of safinamide, sodium currents were measured by patch-clamp recording in rat cortical neurons. Safinamide maximally inhibited the veratridine-induced Glu and GABA release in hippocampus at 15 mg/kg, which reached free brain concentrations of 1.89-1.37 µ M. This dose attenuated veratridine-stimulated Glu (but not GABA) release in subthalamic nucleus, globus pallidus, and substantia nigra reticulata, but not in striatum. Safinamide was ineffective on spontaneous neurotransmitter release. In vitro, safinamide inhibited sodium channels, showing a greater affinity at depolarized (IC 50 = 8 µ M) than at resting (IC 50 = 262 µ M) potentials. We conclude that safinamide inhibits in vivo Glu release from stimulated nerve terminals, likely via blockade of sodium channels at subpopulations of neurons with specific firing patterns. These data are consistent with the anticonvulsant and antiparkinsonian actions of safinamide and provide support for the nondopaminergic mechanism of its action. Copyright © 2018 The Author(s).

Thyroid Functions and Bipolar Affective Disorder

PubMed Central

Chakrabarti, Subho

2011-01-01

Accumulating evidence suggests that hypothalamo-pituitary-thyroid (HPT) axis dysfunction is relevant to the pathophysiology and clinical course of bipolar affective disorder. Hypothyroidism, either overt or more commonly subclinical, appears to the commonest abnormality found in bipolar disorder. The prevalence of thyroid dysfunction is also likely to be greater among patients with rapid cycling and other refractory forms of the disorder. Lithium-treatment has potent antithyroid effects and can induce hypothyroidism or exacerbate a preexisting hypothyroid state. Even minor perturbations of the HPT axis may affect the outcome of bipolar disorder, necessitating careful monitoring of thyroid functions of patients on treatment. Supplementation with high dose thyroxine can be considered in some patients with treatment-refractory bipolar disorder. Neurotransmitter, neuroimaging, and genetic studies have begun to provide clues, which could lead to an improved understanding of the thyroid-bipolar disorder connection, and more optimal ways of managing this potentially disabling condition. PMID:21808723

A Preliminary Study of Gene Polymorphisms Involved in the Neurotransmitters Metabolism of a Homogeneous Spanish Autistic Group

ERIC Educational Resources Information Center

Calahorro, Fernando; Alejandre, Encarna; Anaya, Nuria; Guijarro, Teresa; Sanz, Yolanza; Romero, Auxiliadora; Tienda, Pilar; Burgos, Rafael; Gay, Eudoxia; Sanchez, Vicente; Ruiz-Rubio, Manuel

2009-01-01

Twin studies have shown a strong genetic component for autism. Neurotransmitters, such as serotonin and catecholamines, have been suggested to play a role in the disease since they have an essential function in synaptogenesis and brain development. In this preliminary study, polymorphism of genes implicated in the serotonergic and dopaminergic…

Acute fasting increases somatodendritic dopamine release in the ventral tegmental area

PubMed Central

2015-01-01

Fasting and food restriction alter the activity of the mesolimbic dopamine system to affect multiple reward-related behaviors. Food restriction decreases baseline dopamine levels in efferent target sites and enhances dopamine release in response to rewards such as food and drugs. In addition to releasing dopamine from axon terminals, dopamine neurons in the ventral tegmental area (VTA) also release dopamine from their soma and dendrites, and this somatodendritic dopamine release acts as an autoinhibitory signal to inhibit neighboring VTA dopamine neurons. It is unknown whether acute fasting also affects dopamine release, including the local inhibitory somatodendritic dopamine release in the VTA. In these studies, I have tested whether fasting affects the inhibitory somatodendritic dopamine release within the VTA by examining whether an acute 24-h fast affects the inhibitory postsynaptic current mediated by evoked somatodendritic dopamine release (D2R IPSC). Fasting increased the contribution of the first action potential to the overall D2R IPSC and increased the ratio of repeated D2R IPSCs evoked at short intervals. Fasting also reduced the effect of forskolin on the D2R IPSC and led to a significantly bigger decrease in the D2R IPSC in low extracellular calcium. Finally, fasting resulted in an increase in the D2R IPSCs when a more physiologically relevant train of D2R IPSCs was used. Taken together, these results indicate that fasting caused a change in the properties of somatodendritic dopamine release, possibly by increasing dopamine release, and that this increased release can be sustained under conditions where dopamine neurons are highly active. PMID:26084913

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.

Microelectronics-Based Biosensors Dedicated to the Detection of Neurotransmitters: A Review

PubMed Central

Mirzaei, Maryam; Sawan, Mohamad

2014-01-01

Dysregulation of neurotransmitters (NTs) in the human body are related to diseases such as Parkinson's and Alzheimer's. The mechanisms of several neurological disorders, such as epilepsy, have been linked to NTs. Because the number of diagnosed cases is increasing, the diagnosis and treatment of such diseases are important. To detect biomolecules including NTs, microtechnology, micro and nanoelectronics have become popular in the form of the miniaturization of medical and clinical devices. They offer high-performance features in terms of sensitivity, as well as low-background noise. In this paper, we review various devices and circuit techniques used for monitoring NTs in vitro and in vivo and compare various methods described in recent publications. PMID:25264957

Concomitant Release of Ventral Tegmental Acetylcholine and Accumbal Dopamine by Ghrelin in Rats

PubMed Central

Jerlhag, Elisabet; Janson, Anna Carin; Waters, Susanna; Engel, Jörgen A.

2012-01-01

Ghrelin, an orexigenic peptide, regulates energy balance specifically via hypothalamic circuits. Growing evidence suggest that ghrelin increases the incentive value of motivated behaviours via activation of the cholinergic-dopaminergic reward link. It encompasses the cholinergic afferent projection from the laterodorsal tegmental area (LDTg) to the dopaminergic cells of the ventral tegmental area (VTA) and the mesolimbic dopamine system projecting from the VTA to nucleus accumbens (N.Acc.). Ghrelin receptors (GHS-R1A) are expressed in these reward nodes and ghrelin administration into the LDTg increases accumbal dopamine, an effect involving nicotinic acetylcholine receptors in the VTA. The present series of experiments were undertaken directly to test this hypothesis. Here we show that ghrelin, administered peripherally or locally into the LDTg concomitantly increases ventral tegmental acetylcholine as well as accumbal dopamine release. A GHS-R1A antagonist blocks this synchronous neurotransmitter release induced by peripheral ghrelin. In addition, local perfusion of the unselective nicotinic antagonist mecamylamine into the VTA blocks the ability of ghrelin (administered into the LDTg) to increase N.Acc.-dopamine, but not VTA-acetylcholine. Collectively our data indicate that ghrelin activates the LDTg causing a release of acetylcholine in the VTA, which in turn activates local nicotinic acetylcholine receptors causing a release of accumbal dopamine. Given that a dysfunction in the cholinergic-dopaminergic reward system is involved in addictive behaviours, including compulsive overeating and alcohol use disorder, and that hyperghrelinemia is associated with such addictive behaviours, ghrelin-responsive circuits may serve as a novel pharmacological target for treatment of alcohol use disorder as well as binge eating. PMID:23166710

Dilation of fusion pores by crowding of SNARE proteins

PubMed Central

Wu, Zhenyong; Bello, Oscar D; Thiyagarajan, Sathish; Auclair, Sarah Marie; Vennekate, Wensi; Krishnakumar, Shyam S; O'Shaughnessy, Ben; Karatekin, Erdem

2017-01-01

Hormones and neurotransmitters are released through fluctuating exocytotic fusion pores that can flicker open and shut multiple times. Cargo release and vesicle recycling depend on the fate of the pore, which may reseal or dilate irreversibly. Pore nucleation requires zippering between vesicle-associated v-SNAREs and target membrane t-SNAREs, but the mechanisms governing the subsequent pore dilation are not understood. Here, we probed the dilation of single fusion pores using v-SNARE-reconstituted ~23-nm-diameter discoidal nanolipoprotein particles (vNLPs) as fusion partners with cells ectopically expressing cognate, 'flipped' t-SNAREs. Pore nucleation required a minimum of two v-SNAREs per NLP face, and further increases in v-SNARE copy numbers did not affect nucleation rate. By contrast, the probability of pore dilation increased with increasing v-SNARE copies and was far from saturating at 15 v-SNARE copies per face, the NLP capacity. Our experimental and computational results suggest that SNARE availability may be pivotal in determining whether neurotransmitters or hormones are released through a transient ('kiss and run') or an irreversibly dilating pore (full fusion). DOI: http://dx.doi.org/10.7554/eLife.22964.001 PMID:28346138

Altered neurotransmitter function in CO2-exposed stickleback (Gasterosteus aculeatus): a temperate model species for ocean acidification research.

PubMed

Lai, Floriana; Jutfelt, Fredrik; Nilsson, Göran E

2015-01-01

Studies on the consequences of ocean acidification for the marine ecosystem have revealed behavioural changes in coral reef fishes exposed to sustained near-future CO2 levels. The changes have been linked to altered function of GABAergic neurotransmitter systems, because the behavioural alterations can be reversed rapidly by treatment with the GABAA receptor antagonist gabazine. Characterization of the molecular mechanisms involved would be greatly aided if these can be examined in a well-characterized model organism with a sequenced genome. It was recently shown that CO2-induced behavioural alterations are not confined to tropical species, but also affect the three-spined stickleback, although an involvement of the GABAA receptor was not examined. Here, we show that loss of lateralization in the stickleback can be restored rapidly and completely by gabazine treatment. This points towards a worrying universality of disturbed GABAA function after high-CO2 exposure in fishes from tropical to temperate marine habitats. Importantly, the stickleback is a model species with a sequenced and annotated genome, which greatly facilitates future studies on underlying molecular mechanisms.

Neurotransmitters and pathophysiology of stroke: evidence for the release of glutamate and other transmitters/mediators in animals and humans.

PubMed

Dávalos, A; Shuaib, A; Wahlgren, N G

2000-11-01

There is convincing evidence from animal models of stroke that ischemia leads to an increase in the extracellular concentrations of excitatory amino acids (EAAs), especially glutamate. This accumulation of glutamate, which can reach up to 80 times normal at the centre of an ischemic lesion, is believed to be an important factor for the premature death of neurons that would otherwise survive the ischemic conditions and recover when flow is restored. In the technique of microdialysis, a small probe is inserted into the brain tissue. Fluid passing through the probe is separated from the brain parenchyma by a semipermeable membrane, through which substances released into the brain can diffuse. Analysis of the dialysate allows the nature and time course of release of substances, such as glutamate, to be determined. This technique has been used in patients undergoing resection of cerebral tumors, surgery for epilepsy, head trauma, subarachnoid hemorrhage, and cerebral infarction. Clamping or ligating the blood supply to the lobe about to be excised leads to a rapid accumulation in the dialysate of, among other substances, glutamate. Similar findings have been obtained during lobar resection for the treatment of severe epilepsy. Accumulations of glutamate to approximately 100 times the basal concentration have been found. There are also a few reports of microdialysis being performed in patients undergoing lobectomy after severe strokes or extracranial-intracranial bypass surgery. Again, high concentrations of glutamate have been reported. Another approach is to examine the blood and cerebrospinal fluid (CSF) for traces of EAAs. High concentrations of glutamate have been found in the blood and CSF within 24 hours of the onset of stroke. In animal models, plasma concentrations of glutamate begin to rise some 4 to 6 hours after middle cerebral artery (MCA) occlusions, reaching a peak at about 8 to 24 hours. Similarly, when glutamate is injected into the CSF of rats, there is

Effect of infrared laser irradiation on amino acid neurotransmitters in an epileptic animal model induced by pilocarpine.

PubMed

Radwan, Nasr Mahmoud; El Hay Ahmed, Nawal Abd; Ibrahim, Khayria Mansour; Khedr, Mona Emam; Aziz, Mona A; Khadrawy, Yasser Ashry

2009-06-01

The aim of the present study was to investigate the effect of daily laser irradiation on the levels of amino acid neurotransmitters in the cortex and hippocampus in an epileptic animal model induced by pilocarpine. It has been claimed that at specific wavelengths and energy densities, laser irradiation is a novel and useful tool for the treatment of peripheral and central nervous system injuries and disorders. Adult male albino rats were divided into three groups: control rats, pilocarpinized rats (epileptic animal model), and pilocarpinized rats treated daily with laser irradiation (90 mW at 830 nm) for 7 d. The following parameters were assayed in cortex and hippocampus: amino acid neurotransmitters (excitatory: glutamic acid and aspartate; and inhibitory: gamma-aminobutyric acid [GABA], glycine, and taurine) by high-performance liquid chromatography (HPLC), glucose content, and the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), using a spectrophotometer. Significant increases in the concentrations of glutamic acid, glutamine, glycine, and taurine were recorded in the cortices of pilocarpinized rats, and they returned to initial levels after laser treatment. In the hippocampus, a moderate increase in aspartate accompanied by a significant increase in glycine were observed in the epileptic animal model, and these dropped to near-control values after laser treatment. In addition, a significant increase in cortical AST activity and a significant decrease in ALT activity and glucose content were obtained in the pilocarpinized animals and pilocarpinized rats treated with laser irradiation. In the hippocampus, significant decreases in the activity of AST and ALT and glucose content were recorded in the epileptic animals and in the epileptic animals treated with laser irradiation. Based on the results obtained in this study, it may be suggested that nearinfrared laser irradiation may reverse the neurochemical changes in amino acid

Optimization of ultra-performance liquid chromatography (UPLC) with fluorescence detector (FLD) method for the quantitative determination of selected neurotransmitters in rat brain.

PubMed

Stragierowicz, Joanna; Daragó, Adam; Brzeźnicki, Sławomir; Kilanowicz, Anna

2017-07-26

Glutamate (Glu) and γ-aminobutyric acid (GABA) are the main neurotransmitters in the central nervous system for excitatory and inhibitory processes, respectively. Monitoring these neurotransmitters is an essential tool in establishing pathological functions, among others in terms of occupational exposure to toxic substances. We present modification of the HPLC (high-performance liquid chromatography) to the UPLC (ultra-performance liquid chromatography) method for the simultaneous determination of glutamate and γ-aminobutyric acid in a single injection. The isocratic separation of these neurotransmitter derivatives was performed on Waters Acquity BEH (ethylene bridged hybrid) C18 column with particle size of 1.7 μm at 35°C using a mobile phase consisting of 0.1 M acetate buffer (pH 6.0) and methanol (60:40, v/v) at a flow rate of 0.3 ml/min. The analytes were detected with the fluorescence detector (FLD) using derivatization with o-phthaldialdehyde (OPA), resulting in excitation at 340 nm and emission at 455 nm. Several validation parameters including linearity (0.999), accuracy (101.1%), intra-day precision (1.52-1.84%), inter-day precision (2.47-3.12%), limit of detection (5-30 ng/ml) and quantification (100 ng/ml) were examined. The developed method was also used for the determination of these neurotransmitters in homogenates of selected rat brain structures. The presented UPLC-FLD is characterized by shorter separation time (3.5 min), which is an adaptation of the similar HPLC methods and is an alternative for more expensive references techniques such as liquid chromatography coupled with tandem mass-spectrometry (LC-MS/MS) methods. Med Pr 2017;68(5):583-591. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

Rosiglitazone Suppresses In Vitro Seizures in Hippocampal Slice by Inhibiting Presynaptic Glutamate Release in a Model of Temporal Lobe Epilepsy.

PubMed

Wong, Shi-Bing; Cheng, Sin-Jhong; Hung, Wei-Chen; Lee, Wang-Tso; Min, Ming-Yuan

2015-01-01

Peroxisomal proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor whose agonist, rosiglitazone has a neuroprotective effect to hippocampal neurons in pilocarpine-induced seizures. Hippocampal slice preparations treated in Mg2+ free medium can induce ictal and interictal-like epileptiform discharges, which is regarded as an in vitro model of N-methyl-D-aspartate (NMDA) receptor-mediated temporal lobe epilepsy (TLE). We applied rosiglitazone in hippocampal slices treated in Mg2+ free medium. The effects of rosiglitazone on hippocampal CA1-Schaffer collateral synaptic transmission were tested. We also examined the neuroprotective effect of rosiglitazone toward NMDA excitotoxicity on cultured hippocampal slices. Application of 10 μM rosiglitazone significantly suppressed amplitude and frequency of epileptiform discharges in CA1 neurons. Pretreatment with the PPARγ antagonist GW9662 did not block the effect of rosiglitazone on suppressing discharge frequency, but reverse the effect on suppressing discharge amplitude. Application of rosiglitazone suppressed synaptic transmission in the CA1-Schaffer collateral pathway. By miniature excitatory-potential synaptic current (mEPSC) analysis, rosiglitazone significantly suppressed presynaptic neurotransmitter release. This phenomenon can be reversed by pretreating PPARγ antagonist GW9662. Also, rosiglitazone protected cultured hippocampal slices from NMDA-induced excitotoxicity. The protective effect of 10 μM rosiglitazone was partially antagonized by concomitant high dose GW9662 treatment, indicating that this effect is partially mediated by PPARγ receptors. In conclusion, rosiglitazone suppressed NMDA receptor-mediated epileptiform discharges by inhibition of presynaptic neurotransmitter release. Rosiglitazone protected hippocampal slice from NMDA excitotoxicity partially by PPARγ activation. We suggest that rosiglitazone could be a potential agent to treat patients with TLE.

P-type voltage-dependent calcium channel mediates presynaptic calcium influx and transmitter release in mammalian synapses.

PubMed Central

Uchitel, O D; Protti, D A; Sanchez, V; Cherksey, B D; Sugimori, M; Llinás, R

1992-01-01

We have studied the effect of the purified toxin from the funnel-web spider venom (FTX) and its synthetic analog (sFTX) on transmitter release and presynaptic currents at the mouse neuromuscular junction. FTX specifically blocks the omega-conotoxin- and dihydropyridine-insensitive P-type voltage-dependent Ca2+ channel (VDCC) in cerebellar Purkinje cells. Mammalian neuromuscular transmission, which is insensitive to N- or L-type Ca2+ channel blockers, was effectively abolished by FTX and sFTX. These substances blocked the muscle contraction and the neurotransmitter release evoked by nerve stimulation. Moreover, presynaptic Ca2+ currents recorded extracellularly from the interior of the perineural sheaths of nerves innervating the mouse levator auris muscle were specifically blocked by both natural toxin and synthetic analogue. In a parallel set of experiments, K(+)-induced Ca45 uptake by brain synaptosomes was also shown to be blocked or greatly diminished by FTX and sFTX. These results indicate that the predominant VDCC in the motor nerve terminals, and possibly in a significant percentage of brain synapses, is the P-type channel. Images PMID:1348859

P-type voltage-dependent calcium channel mediates presynaptic calcium influx and transmitter release in mammalian synapses.

PubMed

Uchitel, O D; Protti, D A; Sanchez, V; Cherksey, B D; Sugimori, M; Llinás, R

1992-04-15

We have studied the effect of the purified toxin from the funnel-web spider venom (FTX) and its synthetic analog (sFTX) on transmitter release and presynaptic currents at the mouse neuromuscular junction. FTX specifically blocks the omega-conotoxin- and dihydropyridine-insensitive P-type voltage-dependent Ca2+ channel (VDCC) in cerebellar Purkinje cells. Mammalian neuromuscular transmission, which is insensitive to N- or L-type Ca2+ channel blockers, was effectively abolished by FTX and sFTX. These substances blocked the muscle contraction and the neurotransmitter release evoked by nerve stimulation. Moreover, presynaptic Ca2+ currents recorded extracellularly from the interior of the perineural sheaths of nerves innervating the mouse levator auris muscle were specifically blocked by both natural toxin and synthetic analogue. In a parallel set of experiments, K(+)-induced Ca45 uptake by brain synaptosomes was also shown to be blocked or greatly diminished by FTX and sFTX. These results indicate that the predominant VDCC in the motor nerve terminals, and possibly in a significant percentage of brain synapses, is the P-type channel.

The goldfish nervus terminalis: a luteinizing hormone-releasing hormone and molluscan cardioexcitatory peptide immunoreactive olfactoretinal pathway.

PubMed

Stell, W K; Walker, S E; Chohan, K S; Ball, A K

1984-02-01

Antisera to two putative neurotransmitters, luteinizing hormone-releasing hormone (LHRH) and molluscan cardioexcitatory tetrapeptide (H-Phe-Met-Arg-Phe-NH2; FMRF-amide), bind specifically to neurites in the inner nuclear and inner plexiform layers of the goldfish retina. Retrograde labeling showed that intraocular axon terminals originate from the nervus terminalis, whose cell bodies are located in the olfactory nerves. Double immunocytochemical and retrograde labeling showed that some terminalis neurons project to the retina; others may project only within the brain. All terminalis neurons having proven retinal projections were both LHRH- and FMRF-amide-immunoreactive. The activity of retinal ganglion cells was recorded with microelectrodes in isolated superfused goldfish retinas. In ON- and OFF-center double-color-opponent cells, micromolar FMRF-amide and salmon brain gonadotropin-releasing factor ( [Trp7, Leu8] LHRH) caused increased spontaneous activity in the dark, loss of light-induced inhibition, and increased incidence of light-entrained pulsatile response. The nervus terminalis is therefore a putatively peptidergic retinopetal projection. Sex-related olfactory stimuli may act through it, thereby modulating the output of ganglion cells responsive to color contrast.

Label-Free Neuroproteomics of the Hippocampal-Accumbal Circuit Reveals Deficits in Neurotransmitter and Neuropeptide Signaling in Mice Lacking Ethanol-Sensitive Adenosine Transporter.

PubMed

Oliveros, Alfredo; Starski, Phillip; Lindberg, Daniel; Choi, Sun; Heppelmann, Carrie J; Dasari, Surendra; Choi, Doo-Sup

2017-04-07

The neural circuit of the dorsal hippocampus (dHip) and nucleus accumbens (NAc) contributes to cue-induced learning and addictive behaviors, as demonstrated by the escalation of ethanol-seeking behaviors observed following deletion of the adenosine equilibrative nucleoside transporter 1 (ENT1 -/- ) in mice. Here we perform quantitative LC-MS/MS neuroproteomics in the dHip and NAc of ENT1 -/- mice. Using Ingenuity Pathway Analysis, we identified proteins associated with increased long-term potentiation, ARP2/3-mediated actin cytoskeleton signaling and protein expression patterns suggesting deficits in glutamate degradation, GABAergic signaling, as well as significant changes in bioenergetics and energy homeostasis (oxidative phosphorylation, TCA cycle, and glycolysis). These pathways are consistent with previously reported behavioral and biochemical phenotypes that typify mice lacking ENT1. Moreover, we validated decreased expression of the SNARE complex protein VAMP1 (synaptobrevin-1) in the dHip as well as decreased expression of pro-dynorphin (PDYN), neuroendocrine convertase (PCSK1), and Leu-Enkephalin (dynorphin-A) in the NAc. Taken together, our proteomic approach provides novel pathways indicating that ENT1-regulated signaling is essential for neurotransmitter release and neuropeptide processing, both of which underlie learning and reward-seeking behaviors.

A standardized Hippophae extract (SBL-1) counters neuronal tissue injuries and changes in neurotransmitters: implications in radiation protection.

PubMed

Bala, Madhu; Gupta, Vanita; Prasad, Jagdish

2017-12-01

Effects of a radioprotective, standardized leaf extract (code SBL-1) from traditional medicinal plant, sea buckthorn [Hippophae rhamnoides L. (Elaeagnaceae)], on neurotransmitters and brain injuries in rats showing radiation-induced conditioned taste aversion (CTA), are not known. Understanding CTA in rats is important because its process is considered parallel to nausea and vomiting in humans. This study investigated the levels of neurotransmitters, antioxidant defences and histological changes in rats showing radiation CTA, and their modification by SBL-1. The inbred male Sprague-Dawley rats (age 65 days, weighing 190 ± 10 g) were used. Saccharin-preferring rats were selected using standard procedure and divided into groups. Group I (untreated control) was administered sterile water, group II was 60 Co-γ-irradiated (2 Gy), and group III was administered SBL-1 before irradiation. Observations were recorded up to day 5. Irradiation (2 Gy) caused (i) non-recoverable CTA (≥ 64.7 ± 5.0%); (ii) degenerative changes in cerebral cortex, amygdala and hippocampus; (iii) increases in brain dopamine (DA, 63.4%), norepinephrine (NE, 157%), epinephrine (E, 233%), plasma NE (103%) and E (160%); and (iv) decreases in brain superoxide dismutase (67%), catalase (60%) and glutathione (51%). SBL-1 treatment (12 mg/kg body weight) 30 min before irradiation (i) countered brain injuries, (ii) reduced CTA (38.7 ± 3.0%, day 1) and (iii) normalized brain DA, NE, E, superoxide dismutase, catalase and CTA from day 3 onwards. Radiation CTA was coupled with brain injuries, disturbances in neurotransmitters and antioxidant defences. SBL-1 pretreatment countered these disturbances, indicating neuroprotective action.

Oral administration of circulating precursors for membrane phosphatides can promote the synthesis of new brain synapses

PubMed Central

Cansev, Mehmet; Wurtman, Richard J.; Sakamoto, Toshimasa; Ulus, Ismail H.

2008-01-01

Although cognitive performance in humans and experimental animals can be improved by administering the omega-3 fatty acid docosahexaenoic acid (DHA), the neurochemical mechanisms underlying this effect remain uncertain. In general, nutrients or drugs that modify brain function or behavior do so by affecting synaptic transmission, usually by changing the quantities of particular neurotransmitters present within synaptic clefts or by acting directly on neurotransmitter receptors or signal-transduction molecules. We find that DHA also affects synaptic transmission in mammalian brain: Brain cells of gerbils or rats receiving this fatty acid manifest increased levels of phosphatides and of specific pre- or post-synaptic proteins. They also exhibit increased numbers of dendritic spines on postsynaptic neurons. These actions are markedly enhanced in animals that have also received the other two circulating precursors for phosphatidylcholine – uridine (which gives rise to brain UTP and CTP), and choline (which gives rise to phosphocholine). The actions of DHA are reproduced by eicosapentaenoic acid (EPA), another omega-3 compound, but not by the omega-6 fatty acid arachidonic acid (AA). Administration of circulating phosphatide precursors can also increase neurotransmitter release (acetylcholine; dopamine) and affect animal behavior. Conceivably, this treatment might have use in patients with the synaptic loss that characterizes Alzheimer's disease or other neurodegenerative diseases, or occurs after stroke or brain injury. PMID:18631994

Inhibitory ryanodine prevents ryanodine receptor-mediated Ca²⁺ release without affecting endoplasmic reticulum Ca²⁺ content in primary hippocampal neurons.

PubMed

Adasme, Tatiana; Paula-Lima, Andrea; Hidalgo, Cecilia

2015-02-27

Ryanodine is a cell permeant plant alkaloid that binds selectively and with high affinity to ryanodine receptor (RyR) Ca(2+) release channels. Sub-micromolar ryanodine concentrations activate RyR channels while micromolar concentrations are inhibitory. Several reports indicate that neuronal synaptic plasticity, learning and memory require RyR-mediated Ca(2+)-release, which is essential for muscle contraction. The use of micromolar (inhibitory) ryanodine represents a common strategy to suppress RyR activity in neuronal cells: however, micromolar ryanodine promotes RyR-mediated Ca(2+) release and endoplasmic reticulum Ca(2+) depletion in muscle cells. Information is lacking in this regard in neuronal cells; hence, we examined here if addition of inhibitory ryanodine elicited Ca(2+) release in primary hippocampal neurons, and if prolonged incubation of primary hippocampal cultures with inhibitory ryanodine affected neuronal ER calcium content. Our results indicate that inhibitory ryanodine does not cause Ca(2+) release from the ER in primary hippocampal neurons, even though ryanodine diffusion should produce initially low intracellular concentrations, within the RyR activation range. Moreover, neurons treated for 1 h with inhibitory ryanodine had comparable Ca(2+) levels as control neurons. These combined findings imply that prolonged incubation with inhibitory ryanodine, which effectively abolishes RyR-mediated Ca(2+) release, preserves ER Ca(2+) levels and thus constitutes a sound strategy to suppress neuronal RyR function. Copyright © 2015 Elsevier Inc. All rights reserved.

Synaptic inhibition and γ-aminobutyric acid in the mammalian central nervous system

PubMed Central

OBATA, Kunihiko

2013-01-01

Signal transmission through synapses connecting two neurons is mediated by release of neurotransmitter from the presynaptic axon terminals and activation of its receptor at the postsynaptic neurons. γ-Aminobutyric acid (GABA), non-protein amino acid formed by decarboxylation of glutamic acid, is a principal neurotransmitter at inhibitory synapses of vertebrate and invertebrate nervous system. On one hand glutamic acid serves as a principal excitatory neurotransmitter. This article reviews GABA researches on; (1) synaptic inhibition by membrane hyperpolarization, (2) exclusive localization in inhibitory neurons, (3) release from inhibitory neurons, (4) excitatory action at developmental stage, (5) phenotype of GABA-deficient mouse produced by gene-targeting, (6) developmental adjustment of neural network and (7) neurological/psychiatric disorder. In the end, GABA functions in simple nervous system and plants, and non-amino acid neurotransmitters were supplemented. PMID:23574805

Distribution of serine/threonine kinase SAD-B in mouse peripheral nerve synapse.

PubMed

Hagiwara, Akari; Harada, Kenu; Hida, Yamato; Kitajima, Isao; Ohtsuka, Toshihisa

2011-05-11

The serine/threonine kinase SAD regulates neural functions such as axon/dendrite polarization and neurotransmitter release. In the vertebrate central nervous system, SAD-B, a homolog of Caenorhabditis elegans SAD-1, is associated with synaptic vesicles and the active zone cytomatrix in nerve terminals. However, the distribution of SAD-B in the peripheral nervous system remains elusive. Here, we show that SAD-B is specifically localized to neuromuscular junctions. Although the active zone protein bassoon showed a punctated signal indicating its localization to motor end plates, SAD-B shows relatively diffuse localization indicating its association with both the active zone and synaptic vesicles. Therefore, SAD kinase may regulate neurotransmitter release from motor end plates in a similar manner to its regulation of neurotransmitter release in the central nervous system.

Glutamatergic and GABAergic neurotransmitter cycling and energy metabolism in rat cerebral cortex during postnatal development.

PubMed

Chowdhury, Golam M I; Patel, Anant B; Mason, Graeme F; Rothman, Douglas L; Behar, Kevin L

2007-12-01

The contribution of glutamatergic and gamma-aminobutyric acid (GABA)ergic neurons to oxidative energy metabolism and neurotransmission in the developing brain is not known. Glutamatergic and GABAergic fluxes were assessed in neocortex of postnatal day 10 (P10) and 30 (P30) urethane-anesthetized rats infused intravenously with [1,6-(13)C(2)]glucose for different time intervals (time course) or with [2-(13)C]acetate for 2 to 3 h (steady state). Amino acid levels and (13)C enrichments were determined in tissue extracts ex vivo using (1)H-[(13)C]-NMR spectroscopy. Metabolic fluxes were estimated from the best fits of a three-compartment metabolic model (glutamatergic neurons, GABAergic neurons, and astroglia) to the (13)C-enrichment time courses of amino acids from [1,6-(13)C(2)]glucose, constrained by the ratios of neurotransmitter cycling (V(cyc))-to-tricarboxylic acid (TCA) cycle flux (V(TCAn)) calculated from the steady-state [2-(13)C]acetate enrichment data. From P10 to P30 increases in total neuronal (glutamate plus GABA) TCA cycle flux (3 x ; 0.24+/-0.05 versus 0.71+/-0.07 micromol per g per min, P<0.0001) and total neurotransmitter cycling flux (3.1 to 5 x ; 0.07 to 0.11 (+/-0.03) versus 0.34+/-0.03 micromol per g per min, P<0.0001) were approximately proportional. Incremental changes in total cycling (DeltaV(cyc(tot))) and neuronal TCA cycle flux (DeltaV(TCAn(tot))) between P10 and P30 were 0.23 to 0.27 and 0.47 micromol per g per min, respectively, similar to the approximately 1:2 relationship previously reported for adult cortex. For the individual neurons, increases in V(TCAn) and V(cyc) were similar in magnitude (glutamatergic neurons, 2.7 x versus 2.8 to 4.6 x ; GABAergic neurons, approximately 5 x versus approximately 7 x), although GABAergic flux changes were larger. The findings show that glutamate and GABA neurons undergo large and approximately proportional increases in neurotransmitter cycling and oxidative energy metabolism during this major

Release of the antioxidants ascorbate and urate from a nitrergically-innervated smooth muscle.

PubMed

Lilley, E; Gibson, A

1997-12-01

in release of ascorbate, but not urate, from 6-OHDA-treated muscles. 5. The results demonstrate that significant amounts of ascorbate and urate are released from the rat anococcygeus muscle. Ascorbate, but not urate, release appears to be enhanced by activation of nerves which are resistant to 6-OHDA pretreatment. Since both antioxidants can protect NO from attack by scavenger molecules, their release in nitrergically-innervated tissues may be important for the provision of the correct redox environment to allow NO to fulfill its proposed neurotransmitter role.

Review on fluoride-releasing restorative materials--fluoride release and uptake characteristics, antibacterial activity and influence on caries formation.

PubMed

Wiegand, Annette; Buchalla, Wolfgang; Attin, Thomas

2007-03-01

The purpose of this article was to review the fluoride release and recharge capabilities, and antibacterial properties, of fluoride-releasing dental restoratives, and discuss the current status concerning the prevention or inhibition of caries development and progression. Information from original scientific full papers or reviews listed in PubMed (search term: fluoride release AND (restorative OR glass-ionomer OR compomer OR polyacid-modified composite resin OR composite OR amalgam)), published from 1980 to 2004, was included in the review. Papers dealing with endodontic or orthodontic topics were not taken into consideration. Clinical studies concerning secondary caries development were only included when performed in split-mouth design with an observation period of at least three years. Fluoride-containing dental materials show clear differences in the fluoride release and uptake characteristics. Short- and long-term fluoride releases from restoratives are related to their matrices, setting mechanisms and fluoride content and depend on several environmental conditions. Fluoride-releasing materials may act as a fluoride reservoir and may increase the fluoride level in saliva, plaque and dental hard tissues. However, clinical studies exhibited conflicting data as to whether or not these materials significantly prevent or inhibit secondary caries and affect the growth of caries-associated bacteria compared to non-fluoridated restoratives. Fluoride release and uptake characteristics depend on the matrices, fillers and fluoride content as well as on the setting mechanisms and environmental conditions of the restoratives. Fluoride-releasing materials, predominantly glass-ionomers and compomers, did show cariostatic properties and may affect bacterial metabolism under simulated cariogenic conditions in vitro. However, it is not proven by prospective clinical studies whether the incidence of secondary caries can be significantly reduced by the fluoride release of

Dietary Neurotransmitters: A Narrative Review on Current Knowledge

PubMed Central

Dell’Osso, Bernardo; Malgaroli, Antonio; Banfi, Giuseppe; Zanaboni Dina, Carlotta; Galentino, Roberta; Porta, Mauro

2018-01-01

Foods are natural sources of substances that may exert crucial effects on the nervous system in humans. Some of these substances are the neurotransmitters (NTs) acetylcholine (ACh), the modified amino acids glutamate and γ-aminobutyric acid (GABA), and the biogenic amines dopamine, serotonin (5-HT), and histamine. In neuropsychiatry, progressive integration of dietary approaches in clinical routine made it necessary to discern the more about some of these dietary NTs. Relevant books and literature from PubMed and Scopus databases were searched for data on food sources of Ach, glutamate, GABA, dopamine, 5-HT, and histamine. Different animal foods, fruits, edible plants, roots, and botanicals were reported to contain NTs. These substances can either be naturally present, as part of essential metabolic processes and ecological interactions, or derive from controlled/uncontrolled food technology processes. Ripening time, methods of preservation and cooking, and microbial activity further contributes to NTs. Moreover, gut microbiota are considerable sources of NTs. However, the significance of dietary NTs intake needs to be further investigated as there are no significant data on their bioavailability, neuronal/non neuronal effects, or clinical implications. Evidence-based interventions studies should be encouraged. PMID:29748506

Substrates for Neuronal Cotransmission With Neuropeptides and Small Molecule Neurotransmitters in Drosophila

PubMed Central

Nässel, Dick R.

2018-01-01

It has been known for more than 40 years that individual neurons can produce more than one neurotransmitter and that neuropeptides often are colocalized with small molecule neurotransmitters (SMNs). Over the years much progress has been made in understanding the functional consequences of cotransmission in the nervous system of mammals. There are also some excellent invertebrate models that have revealed roles of coexpressed neuropeptides and SMNs in increasing complexity, flexibility, and dynamics in neuronal signaling. However, for the fly Drosophila there are surprisingly few functional studies on cotransmission, although there is ample evidence for colocalization of neuroactive compounds in neurons of the CNS, based both on traditional techniques and novel single cell transcriptome analysis. With the hope to trigger interest in initiating cotransmission studies, this review summarizes what is known about Drosophila neurons and neuronal circuits where different neuropeptides and SMNs are colocalized. Coexistence of neuroactive substances has been recorded in different neuron types such as neuroendocrine cells, interneurons, sensory cells and motor neurons. Some of the circuits highlighted here are well established in the analysis of learning and memory, circadian clock networks regulating rhythmic activity and sleep, as well as neurons and neuroendocrine cells regulating olfaction, nociception, feeding, metabolic homeostasis, diuretic functions, reproduction, and developmental processes. One emerging trait is the broad role of short neuropeptide F in cotransmission and presynaptic facilitation in a number of different neuronal circuits. This review also discusses the functional relevance of coexisting peptides in the intestine. Based on recent single cell transcriptomics data, it is likely that the neuronal systems discussed in this review are just a fraction of the total set of circuits where cotransmission occurs in Drosophila. Thus, a systematic search for

Neuroendocrine abnormalities in hypothalamic amenorrhea: spectrum, stability, and response to neurotransmitter modulation.

PubMed

Perkins, R B; Hall, J E; Martin, K A

1999-06-01

To characterize the neuroendocrine patterns of abnormal GnRH secretion in hypothalamic amenorrhea (HA), 49 women with primary and secondary HA underwent frequent sampling of LH in a total of 72 baseline studies over 12-24 h. A subset of women participated in more than one study to address 1) the variability of LH pulse patterns over time; and 2) the impact of modulating opioid, dopaminergic, and adrenergic tone on LH secretory patterns. The frequency and amplitude of LH secretion was compared with that seen in the early follicular phase (EFP) of normally cycling women. The spectrum of abnormalities of LH pulses was 8% apulsatile, 27% low frequency/low amplitude, 8% low amplitude/normal frequency, 43% low frequency/normal amplitude, 14% normal frequency/normal amplitude. Of patients studied overnight, 45% demonstrated a pubertal pattern of augmented LH secretion during sleep. Of patients studied repeatedly, 75% demonstrated at least 2 different patterns of LH secretion, and 33% reverted at least once to a normal pattern of secretion. An increase in LH pulse frequency was seen in 12 of 15 subjects in response to naloxone (opioid receptor antagonist). Clonidine (alpha-2 adrenergic agonist) was associated with a decrease in mean LH in 3 of 3 subjects. An increase in LH pulse frequency was seen in 4 of 8 subjects in response to metoclopramide (dopamine receptor antagonist), but the response was not statistically significant. Baseline abnormalities in LH secretion did not appear to influence response to neurotransmitter modulation. 1) HA represents a spectrum of disordered GnRH secretion that can vary over time; 2) LH pulse patterns at baseline do not appear to influence the ability to respond to neurotransmitter modulation; 3) Opioid and adrenergic tone appear to influence the hypothalamic GnRH pulse generator in some individuals with HA.

Olfactory bulb short axon cell release of GABA and dopamine produces a temporally biphasic inhibition-excitation response in external tufted cells

PubMed Central

Liu, Shaolin; Plachez, Celine; Shao, Zuoyi; Puche, Adam; Shipley, Michael T.

2013-01-01

Evidence for co-expression of two or more classic neurotransmitters in neurons has increased but less is known about co-transmission. Ventral tegmental area (VTA) neurons, co-release dopamine (DA), the excitatory transmitter glutamate and the inhibitory transmitter GABA onto target cells in the striatum. Olfactory bulb (OB) short axon cells (SACs) form interglomerular connections and co-express markers for dopamine (DA) and GABA. Using an optogenetic approach we provide evidence that mouse OB SACs release both GABA and DA onto external tufted cells (ETCs) in other glomeruli. Optical activation of channelrhodopsin specifically expressed in DAergic SACs produced a GABAA receptor-mediated monosynaptic inhibitory response followed by DA-D1-like receptor-mediated excitatory response in ETCs. The GABAA receptor-mediated hyperpolarization activates Ih current in ETCs; synaptically released DA increases Ih, which enhances post-inhibitory rebound spiking. Thus, the opposing actions of synaptically released GABA and DA are functionally integrated by Ih to generate an inhibition-to-excitation “switch” in ETCs. Consistent with the established role of Ih in ETC burst firing, we show that endogenous DA release increases ETC spontaneous bursting frequency. ETCs transmit sensory signals to mitral/tufted output neurons and drive intraglomerular inhibition to shape glomerulus output to downstream olfactory networks. GABA and DA co-transmission from SACs to ETCs may play a key role in regulating output coding across the glomerular array. PMID:23407950

Toward Serotonin Fluorescent False Neurotransmitters: Development of Fluorescent Dual Serotonin and Vesicular Monoamine Transporter Substrates for Visualizing Serotonin Neurons.

PubMed

Henke, Adam; Kovalyova, Yekaterina; Dunn, Matthew; Dreier, Dominik; Gubernator, Niko G; Dincheva, Iva; Hwu, Christopher; Šebej, Peter; Ansorge, Mark S; Sulzer, David; Sames, Dalibor

2018-05-16

Ongoing efforts in our laboratories focus on design of optical reporters known as fluorescent false neurotransmitters (FFNs) that enable the visualization of uptake into, packaging within, and release from individual monoaminergic neurons and presynaptic sites in the brain. Here, we introduce the molecular probe FFN246 as an expansion of the FFN platform to the serotonergic system. Combining the acridone fluorophore with the ethylamine recognition element of serotonin, we identified FFN54 and FFN246 as substrates for both the serotonin transporter and the vesicular monoamine transporter 2 (VMAT2). A systematic structure-activity study revealed the basic structural chemotype of aminoalkyl acridones required for serotonin transporter (SERT) activity and enabled lowering the background labeling of these probes while maintaining SERT activity, which proved essential for obtaining sufficient signal in the brain tissue (FFN246). We demonstrate the utility of FFN246 for direct examination of SERT activity and SERT inhibitors in 96-well cell culture assays, as well as specific labeling of serotonergic neurons of the dorsal raphe nucleus in the living tissue of acute mouse brain slices. While we found only minor FFN246 accumulation in serotonergic axons in murine brain tissue, FFN246 effectively traces serotonin uptake and packaging in the soma of serotonergic neurons with improved photophysical properties and loading parameters compared to known serotonin-based fluorescent tracers.

Endocannabinoids control vesicle release mode at midbrain periaqueductal grey inhibitory synapses.

PubMed

Aubrey, Karin R; Drew, Geoffrey M; Jeong, Hyo-Jin; Lau, Benjamin K; Vaughan, Christopher W

2017-01-01

The midbrain periaqueductal grey (PAG) forms part of an endogenous analgesic system which is tightly regulated by the neurotransmitter GABA. The role of endocannabinoids in regulating GABAergic control of this system was examined in rat PAG slices. Under basal conditions GABAergic neurotransmission onto PAG output neurons was multivesicular. Activation of the endocannabinoid system reduced GABAergic inhibition by reducing the probability of release and by shifting release to a univesicular mode. Blockade of endocannabinoid system unmasked a tonic control over the probability and mode of GABA release. These findings provides a mechanistic foundation for the control of the PAG analgesic system by disinhibition. The midbrain periaqueductal grey (PAG) has a crucial role in coordinating endogenous analgesic responses to physiological and psychological stressors. Endocannabinoids are thought to mediate a form of stress-induced analgesia within the PAG by relieving GABAergic inhibition of output neurons, a process known as disinhibition. This disinhibition is thought to be achieved by a presynaptic reduction in GABA release probability. We examined whether other mechanisms have a role in endocannabinoid modulation of GABAergic synaptic transmission within the rat PAG. The group I mGluR agonist DHPG ((R,S)-3,5-dihydroxyphenylglycine) inhibited evoked IPSCs and increased their paired pulse ratio in normal external Ca 2+ , and when release probability was reduced by lowering Ca 2+ . However, the effect of DHPG on the coefficient of variation and kinetics of evoked IPSCs differed between normal and low Ca 2+ . Lowering external Ca 2+ had a similar effect on evoked IPSCs to that observed for DHPG in normal external Ca 2+ . The low affinity GABA A receptor antagonist TPMPA ((1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid) inhibited evoked IPSCs to a greater extent in low than in normal Ca 2+ . Together these findings indicate that the normal mode of GABA release is

Dietary uridine-5'-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats.

PubMed

Wang, Lei; Pooler, Amy M; Albrecht, Meredith A; Wurtman, Richard J

2005-01-01

Membrane phospholipids like phosphatidylcholine (PC) are required for cellular growth and repair, and specifically for synaptic function. PC synthesis is controlled by cellular levels of its precursor, cytidine-5'-diphosphate choline (CDP-choline), which is produced from cytidine triphosphate (CTP) and phosphocholine. In rat PC12 cells exogenous uridine was shown to elevate intracellular CDP-choline levels, by promoting the synthesis of uridine triphosphate (UTP), which was partly converted to CTP. In such cells uridine also enhanced the neurite outgrowth produced by nerve growth factor (NGF). The present study assessed the effect of dietary supplementation with uridine-5'-monophosphate disodium (UMP-2Na+, an additive in infant milk formulas) on striatal dopamine (DA) release in aged rats. Male Fischer 344 rats consumed either a control diet or one fortified with 2.5% UMP for 6 wk, ad libitum. In vivo microdialysis was then used to measure spontaneous and potassium (K+)-evoked DA release in the right striatum. Potassium (K+)-evoked DA release was significantly greater among UMP-treated rats, i.e., 341+/-21% of basal levels vs. 283+/-9% of basal levels in control rats (p<0.05); basal DA release was unchanged. In general, each animal's K+-evoked DA release correlated with its striatal DA content, measured postmortem. The levels of neurofilament-70 and neurofilament-M proteins, biomarkers of neurite outgrowth, increased to 182+/-25% (p<0.05) and 221+/-34% (p<0.01) of control values, respectively, with UMP consumption. Hence, UMP treatment not only enhances membrane phosphatide production but also can modulate two membrane-dependent processes, neurotransmitter release and neurite outgrowth, in vivo.

Changes in the expression of neurotransmitter receptors in Parkin and DJ-1 knockout mice--A quantitative multireceptor study.

PubMed

Cremer, J N; Amunts, K; Schleicher, A; Palomero-Gallagher, N; Piel, M; Rösch, F; Zilles, K

2015-12-17

Parkinson's disease (PD) is a well-characterized neurological disorder with regard to its neuropathological and symptomatic appearance. At the genetic level, mutations of particular genes, e.g. Parkin and DJ-1, were found in human hereditary PD with early onset. Neurotransmitter receptors constitute decisive elements in neural signal transduction. Furthermore, since they are often altered in neurological and psychiatric diseases, receptors have been successful targets for pharmacological agents. However, the consequences of PD-associated gene mutations on the expression of transmitter receptors are largely unknown. Therefore, we studied the expression of 16 different receptor binding sites of the neurotransmitters glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine by means of quantitative receptor autoradiography in Parkin and DJ-1 knockout mice. These knockout mice exhibit electrophysiological and behavioral deficits, but do not show the typical dopaminergic cell loss. We demonstrated differential changes of binding site densities in eleven brain regions. Most prominently, we found an up-regulation of GABA(B) and kainate receptor densities in numerous cortical areas of Parkin and DJ-1 knockout mice, as well as increased NMDA but decreased AMPA receptor densities in different brain regions of the Parkin knockout mice. The alterations of three different glutamate receptor types may indicate the potential relevance of the glutamatergic system in the pathogenesis of PD. Furthermore, the cholinergic M1, M2 and nicotinic receptors as well as the adrenergic α2 and the adenosine A(2A) receptors showed differentially increased densities in Parkin and DJ-1 knockout mice. Taken together, knockout of the PD-associated genes Parkin or DJ-1 results in differential changes of neurotransmitter receptor densities, highlighting a possible role of altered non-dopaminergic, and in particular of glutamatergic neurotransmission in PD pathogenesis. Copyright

In Vivo Assessment of Neurotransmitters and Modulators with Magnetic Resonance Spectroscopy: Application to Schizophrenia

PubMed Central

Wijtenburg, S. Andrea; Yang, Shaolin; Fischer, Bernard A.; Rowland, Laura M.

2015-01-01

In vivo measurement of neurotransmitters and modulators is now feasible with advanced proton magnetic resonance spectroscopy (1H-MRS) techniques. This review provides a basic tutorial of MRS, describes the methods available to measure brain glutamate, glutamine, γ-aminobutyric acid, glutathione, N-acetylaspartylglutamate, glycine, and serine at magnetic field strengths of 3Tesla or higher, and summarizes the neurochemical findings in schizophrenia. Overall, 1H-MRS holds great promise for producing biomarkers that can serve as treatment targets, prediction of disease onset, or illness exacerbation in schizophrenia and other brain diseases. PMID:25614132

[The interaction between gamma-aminobutyric acid and other related neurotransmitters in depression].

PubMed

Li, Zhen; An, Shu-Cheng; Li, Jiang-Na

2014-06-01

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system (CNS) in mammalian, which involved in several mood disorders such as anxiety, depression and schizophrenia. Nowadays, there are growing evidences showed that the depression is concerned with a deficiency in brain GABA. However, there are numerous studies based on the monoamine hypothesis and glutamatergic dysfunction, while the study on GABA is relatively less and scattered. Our aim is to discuss the relationship between depression and GABA by introducing the role of GABA receptors and the interaction between GABA and 5-hydroxytryptamine, dopamine and glutamic acid. It provides new ideas for further study on the pathogenesis and therapy of depression.

Dwarf mistletoe-infected red fir: growth after release

Treesearch

Robert F. Scharpf

1979-01-01

Release cutting, live crown ratio, diameter-at-breast height, and dwarf mistletoe (Arceuthobium abietinum f. sp. magnificae). acted to affect radial and height growth of red firs (Abies magnifica A. Murr.). Infected and noninfected red firs responded well to release as expressed by increased radial growth: growth...

Neurosteroid biosynthesis: enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides.

PubMed

Do Rego, Jean Luc; Seong, Jae Young; Burel, Delphine; Leprince, Jerôme; Luu-The, Van; Tsutsui, Kazuyoshi; Tonon, Marie-Christine; Pelletier, Georges; Vaudry, Hubert

2009-08-01

Neuroactive steroids synthesized in neuronal tissue, referred to as neurosteroids, are implicated in proliferation, differentiation, activity and survival of nerve cells. Neurosteroids are also involved in the control of a number of behavioral, neuroendocrine and metabolic processes such as regulation of food intake, locomotor activity, sexual activity, aggressiveness, anxiety, depression, body temperature and blood pressure. In this article, we summarize the current knowledge regarding the existence, neuroanatomical distribution and biological activity of the enzymes responsible for the biosynthesis of neurosteroids in the brain of vertebrates, and we review the neuronal mechanisms that control the activity of these enzymes. The observation that the activity of key steroidogenic enzymes is finely tuned by various neurotransmitters and neuropeptides strongly suggests that some of the central effects of these neuromodulators may be mediated via the regulation of neurosteroid production.

Effects of dietary amino acids, carbohydrates, and choline on neurotransmitter synthesis

NASA Technical Reports Server (NTRS)

Wurtman, Richard J.

1988-01-01

The ability of a meal to increase or decrease brain neurotransmitter synthesis has been studied. It is concluded that brain serotonin synthesis is directly controlled by the proportions of carbohydrate to protein in meals and snacks that increase or decrease brain tryptophan levels, thereby changing the substrate saturation of tryptophan hydroxylase and the rate of serotonin synthesis. The ability of serotoninergic neurons to have their output coupled to dietary macronutrients enables them to function as sensors of peripheral metabolism, and to subserve an important role in the control of appetite. The robust and selective responses of catecholaminergic and cholinergic neurons to supplemental tyrosine and choline suggest that these compounds may become useful as a new type of drug for treating deseases or conditions in which adequate quantities of the transmitter would otherwise be unavailable.

Chitosan coated carbon fiber microelectrode for selective in vivo detection of neurotransmitters in live zebrafish embryos

PubMed Central

Özel, Rıfat Emrah; Wallace, Kenneth N.; Andreescu, Silvana

2011-01-01

We report the development of a chitosan modified carbon fiber microelectrode for in vivo detection of serotonin. We find that chitosan has the ability to reject physiological levels of ascorbic acid interferences and facilitate selective and sensitive detection of in vivo levels of serotonin, a common catecholamine neurotransmitter. Presence of chitosan on the microelectrode surface was investigated using scanning electron microscopy (SEM) and cyclic voltammetry (CV). The electrode was characterized using differential pulse voltammetry (DPV). A detection limit of 1.6 nM serotonin with a sensitivity of 5.12 nA/µM, a linear range from 2 to 100 nM and a reproducibility of 6.5 % for n=6 electrodes were obtained. Chitosan modified microelectrodes selectively measure serotonin in presence of physiological levels of ascorbic acid. In vivo measurements were performed to measure concentration of serotonin in the live embryonic zebrafish intestine. The sensor quantifies in vivo intestinal levels of serotonin while successfully rejecting ascorbic acid interferences. We demonstrate that chitosan can be used as an effective coating to reject ascorbic acid interferences at carbon fiber microelectrodes, as an alternative to Nafion, and that chitosan modified microelectrodes are reliable tools for in vivo monitoring of changes in neurotransmitter levels. PMID:21601035

Validity of urinary monoamine assay sales under the “spot baseline urinary neurotransmitter testing marketing model”

PubMed Central

Hinz, Marty; Stein, Alvin; Uncini, Thomas

2011-01-01

Spot baseline urinary monoamine assays have been used in medicine for over 50 years as a screening test for monoamine-secreting tumors, such as pheochromocytoma and carcinoid syndrome. In these disease states, when the result of a spot baseline monoamine assay is above the specific value set by the laboratory, it is an indication to obtain a 24-hour urine sample to make a definitive diagnosis. There are no defined applications where spot baseline urinary monoamine assays can be used to diagnose disease or other states directly. No peer-reviewed published original research exists which demonstrates that these assays are valid in the treatment of individual patients in the clinical setting. Since 2001, urinary monoamine assay sales have been promoted for numerous applications under the “spot baseline urinary neurotransmitter testing marketing model”. There is no published peer-reviewed original research that defines the scientific foundation upon which the claims for these assays are made. On the contrary, several articles have been published that discredit various aspects of the model. To fill the void, this manuscript is a comprehensive review of the scientific foundation and claims put forth by laboratories selling urinary monoamine assays under the spot baseline urinary neurotransmitter testing marketing model. PMID:21912487

Anandamide Revisited: How Cholesterol and Ceramides Control Receptor-Dependent and Receptor-Independent Signal Transmission Pathways of a Lipid Neurotransmitter.

PubMed

Di Scala, Coralie; Fantini, Jacques; Yahi, Nouara; Barrantes, Francisco J; Chahinian, Henri

2018-05-22

Anandamide is a lipid neurotransmitter derived from arachidonic acid, a polyunsaturated fatty acid. The chemical differences between anandamide and arachidonic acid result in a slightly enhanced solubility in water and absence of an ionisable group for the neurotransmitter compared with the fatty acid. In this review, we first analyze the conformational flexibility of anandamide in aqueous and membrane phases. We next study the interaction of the neurotransmitter with membrane lipids and discuss the molecular basis of the unexpected selectivity of anandamide for cholesterol and ceramide from among other membrane lipids. We show that cholesterol behaves as a binding partner for anandamide, and that following an initial interaction mediated by the establishment of a hydrogen bond, anandamide is attracted towards the membrane interior, where it forms a molecular complex with cholesterol after a functional conformation adaptation to the apolar membrane milieu. The complex is then directed to the anandamide cannabinoid receptor (CB1) which displays a high affinity binding pocket for anandamide. We propose that cholesterol may regulate the entry and exit of anandamide in and out of CB1 by interacting with low affinity cholesterol recognition sites (CARC and CRAC) located in transmembrane helices. The mirror topology of cholesterol binding sites in the seventh transmembrane domain is consistent with the delivery, extraction and flip-flop of anandamide through a coordinated cholesterol-dependent mechanism. The binding of anandamide to ceramide illustrates another key function of membrane lipids which may occur independently of protein receptors. Interestingly, ceramide forms a tight complex with anandamide which blocks the degradation pathway of both lipids and could be exploited for anti-cancer therapies.

Neurobiological mechanisms of acupuncture for some common illnesses: a clinician's perspective.

PubMed

Cheng, Kwokming James

2014-06-01

This paper presents some previously proposed neurobiological mechanisms on how acupuncture may work in some clinical applications from a clinician's perspective. For the treatment of musculoskeletal conditions, the proposed mechanisms included microinjury, increased local blood flow, facilitated healing, and analgesia. Acupuncture may trigger a somatic autonomic reflex, thereby affecting the gastric and cardiovascular functions. Acupuncture may also change the levels of neurotransmitters such as serotonin and dopamine, thereby affecting the emotional state and craving. This mechanism may form the basis for the treatment of smoking cessation. By affecting other pain-modulating neurotransmitters such as met-enkephalin and substance P along the nociceptive pathway, acupuncture may relieve headache. Acupuncture may affect the hypothalamus pituitary axis and reduce the release of the luteinizing hormone in the treatment of polycystic ovary syndrome. In addition, two other approaches to the acupuncture mechanism, the fascia connective tissue network and the primo vascular system, are briefly reviewed. Finally, the idea of true versus sham acupuncture points, which are commonly used in clinical trials, is examined because the difference between true and sham points does not exist in the neurobiological model. Copyright © 2013. Published by Elsevier B.V.

Proteases for Processing Proneuropeptides into Peptide Neurotransmitters and Hormones

PubMed Central

Hook, Vivian; Funkelstein, Lydiane; Lu, Douglas; Bark, Steven; Wegrzyn, Jill; Hwang, Shin-Rong

2009-01-01

Peptide neurotransmitters and peptide hormones, collectively known as neuropeptides, are required for cell-cell communication in neurotransmission and for regulation of endocrine functions. Neuropeptides are synthesized from protein precursors (termed proneuropeptides or prohormones) that require proteolytic processing primarily within secretory vesicles that store and secrete the mature neuropeptides to control target cellular and organ systems. This review describes interdisciplinary strategies that have elucidated two primary protease pathways for prohormone processing consisting of the cysteine protease pathway mediated by secretory vesicle cathepsin L and the well-known subtilisin-like proprotein convertase pathway that together support neuropeptide biosynthesis. Importantly, this review discusses important areas of current and future biomedical neuropeptide research with respect to biological regulation, inhibitors, structural features of proneuropeptide and protease interactions, and peptidomics combined with proteomics for systems biological approaches. Future studies that gain in-depth understanding of protease mechanisms for generating active neuropeptides will be instrumental for translational research to develop pharmacological strategies for regulation of neuropeptide functions. Pharmacological applications for neuropeptide research may provide valuable therapeutics in health and disease. PMID:18184105

Forskolin and protein kinase inhibitors differentially affect hair cell potassium currents and transmitter release at the cytoneural junction in the isolated frog labyrinth.

PubMed

Rossi, Maria Lisa; Rubbini, Gemma; Martini, Marta; Canella, Rita; Fesce, Riccardo

2017-08-15

The post-transductional elaboration of sensory input at the frog semicircular canal has been studied by correlating the effects of drugs that interfere with phosphorylation processes on: (i) potassium conductances in isolated hair cell and (ii) transmitter release at the cytoneural junction in the intact labyrinth. At hair cells, delayed potassium currents (IKD) undergo voltage- and time-dependent inactivation; inactivation removal requires ATP, is sensitive to kinase blockade, but is unaffected by exogenous application of cyclic nucleotides. We report here that forskolin, an activator of endogenous adenylyl cyclase, enhances IKD inactivation removal in isolated hair cells, but produces an overall decrease in IKD amplitude consistent with the direct blocking action of the drug on several families of K channels. In the intact labyrinth, forskolin enhances transmitter release, consistent with such depression of K conductances. Kinase blockers - H-89 and KT5823 - have been shown to reduce IKD inactivation removal and IKD amplitude at isolated hair cells. In the labyrinth, the effects of these drugs on junctional activity are quite variable, with predominant inhibition of transmitter release, rather than the enhancement expected from the impairment of K currents. The overall action of forskolin and kinase inhibitors on K conductances is similar (depression), but they have opposite effects on transmitter release: this indicates that some intermediate steps between the bioelectric control of hair cell membrane potential and transmitter release are affected in opposite ways and therefore are presumably regulated by protein phosphorylation. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Impact of Release Rates on the Effectiveness of Augmentative Biological Control Agents

PubMed Central

Crowder, David W.

2007-01-01

To access the effect of augmentative biological control agents, 31 articles were reviewed that investigated the impact of release rates of 35 augmentative biological control agents on the control of 42 arthropod pests. In 64% of the cases, the release rate of the biological control agent did not significantly affect the density or mortality of the pest insect. Results where similar when parasitoidsor predators were utilized as the natural enemy. Within any order of natural enemy, there were more cases where release rates did not affect augmentative biological control than cases where release rates were significant. There were more cases in which release rates did not affect augmentative biological control when pests were from the orders Hemiptera, Acari, or Diptera, but not with pests from the order Lepidoptera. In most cases, there was an optimal release rate that produced effective control of a pest species. This was especially true when predators were used as a biological control agent. Increasing the release rate above the optimal rate did not improve control of the pest and thus would be economically detrimental. Lower release rates were of ten optimal when biological control was used in conjunction with insecticides. In many cases, the timing and method of biological control applications were more significant factors impacting the effectiveness of biological control than the release rate. Additional factors that may limit the relative impact of release rates include natural enemy fecundity, establishment rates, prey availability, dispersal, and cannibalism. PMID:20307240

Further characterization of [3H]gamma-aminobutyric acid release from isolated neuronal growth cones: role of intracellular Ca2+ stores.

PubMed

Lockerbie, R O; Gordon-Weeks, P R

1986-04-01

We have recently shown that growth cones isolated from neonatal rat forebrain possess uptake and release mechanisms for the neurotransmitter gamma-aminobutyric acid. About half of the K+-induced release of [3H]gamma-aminobutyric acid from isolated growth cones is dependent on extracellular Ca2+. The remaining component of the [3H]gamma-aminobutyric acid release is unaffected by removal of extracellular Ca2+ and is resistant to blockade by the voltage-sensitive Ca2+-channel blocker methoxyverapamil. In the present series of experiments we have used caffeine to assess the possible role of intracellular stores of Ca2+ in supporting that component of the K+-induced release of [3H]gamma-aminobutyric acid from isolated growth cones that is independent of extracellular Ca2+. We have chosen caffeine because of its well established effect of releasing Ca2+ from smooth endoplasmic reticulum in muscle. We found that caffeine can release [3H]gamma-aminobutyric acid from isolated growth cones. This effect persists in Ca2+-free medium, in the presence of methoxyverapamil and in the absence of Na+. Furthermore, isobutylmethylxanthine could not substitute for caffeine suggesting that the caffeine effect is not due to phosphodiesterase inhibition and the subsequent rise in intracellular cyclic nucleotides. A combination of the mitochondrial poisons, Antimycin A and sodium azide had no effect on the release of [3H]gamma-aminobutyric acid induced either by caffeine or by high K+. We conclude that caffeine causes the release of Ca2+ from a non-mitochondrial store within the growth cone and that this Ca2+ store supports that component of the K+-induced release of [3H]gamma-aminobutyric acid that is independent of extracellular Ca2+.

The nervus terminalis in amphibians: anatomy, chemistry and relationship with the hypothalamic gonadotropin-releasing hormone system.

PubMed

Muske, L E; Moore, F L

1988-01-01

The nervus terminalis (TN), a component of the olfactory system, is found in most vertebrates. The TN of some fishes and mammals contains neurons immunoreactive (ir) to gonadotropin-releasing hormone (LHRH), and to several other neuropeptides and neurotransmitter systems, but there is little information on TN chemistry in other vertebrate taxa. Using immunocytochemical techniques, we found LHRH-ir neurons in amphibian TNs. In anurans, but not in a urodele, the TN was also found to contain Phe-Met-Arg-Phe-NH2 (FMRFamide) immunoreactivity. LHRH-ir neurons of the TN and those of the septal-hypothalamic system are morphologically homogeneous and form a distinct anatomical continuum in amphibians. Based upon topographical and cytological criteria, we hypothesize that LHRH-ir systems in vertebrates might derive embryonically from the TN.

Radon Release and Its Simulated Effect on Radiation Doses.

PubMed

Orabi, Momen

2017-03-01

One of the main factors that affect the uncertainty in calculating the gamma-radiation absorbed dose rate inside a room is the variation in the degree of secular equilibrium of the considered radioactive series. A component of this factor, considered in this paper, is the release of radon (Rn) from building materials to the living space of the room. This release takes place through different steps. These steps are represented and mathematically formulated. The diffusion of radon inside the material is described by Fick's second law. Some of the factors affecting the radon release rate (e.g. covering walls, moisture, structure of the building materials, etc.) are discussed. This scheme is used to study the impact of radon release on the gamma-radiation absorbed dose rate inside a room. The investigation is carried out by exploiting the MCNP simulation software. Different building materials are considered with different radon release rates. Special care is given to Rn due to its relatively higher half-life and higher indoor concentration than the other radon isotopes. The results of the presented model show that the radon release is of a significant impact in some building materials.

Neurotransmitter involvement in development and maintenance of the auditory space map in the guinea pig superior colliculus.

PubMed

Ingham, N J; Thornton, S K; McCrossan, D; Withington, D J

1998-12-01

Neurotransmitter involvement in development and maintenance of the auditory space map in the guinea pig superior colliculus. J. Neurophysiol. 80: 2941-2953, 1998. The mammalian superior colliculus (SC) is a complex area of the midbrain in terms of anatomy, physiology, and neurochemistry. The SC bears representations of the major sensory modalites integrated with a motor output system. It is implicated with saccade generation, in behavioral responses to novel sensory stimuli and receives innervation from diverse regions of the brain using many neurotransmitter classes. Ethylene-vinyl acetate copolymer (Elvax-40W polymer) was used here to deliver chronically neurotransmitter receptor antagonists to the SC of the guinea pig to investigate the potential role played by the major neurotransmitter systems in the collicular representation of auditory space. Slices of polymer containing different drugs were implanted onto the SC of guinea pigs before the development of the SC azimuthal auditory space map, at approximately 20 days after birth (DAB). A further group of animals was exposed to aminophosphonopentanoic acid (AP5) at approximately 250 DAB. Azimuthal spatial tuning properties of deep layer multiunits of anesthetized guinea pigs were examined approximately 20 days after implantation of the Elvax polymer. Broadband noise bursts were presented to the animals under anechoic, free-field conditions. Neuronal responses were used to construct polar plots representative of the auditory spatial multiunit receptive fields (MURFs). Animals exposed to control polymer could develop a map of auditory space in the SC comparable with that seen in unimplanted normal animals. Exposure of the SC of young animals to AP5, 6-cyano-7-nitroquinoxaline-2,3-dione, or atropine, resulted in a reduction in the proportion of spatially tuned responses with an increase in the proportion of broadly tuned responses and a degradation in topographic order. Thus N-methyl--aspartate (NMDA) and non

Dietary folate and choline status differentially affect lipid metabolism and behavior-mediated neurotransmitters in young rats

USDA-ARS?s Scientific Manuscript database

The relationship between choline and folate metabolisms is an important issue due to the essential role of these nutrients in brain plasticity and cognitive functions. Present study was designed to investigate whether modification of the dietary folate-choline status in young rats would affect brain...

Long-Range Regulatory Polymorphisms Affecting a GABA Receptor Constitute a Quantitative Trait Locus (QTL) for Social Behavior in Caenorhabditis elegans

PubMed Central

Bendesky, Andres; Pitts, Jason; Rockman, Matthew V.; Chen, William C.; Tan, Man-Wah; Kruglyak, Leonid; Bargmann, Cornelia I.

2012-01-01

Aggregation is a social behavior that varies between and within species, providing a model to study the genetic basis of behavioral diversity. In the nematode Caenorhabditis elegans, aggregation is regulated by environmental context and by two neuromodulatory pathways, one dependent on the neuropeptide receptor NPR-1 and one dependent on the TGF-β family protein DAF-7. To gain further insight into the genetic regulation of aggregation, we characterize natural variation underlying behavioral differences between two wild-type C. elegans strains, N2 and CB4856. Using quantitative genetic techniques, including a survey of chromosome substitution strains and QTL analysis of recombinant inbred lines, we identify three new QTLs affecting aggregation in addition to the two known N2 mutations in npr-1 and glb-5. Fine-mapping with near-isogenic lines localized one QTL, accounting for 5%–8% of the behavioral variance between N2 and CB4856, 3′ to the transcript of the GABA neurotransmitter receptor gene exp-1. Quantitative complementation tests demonstrated that this QTL affects exp-1, identifying exp-1 and GABA signaling as new regulators of aggregation. exp-1 interacts genetically with the daf-7 TGF-β pathway, which integrates food availability and population density, and exp-1 mutations affect the level of daf-7 expression. Our results add to growing evidence that genetic variation affecting neurotransmitter receptor genes is a source of natural behavioral variation. PMID:23284308

Behavioral correlates of cerebrospinal fluid amino acid and biogenic amine neurotransmitter alterations in dementia.

PubMed

Vermeiren, Yannick; Le Bastard, Nathalie; Van Hemelrijck, An; Drinkenburg, Wilhelmus H; Engelborghs, Sebastiaan; De Deyn, Peter P

2013-09-01

Behavioral and psychological signs and symptoms of dementia (BPSD) are a heterogeneous group of behavioral and psychiatric disturbances occurring in dementia patients of any etiology. Research suggests that altered activities of dopaminergic, serotonergic, (nor)adrenergic, as well as amino acid neurotransmitter systems play a role in the etiopathogenesis of BPSD. In this study we attempted to identify cerebrospinal fluid (CSF) neurochemical correlates of BPSD to provide further insight into its underlying neurochemical pathophysiological mechanisms. Patients with probable Alzheimer's disease (AD; n = 202), probable AD with cerebrovascular disease (n = 37), probable frontotemporal dementia (FTD; n = 32), and probable dementia with Lewy bodies (DLB; n = 26) underwent behavioral assessment and lumbar puncture. CSF levels of six amino acids and several biogenic amines and metabolites were analyzed using ultraperformance liquid chromatography with fluorescence detection and reversed-phase high-performance liquid chromatography with fluorescence detection. In the AD patients, CSF homovanillic acid/5-hydroxyindoleacetic acid (HVA/5HIAA) ratios correlated positively with anxieties/phobias, whereas CSF levels of taurine correlated negatively with depression and behavioral disturbances in general. In FTD patients, CSF levels of glutamate correlated negatively with verbally agitated behavior. In DLB patients, CSF levels of HVA correlated negatively with hallucinations. Several neurotransmitter systems can be linked to one specific behavioral syndrome depending on the dementia subtype. In addition to biogenic amines and metabolites, amino acids seem to play a major role in the neurochemical etiology of BPSD as well. Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

One Cycle Fuels Another: The Energetics of Neurotransmitter Release.

PubMed

Silm, Katlin; Edwards, Robert H

2017-02-08

In this issue of Neuron, Ashrafi et al. (2017) show that activity induces translocation of the insulin-regulated glucose transporter GLUT4 to the plasma membrane, where it sustains the ATP production required for synaptic vesicle cycling. However, translocation occurs from presynaptic membranes other than synaptic vesicles and involves a distinct molecular mechanism. Copyright © 2017 Elsevier Inc. All rights reserved.

Serotonin release varies with brain tryptophan levels

NASA Technical Reports Server (NTRS)

Schaechter, Judith D.; Wurtman, Richard J.

1990-01-01

This study examines directly the effects on serotonin release of varying brain tryptophan levels within the physiologic range. It also addresses possible interactions between tryptophan availability and the frequency of membrane depolarization in controlling serotonin release. We demonstrate that reducing tryptophan levels in rat hypothalamic slices (by superfusing them with medium supplemented with 100 microM leucine) decreases tissue serotonin levels as well as both the spontaneous and the electrically-evoked serotonin release. Conversely, elevating tissue tryptophan levels (by superfusing slices with medium supplemented with 2 microM tryptophan) increases both the tissue serotonin levels and the serotonin release. Serotonin release was found to be affected independently by the tryptophan availability and the frequency of electrical field-stimulation (1-5 Hz), since increasing both variables produced nearly additive increases in release. These observations demonstrate for the first time that both precursor-dependent elevations and reductions in brain serotonin levels produce proportionate changes in serotonin release, and that the magnitude of the tryptophan effect is unrelated to neuronal firing frequency. The data support the hypothesis that serotonin release is proportionate to intracellular serotonin levels.

Synaptically evoked Ca2+ release from intracellular stores is not influenced by vesicular zinc in CA3 hippocampal pyramidal neurones.

PubMed

Evstratova, Alesya; Tóth, Katalin

2011-12-01

The co-release of neuromodulatory substances in combination with classic neurotransmitters such as glutamate and GABA from individual presynaptic nerve terminals has the capacity to dramatically influence synaptic efficacy and plasticity. At hippocampal mossy fibre synapses vesicular zinc is suggested to serve as a cotransmitter capable of regulating calcium release from internal stores in postsynaptic CA3 pyramidal cells. Here we investigated this possibility using combined intracellular ratiometric calcium imaging and patch-clamp recording techniques. In acute hippocampal slices a brief train of mossy fibre stimulation produced a large, delayed postsynaptic Ca(2+) wave that was spatially restricted to the proximal apical dendrites of CA3 pyramidal cells within stratum lucidum. This calcium increase was sensitive to intracellularly applied heparin indicating reliance upon release from internal stores and was triggered by activation of both group I metabotropic glutamate and NMDA receptors. Importantly, treatment of slices with the membrane-impermeant zinc chelator CaEDTA did not influence the synaptically evoked postsynaptic Ca(2+) waves. Moreover, mossy fibre stimulus evoked postsynaptic Ca(2+) signals were not significantly different between wild-type and zinc transporter 3 (ZnT3) knock-out animals. Considered together our data do not support a role for vesicular zinc in regulating mossy fibre evoked Ca(2+) release from CA3 pyramidal cell internal stores.

Synaptically evoked Ca2+ release from intracellular stores is not influenced by vesicular zinc in CA3 hippocampal pyramidal neurones

PubMed Central

Evstratova, Alesya; Tóth, Katalin

2011-01-01

Abstract The co-release of neuromodulatory substances in combination with classic neurotransmitters such as glutamate and GABA from individual presynaptic nerve terminals has the capacity to dramatically influence synaptic efficacy and plasticity. At hippocampal mossy fibre synapses vesicular zinc is suggested to serve as a cotransmitter capable of regulating calcium release from internal stores in postsynaptic CA3 pyramidal cells. Here we investigated this possibility using combined intracellular ratiometric calcium imaging and patch-clamp recording techniques. In acute hippocampal slices a brief train of mossy fibre stimulation produced a large, delayed postsynaptic Ca2+ wave that was spatially restricted to the proximal apical dendrites of CA3 pyramidal cells within stratum lucidum. This calcium increase was sensitive to intracellularly applied heparin indicating reliance upon release from internal stores and was triggered by activation of both group I metabotropic glutamate and NMDA receptors. Importantly, treatment of slices with the membrane-impermeant zinc chelator CaEDTA did not influence the synaptically evoked postsynaptic Ca2+ waves. Moreover, mossy fibre stimulus evoked postsynaptic Ca2+ signals were not significantly different between wild-type and zinc transporter 3 (ZnT3) knock-out animals. Considered together our data do not support a role for vesicular zinc in regulating mossy fibre evoked Ca2+ release from CA3 pyramidal cell internal stores. PMID:21986206

Investigation of the effect of tablet surface area/volume on drug release from hydroxypropylmethylcellulose controlled-release matrix tablets.

PubMed

Reynolds, Thomas D; Mitchell, Shawn A; Balwinski, Karen M

2002-04-01

The purpose of this study was to investigate the influence of tablet surface area/volume (SA/Vol) on drug release from controlled-release matrix tablets containing hydroxypropylmethylcellulose (HPMC). Soluble drugs (promethazine HCl, diphenhydramine HCl, and propranolol HCl) were utilized in this study to give predominantly diffusion-controlled release. Drug release from HPMC matrix tablets with similar values of SA/Vol was comparable within the same tablet shape (i.e., flat-faced round tablets) and among different shapes (i.e., oval, round concave, flat-faced beveled-edge, and flat-faced round tablets). Tablets having the same surface area but different SA/Vol values did not result in similar drug release; tablets with larger SA/Vol values hadfaster release profiles. Utility of SA/Vol to affect drug release was demonstrated by changing drug doses, and altering tablet shape to adjust SA/Vol. When SA/Vol was held constant, similar release profiles were obtained with f2 metric values greater than 70. Thus, surface area/volume is one of the key variables in controlling drug release from HPMC matrix tablets. Proper use of this variable has practical application by formulators who may need to duplicate drug release profiles from tablets of different sizes and different shapes.

Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn; Zhang, Dong-Mei; Yu, Xiao-Jing

The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiacmore » atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE

Paired-pulse facilitation and depression at unitary synapses in rat hippocampus: quantal fluctuation affects subsequent release.

PubMed Central

Debanne, D; Guérineau, N C; Gähwiler, B H; Thompson, S M

1996-01-01

1. Excitatory synaptic transmission between pairs of monosynaptically coupled pyramidal cells was examined in rat hippocampal slice cultures. Action potentials were elicited in single CA3 pyramidal cells impaled with microelectrodes and unitary excitatory postsynaptic currents (EPSCs) were recorded in whole-cell voltage-clamped CA1 or CA3 cells. 2. The amplitude of successive unitary EPSCs in response to single action potentials varied. The amplitude of EPSCs was altered by adenosine or changes in the [Mg2+]/[CA2+] ratio. We conclude that single action potentials triggered the release of multiple quanta of glutamate. 3. When two action potentials were elicited in the presynaptic cell, the amplitude of the second EPSC was inversely related to the amplitude of the first. Paired-pulse facilitation (PPF) was observed when the first EPSC was small, i.e. the second EPSC was larger than the first, whereas paired-pulse depression (PPD) was observed when the first EPSC was large. 4. The number of trials displaying PPD was greater when release probability was increased, and smaller when release probability was decreased. 5. PPD was not postsynaptically mediated because it was unaffected by decreasing ionic flux with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or receptor desensitization with aniracetam. 6. PPF was maximal at an interstimulus interval of 70 ms and recovered within 500 ms. Recovery from PPD occurred within 5 s. 7. We propose that multiple release sites are formed by the axon of a CA3 pyramidal cell and a single postsynaptic CA1 or CA3 cell. PPF is observed if the first action potential fails to release transmitter at most release sites. PPD is observed if the first action potential successfully triggers release at most release sites. 8. Our observations of PPF are consistent with the residual calcium hypothesis. We conclude that PPD results from a decrease in quantal content, perhaps due to short-term depletion of readily releasable vesicles. PMID:9011608

VMAT2-mediated neurotransmission from midbrain leptin receptor neurons in feeding regulation

USDA-ARS?s Scientific Manuscript database

Leptin receptors (LepRs) expressed in the midbrain contribute to the action of leptin on feeding regulation. The midbrain neurons release a variety of neurotransmitters including dopamine (DA), glutamate and GABA. However, which neurotransmitter mediates midbrain leptin action on feeding remains unc...

Effects of Chailong Jieyu Pill on Behavior, Monoamine Neurotransmitters, and Corticosteroid Receptors in a Rat Model of Anxiety Disorder.

PubMed

Feng, Guang-Kui; Ma, Xian-Jun; Chen, Yin-Yi; Bian, Guang-Rong; Yang, Chao; Gu, Bao-Dong

2018-01-01

Chailong Jieyu Pill (CJP) is composed of Radix Bupleuri, Radix Scutellariae, Rhizoma Pinelliae Preparata, Radix Codonopsis, Radix Glycyrrhizae preparata , keel, Concha Ostreae, Concha Margaritifera Usta, Rhizoma Zingiberis Recens , and Fructus Jujubae . CJP has shown good clinical effects on improving anxiety disorders. However, as the mechanism underlying such benefits remains unclear, the aim of this study was to investigate the mechanism of action for CJP on anxiety-related behaviors in a rat model of anxiety disorder. After establishing a rat model of anxiety disorder using uncertain empty bottle stimulation, rats were divided into control, model, citalopram, low-dose CJP, and high-dose CJP groups. After 1 month of administration, effects of treatments on rat appearance, body weight, and open-field test scores were observed. In addition, hippocampal monoamine neurotransmitter (5-hydroxytryptamine, dopamine, and norepinephrine) contents were measured with an enzyme-linked immunosorbent assay, and mRNA expression of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) were measured with reverse transcription-polymerase chain reaction. CJP increased rat weight, and this effect was increased in the high-dose CJP group compared with the citalopram group ( P < 0.05). CJP also elevated open-field test scores compared with the citalopram group ( P < 0.05). While CJP decreased monoamine neurotransmitter contents in rat hippocampus, the regulatory effect of CJP on 5-hydroxytryptamine was reduced compared with citalopram ( P < 0.01). CJP upregulated GR mRNA expression in both low-dose ( P < 0.05) and high-dose ( P < 0.01) CJP groups, but only the latter significantly downregulated MR mRNA expression and showed enhanced effects compared with citalopram ( P < 0.05). Thus, CJP likely exerted its significant antianxiety effect by diminishing monoamine neurotransmitters and regulating mRNA expression of MR and GR in the hippocampus of our rat model of anxiety

Blockade of glutamate release by botulinum neurotoxin type A in humans: A dermal microdialysis study

PubMed Central

da Silva, Larissa Bittencourt; Karshenas, Ali; Bach, Flemming W; Rasmussen, Sten; Arendt-Nielsen, Lars; Gazerani, Parisa

2014-01-01

BACKGROUND: The analgesic action of botulinum neurotoxin type A (BoNTA) has been linked to the blockade of peripheral release of neuropeptides and neurotransmitters in animal models; however, there is no direct evidence of this in humans. OBJECTIVES: To investigate the effect of BoNTA on glutamate release in humans, using an experimental model of pain and sensitization provoked by capsaicin plus mild heat. METHODS: Twelve healthy volunteers (six men, six women) were pretreated with BoNTA (10 U) on the volar forearm and with a saline control on the contralateral side. Dermal microdialysis was applied one week later to collect interstitial samples before and after the application of a capsaicin patch (8%) plus mild heat (40°C/60 min) to provoke glutamate release, pain and vasodilation. Samples were collected every hour for 3 h using linear microdialysis probes (10 mm, 100 kD). Dialysate was analyzed for glutamate concentration. Pain intensity and skin vasomotor reactions (temperature and blood flow changes) were also recorded. RESULTS: BoNTA significantly reduced glutamate release compared with saline (P<0.05). The provoked pain intensity was lower in the BoNTA-pretreated arm (P<0.01). The reduction in pain scores was not correlated with glutamate level. Cutaneous blood flow (P<0.05), but not cutaneous temperature (P≥0.05), was significantly reduced by BoNTA. There was a correlation between glutamate level and skin blood flow (r=0.58/P<0.05) but not skin temperature (P≥0.05). No differences according to sex were observed in any response. CONCLUSIONS: The present study provided the first direct evidence supporting the inhibitory effect of BoNTA on glutamate release in human skin, which is potentially responsible for some of the analgesic action of BoNTA. PMID:24851237

The goldfish nervus terminalis: a luteinizing hormone-releasing hormone and molluscan cardioexcitatory peptide immunoreactive olfactoretinal pathway.

PubMed Central

Stell, W K; Walker, S E; Chohan, K S; Ball, A K

1984-01-01

Antisera to two putative neurotransmitters, luteinizing hormone-releasing hormone (LHRH) and molluscan cardioexcitatory tetrapeptide (H-Phe-Met-Arg-Phe-NH2; FMRF-amide), bind specifically to neurites in the inner nuclear and inner plexiform layers of the goldfish retina. Retrograde labeling showed that intraocular axon terminals originate from the nervus terminalis, whose cell bodies are located in the olfactory nerves. Double immunocytochemical and retrograde labeling showed that some terminalis neurons project to the retina; others may project only within the brain. All terminalis neurons having proven retinal projections were both LHRH- and FMRF-amide-immunoreactive. The activity of retinal ganglion cells was recorded with microelectrodes in isolated superfused goldfish retinas. In ON- and OFF-center double-color-opponent cells, micromolar FMRF-amide and salmon brain gonadotropin-releasing factor ( [Trp7, Leu8] LHRH) caused increased spontaneous activity in the dark, loss of light-induced inhibition, and increased incidence of light-entrained pulsatile response. The nervus terminalis is therefore a putatively peptidergic retinopetal projection. Sex-related olfactory stimuli may act through it, thereby modulating the output of ganglion cells responsive to color contrast. Images PMID:6199789