Neurosteroids and GABA-A Receptor Function
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Amnestic Concentrations of Sevoflurane Inhibit Synaptic
Anesthesiology 2008; 108:447–56 Copyright © 2008, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Amnestic Concentrations of Sevoflurane Inhibit Synaptic Plasticity of Hippocampal CA1 Neurons through ␥-Aminobutyric Acid–mediated Mechanisms Junko Ishizeki, M.D.,* Koichi Nishikawa, M.D., Ph.D.,† Kazuhiro Kubo, M.D.,‡ Shigeru Saito, M.D., Ph.D.,§ Fumio Goto, M.D., Ph.D. Background: The cellular mechanisms of anesthetic-induced for surgical procedures do not have recollection of ac- amnesia are still poorly understood. The current study exam- tually being awake despite being awake and cooperative ined sevoflurane at various concentrations in the CA1 region of during the procedure.1 Galinkin et al.2 compared sub- rat hippocampal slices for effects on excitatory synaptic trans- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/108/3/447/366512/0000542-200803000-00017.pdf by guest on 29 September 2021 mission and on long-term potentiation (LTP), as a possible jective, psychomotor, cognitive, and analgesic effects of mechanism contributing to anesthetic-induced loss of recall. sevoflurane (0.3% and 0.6%) with those of nitrous oxide Methods: Population spikes and field excitatory postsynaptic at equal minimum alveolar concentrations (MACs) in potentials were recorded using extracellular electrodes after healthy volunteers. They found that sevoflurane pro- electrical stimulation of Schaffer-collateral-commissural fiber inputs. Paired pulse facilitation was used as a measure of pre- duced a greater degree of amnesia and psychomotor synaptic effects of the anesthetic. LTP was induced using tetanic impairment than did an equal MAC of nitrous oxide but stimulation (100 Hz, 1 s). Sevoflurane at concentrations from had no analgesic actions. -
Picrotoxin-Like Channel Blockers of GABAA Receptors
COMMENTARY Picrotoxin-like channel blockers of GABAA receptors Richard W. Olsen* Department of Molecular and Medical Pharmacology, Geffen School of Medicine, University of California, Los Angeles, CA 90095-1735 icrotoxin (PTX) is the prototypic vous system. Instead of an acetylcholine antagonist of GABAA receptors (ACh) target, the cage convulsants are (GABARs), the primary media- noncompetitive GABAR antagonists act- tors of inhibitory neurotransmis- ing at the PTX site: they inhibit GABAR Psion (rapid and tonic) in the nervous currents and synapses in mammalian neu- system. Picrotoxinin (Fig. 1A), the active rons and inhibit [3H]dihydropicrotoxinin ingredient in this plant convulsant, struc- binding to GABAR sites in brain mem- turally does not resemble GABA, a sim- branes (7, 9). A potent example, t-butyl ple, small amino acid, but it is a polycylic bicyclophosphorothionate, is a major re- compound with no nitrogen atom. The search tool used to assay GABARs by compound somehow prevents ion flow radio-ligand binding (10). through the chloride channel activated by This drug target appears to be the site GABA in the GABAR, a member of the of action of the experimental convulsant cys-loop, ligand-gated ion channel super- pentylenetetrazol (1, 4) and numerous family. Unlike the competitive GABAR polychlorinated hydrocarbon insecticides, antagonist bicuculline, PTX is clearly a including dieldrin, lindane, and fipronil, noncompetitive antagonist (NCA), acting compounds that have been applied in not at the GABA recognition site but per- huge amounts to the environment with haps within the ion channel. Thus PTX major agricultural economic impact (2). ͞ appears to be an excellent example of al- Some of the other potent toxicants insec- losteric modulation, which is extremely ticides were also radiolabeled and used to important in protein function in general characterize receptor action, allowing and especially for GABAR (1). -
Redalyc.Timing of Progesterone and Allopregnanolone Effects in a Serial
Salud Mental ISSN: 0185-3325 [email protected] Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz México Contreras, Carlos M.; Rodríguez-Landa, Juan Francisco; Bernal-Morales, Blandina; Gutiérrez-García, Ana G.; Saavedra, Margarita Timing of progesterone and allopregnanolone effects in a serial forced swim test Salud Mental, vol. 34, núm. 4, julio-agosto, 2011, pp. 309-314 Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz Distrito Federal, México Available in: http://www.redalyc.org/articulo.oa?id=58221317003 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative Salud Mental 2011;34:309-314Timing of progesterone and allopregnanolone effects in a serial forced swim test Timing of progesterone and allopregnanolone effects in a serial forced swim test Carlos M. Contreras,1,2 Juan Francisco Rodríguez-Landa,1 Blandina Bernal-Morales,1 Ana G. Gutiérrez-García,1,3 Margarita Saavedra1,4 Artículo original SUMMARY Total time in immobility was the highest and remained at similar levels only in the control group throughout the seven sessions of the The forced swim test (FST) is commonly employed to test the potency serial-FST. In the allopregnanolone group a reduction in immobility of drugs to reduce immobility as an indicator of anti-despair. Certainly, was observed beginning 0.5 h after injection and lasted approximately antidepressant drugs reduce the total time of immobility and enlarge 1.5 h. Similarly, progesterone reduced immobility beginning 1.0 h the latency to the first immobility period. -
GABAA Transmission Is a Critical Step in the Process of Triggering Homeostatic Increases in Quantal Amplitude
GABAA transmission is a critical step in the process of triggering homeostatic increases in quantal amplitude Jennifer C. Wilhelm and Peter Wenner* Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322 Communicated by Lynn T. Landmesser, Case Western Reserve University, Cleveland, OH, June 23, 2008 (received for review March 1, 2008) When activity levels are altered over days, a network of cells is models suggests that reducing network activity produces a corre- capable of recognizing this perturbation and triggering several dis- sponding reduction in cellular spiking activity, thereby reducing tinct compensatory changes that should help to recover and maintain intracellular calcium levels in a postsynaptic cell. In this model, the original activity levels homeostatically. One feature commonly which we will refer to as the cell activity model, the postsynaptic cell observed after activity blockade has been a compensatory increase in senses changes in intracellular calcium levels as a measure of altered excitatory quantal amplitude. The sensing machinery that detects activity and triggers compensatory changes in mPSC amplitude. altered activity levels is a central focus of the field currently, but thus However, the studies that have inspired this model not only block far it has been elusive. The vast majority of studies that reduce spiking activity, they also block or reduce neurotransmitter binding network activity also reduce neurotransmission. We address the to its receptor and any associated downstream signaling cascades. possibility that reduced neurotransmission can trigger increases in Thus, it remains possible that neurotransmission is a critical step in quantal amplitude. In this work, we blocked glutamatergic or GABAA the sensing process that triggers changes in quantal amplitude. -
Neurotransmitters-Drugs Andbrain Function.Pdf
Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Edited by R. A. Webster Department of Pharmacology, University College London, UK JOHN WILEY & SONS, LTD Chichester Á New York Á Weinheim Á Brisbane Á Singapore Á Toronto Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Copyright # 2001 by John Wiley & Sons Ltd. Bans Lane, Chichester, West Sussex PO19 1UD, UK National 01243 779777 International ++44) 1243 779777 e-mail +for orders and customer service enquiries): [email protected] Visit our Home Page on: http://www.wiley.co.uk or http://www.wiley.com All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1P0LP,UK, without the permission in writing of the publisher. Other Wiley Editorial Oces John Wiley & Sons, Inc., 605 Third Avenue, New York, NY 10158-0012, USA WILEY-VCH Verlag GmbH, Pappelallee 3, D-69469 Weinheim, Germany John Wiley & Sons Australia, Ltd. -
GABA Receptors
D Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews Review No.7 / 1-2011 GABA receptors Wolfgang Froestl , CNS & Chemistry Expert, AC Immune SA, PSE Building B - EPFL, CH-1015 Lausanne, Phone: +41 21 693 91 43, FAX: +41 21 693 91 20, E-mail: [email protected] GABA Activation of the GABA A receptor leads to an influx of chloride GABA ( -aminobutyric acid; Figure 1) is the most important and ions and to a hyperpolarization of the membrane. 16 subunits with γ most abundant inhibitory neurotransmitter in the mammalian molecular weights between 50 and 65 kD have been identified brain 1,2 , where it was first discovered in 1950 3-5 . It is a small achiral so far, 6 subunits, 3 subunits, 3 subunits, and the , , α β γ δ ε θ molecule with molecular weight of 103 g/mol and high water solu - and subunits 8,9 . π bility. At 25°C one gram of water can dissolve 1.3 grams of GABA. 2 Such a hydrophilic molecule (log P = -2.13, PSA = 63.3 Å ) cannot In the meantime all GABA A receptor binding sites have been eluci - cross the blood brain barrier. It is produced in the brain by decarb- dated in great detail. The GABA site is located at the interface oxylation of L-glutamic acid by the enzyme glutamic acid decarb- between and subunits. Benzodiazepines interact with subunit α β oxylase (GAD, EC 4.1.1.15). It is a neutral amino acid with pK = combinations ( ) ( ) , which is the most abundant combi - 1 α1 2 β2 2 γ2 4.23 and pK = 10.43. -
Dynamic Regulation of the GABAA Receptor Function by Redox Mechanisms S
Supplemental material to this article can be found at: http://molpharm.aspetjournals.org/content/suppl/2016/07/20/mol.116.105205.DC1 1521-0111/90/3/326–333$25.00 http://dx.doi.org/10.1124/mol.116.105205 MOLECULAR PHARMACOLOGY Mol Pharmacol 90:326–333, September 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics MINIREVIEW—A LATIN AMERICAN PERSPECTIVE ON ION CHANNELS Dynamic Regulation of the GABAA Receptor Function by Redox Mechanisms s Daniel J. Calvo and Andrea N. Beltrán González Laboratorio de Neurobiología Celular y Molecular, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular Downloaded from ¨Dr. Héctor N. Torres¨ (INGEBI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires, Argentina (D.J.C., A.N.B.G.) Received May 15, 2016; accepted July 14, 2016 ABSTRACT molpharm.aspetjournals.org Oxidizing and reducing agents, which are currently involved normally present in neurons and glia or are endogenously in cell metabolism and signaling pathways, can regulate fast generated in these cells under physiologic states or during inhibitory neurotransmission mediated by GABA receptors in the oxidative stress (e.g., hydrogen peroxide, superoxide and hy- nervous system. A number of in vitro studies have shown that droxyl radicals, nitric oxide, ascorbic acid, and glutathione), diverse redox compounds, including redox metabolites and induce potentiating or inhibiting actions on different native and reactive oxygen and nitrogen species, modulate phasic and recombinant GABAA receptor subtypes. Based on these results, it tonic responses mediated by neuronal GABAA receptors through is thought that redox signaling might represent a homeostatic both presynaptic and postsynaptic mechanisms. -
Exploring the Activity of an Inhibitory Neurosteroid at GABAA Receptors
1 Exploring the activity of an inhibitory neurosteroid at GABAA receptors Sandra Seljeset A thesis submitted to University College London for the Degree of Doctor of Philosophy November 2016 Department of Neuroscience, Physiology and Pharmacology University College London Gower Street WC1E 6BT 2 Declaration I, Sandra Seljeset, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I can confirm that this has been indicated in the thesis. 3 Abstract The GABAA receptor is the main mediator of inhibitory neurotransmission in the central nervous system. Its activity is regulated by various endogenous molecules that act either by directly modulating the receptor or by affecting the presynaptic release of GABA. Neurosteroids are an important class of endogenous modulators, and can either potentiate or inhibit GABAA receptor function. Whereas the binding site and physiological roles of the potentiating neurosteroids are well characterised, less is known about the role of inhibitory neurosteroids in modulating GABAA receptors. Using hippocampal cultures and recombinant GABAA receptors expressed in HEK cells, the binding and functional profile of the inhibitory neurosteroid pregnenolone sulphate (PS) were studied using whole-cell patch-clamp recordings. In HEK cells, PS inhibited steady-state GABA currents more than peak currents. Receptor subtype selectivity was minimal, except that the ρ1 receptor was largely insensitive. PS showed state-dependence but little voltage-sensitivity and did not compete with the open-channel blocker picrotoxinin for binding, suggesting that the channel pore is an unlikely binding site. By using ρ1-α1/β2/γ2L receptor chimeras and point mutations, the binding site for PS was probed. -
Thesis Rests with Its Author
University of Bath PHD A modelling study of the ligand-gated ion-channel superfamily of receptors Cockcroft, Victor Barrie Award date: 1992 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 08. Oct. 2021 A MODELLING STUDY OF THE LIGAND-GATED ION-CHANNEL SUPERFAMILY OF RECEPTORS. submitted by Victor Barrie Cockcroft for the degree of Ph.D. at the University of Bath 1992 Copyright Attention is drawn to the fact that the copyright of this thesis rests with its author. This copy of the thesis has been supplied on the condition that anyone who con sults it is understood to recognize that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published with out the prior written consent of the author. -
Antinociceptive Activity of a Neurosteroid Tetrahydrodeoxycorticosterone (5Cx-Pregnan-3Cx-21-Diol-20-One) and Its Possible Mechanism(S) of Action
Indian Journal of Experimental Biology Vol. 39, December 2001, pp. 1299-1301 Antinociceptive activity of a neurosteroid tetrahydrodeoxycorticosterone (5cx-pregnan-3cx-21-diol-20-one) and its possible mechanism(s) of action P K Mediratta, M Gambhir, K K Sharma & M Ray Department of Pharmacology, University College of Medical Sciences and GTB Hospital, Delhi II 0095, India Fax: 91-11-2299495; E-mail: [email protected]/[email protected] Received 9 Apri/2001; revised 2 July 2001 The present study investigates the effects of a neurosteroid tetrahydrodeoxycorticosterone (5a-pregnan-3a-21-diol-20- one) in two experimental models of pain sensitivity in mice. Tetrahydrodeoxycorticosterone (2.5, 5 mg!kg, ip) dose dependently decreased the licking response in formalin test and increased the tail flick latency (TFL) in tail flick test. Bicuculline (2 mg/kg, ip), a GABAA receptor antagonist blocked the antinociceptive effect of tetrahydrodeoxy corticosterone in TFL test but failed to modulate licking response in formalin test. Naloxone (I mglkg, ip), an opioid antagonist effectively attenuated the analgesic effect of tetrahydrodeoxycorticosterone in both the models. Tetrahydrodeoxycorticosterone pretreatment potentiated the anti nociceptive response of morphine, an opioid compound and nimodipine, a calcium channel blocker in formalin as well as TFL test. Thus, tetrahydrodeoxycorticosterone exerts an analgesic effect, which may be mediated by modulating GABA-ergic and/or opioid-ergic mechanisms and voltage-gated calcium channels. It is now well known that some of the steroids like Allopregnanolone has been shown to exhibit progesterone can act on central nervous system (CNS) antinociceptive effect against an aversive thermal to produce a number of endocrine and behavioral stimulus 10 and in a rat mechanical visceral pain 11 effects. -
Effect of Isopregnanolone on Rapid Tolerance to the Anxiolytic Effect of Ethanol Influência Da Isopregnenolona Na Tolerância R
18 ORIGINAL ARTICLE Effect of isopregnanolone on rapid tolerance to the anxiolytic effect of ethanol Influência da isopregnenolona na tolerância rápida ao efeito ansiolítico do etanol Thaize Debatin,1 Adriana Dias Elpo Barbosa2 Original version accepted in Portuguese Abstract Objective: It has been shown that neurosteroids can either block or stimulate the development of chronic and rapid tolerance to the incoordination and hypothermia caused by ethanol consumption. The aim of the present study was to investigate the influence of isopregnanolone on the development of rapid tolerance to the anxiolytic effect of ethanol in mice. Method: Male Swiss mice were pretreated with isopregnanolone (0.05, 0.10 or 0.20 mg/kg) 30 min before administration of ethanol (1.5 g/kg). Twenty-four hours later, all animals we tested using the plus-maze apparatus. The first experiment defined the doses of ethanol that did or did not induce rapid tolerance to the anxiolytic effect of ethanol. In the second, the influence of pretreatment of mice with isopregnanolone (0.05, 0.10 or 0.20 mg/kg) on rapid tolerance to ethanol (1.5 g/kg) was studied. Conclusions: The results show that pretreatment with isopregnanolone interfered with the development of rapid tolerance to the anxiolytic effect of ethanol. Keywords: Ethanol; Drug tolerance; Anti-anxiety agents; Mice; Alcoholism Resumo Objetivo: Estudos prévios têm mostrado que os neuroesteróides podem bloquear ou estimular o desenvolvimento da tolerância rápida e crônica aos efeitos de incoordenação e hipotermia produzidos pelo etanol. O objetivo do presente estudo foi investigar a influência da isopregnenolona sobre o desenvolvimento da tolerância rápida ao efeito ansiolítico do etanol em camundongos. -
Assessment of Molecular Action of Direct Gating and Allosteric Modulatory Effects of Carisoprodol (Somartm) on GABA a Receptors
Graduate Theses, Dissertations, and Problem Reports 2015 Assessment of molecular action of direct gating and allosteric modulatory effects of carisoprodol (SomaRTM) on GABA A receptors Manoj Kumar Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation Kumar, Manoj, "Assessment of molecular action of direct gating and allosteric modulatory effects of carisoprodol (SomaRTM) on GABA A receptors" (2015). Graduate Theses, Dissertations, and Problem Reports. 6022. https://researchrepository.wvu.edu/etd/6022 This Dissertation is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. ASSESSMENT OF MOLECULAR ACTION OF DIRECT GATING AND ALLOSTERIC MODULATORY EFFECTS OF MEPROBAMATE (MILTOWN®) ON GABAA RECEPTORS Manish Kumar, MD, MS Dissertation submitted to the School of Pharmacy at West Virginia University in partial fulfillment of Requirements