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The Effects of 5-Hydroxytryptamine on Rat Dorsal Vagal Preganglionic Motoneurones in Vitro

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The Effects of 5-Hydroxytryptamine on Rat Dorsal Vagal Preganglionic Motoneurones in Vitro (U)^Aru f(uv 2807713449 THE EFFECTS OF 5-HYDROXYTRYPTAMINE ON RAT DORSAL VAGAL PREGANGLIONIC MOTONEURONES IN VITRO BY ANTHONY PAUL ALBERT B.Sc. M.Sc Thesis submitted for the degree of Doctor of Philosophy to the Faculty of Science of the University of London Department of Physiology Royal Free Hospital School of Medicine Rowland Hill Street Hampstead London NW3 2PF ProQuest Number: 10017410 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10017410 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ACKNOWLEDGEMENTS I would like to thank Dr. Susan Deuchars, Dr. Penny Brooks and Professor K. M. Spyer for their supervision over the past three years. I would particularly like to thank Sue for all her advice, encouragement and support during my PhD. I am very grateful! to Professor K.M. Spyer for providing me with the opportunity to work in the Department of Physiology at the Royal Free Hospital and to The Wellcome Trust for their sponsorship. I would also like to thank Dr. James Deuchars for his help with the histological techniques, Dr. Dave Jordan and Dr. James Halliwell for their guidance and advice and Mrs. Shirley-Anne Jurmann for her administration skills during my thesis. ABSTRACT The dorsal motor nucleus of the vagus (DMN) is located in the dorsomedial medulla oblongata. It mainly contains dorsal vagal preganglionic neurones (DVMs) which control many autonomic functions. Immunocytochemical studies have shown that 5-hydroxytryptamine (5-HT) is present in nerve fibres and nerve terminals innervating the DMN. In addition, ligand-binding studies and in situ hybridisation studies have localised a number of 5-HT receptor subtypes in the DMN. This suggests that 5-HT may have an important role in modulating the activity of DVMs. The aim of my thesis was to examine the subthreshold effects of 5-HT on visually-identified DVMs using a thin brainstem slice preparation in combination with the whole-cell recording patch- clamp configuration in current-clamp and voltage-clamp modes. In over 95 % of DVMs tested in current-clamp mode, applications of 5-HT elicited slow, prolonged excitatory effects which were dose-dependent and did not exhibit desensitization or run-down during recordings lasting over two hours. The excitatory responses to 5-HT were maintained in a media which blocked synaptic transmission indicating that the effects were mediated via postsynaptic 5-HT receptors. Furthermore, 5-HT elicited increases in baseline noise suggesting that the amine also enhanced the levels of postsynaptic potentials (PSPs) by activating presynaptic 5-HT receptors. The direct, postsynaptic excitatory effects of 5-HT were abolished or attenuated significantly (p <0.05) by the superfusion of the 5 -HT2a/2c receptor antagonists ketanserin and LY 53,857 and the 5 -HTia/2a receptor antagonist spiperone. The 5-HTiy^ receptor antagonist pindobind.5-HTiA and the 5 -HT4 receptor antagonist GR 113808A had no effects on the excitatory responses of 5-HT. Superfusion of the 5 -HT3 receptor antagonists ICS-205-930 and MDL 7222 did not significantly (p>0.05) attenuate the effects of 5-HT on DVMs. The excitatory effects of 5-HT on DVMs were mimicked by the 5-HT2a/2c receptor agonist ol- methyl-5-HT, the 5-HTi/2 receptor agonist 5-CT and the non-selective 5-HT agonist 5-MEOT. Applications of the 5-HTg receptor agonist 2-methyl-5-HT evoked small subthreshold excitatory effects associated with increases in baseline noise. In all DVMs tested in voltage clamp mode, applications of 5-HT, a-methyl-5- HT and 5-CT evoked subthreshold inward currents that were associated with changes in three different ion currents; reductions of an outward rectifying current and an inward rectifying current and the augmentation of a hyperpolarization-activated or \ current. Combinations of the changes in the outward rectifying and Kir currents were observed in the same DVMs. The present study concludes that 5-HT elicits direct, postsynaptic subthreshold excitatory effects on DVMs via the activation of 5-HTja receptors which are coupled to the modulation of at least three different ion channels. The mechanisms by which the 5-HT2a receptors are coupled to the ion channels, the possible physiological functions of the activation of 5 -HT2A receptors and the potential sources of 5-HT inputs onto DVMs are discussed. ABBREVIATIONS A5 - A5 region of the pons AC - Adenylate cyclase Ach - Acetylcholine aCSF - Artificial cerebrospinal fluid AHP - After-hyperpolarization 4-AP - 4-Aminopyridine BKc, - Large conductance Ca^^-activated channel Cg - 8 th cervical vertebra cAMP - Cyclic adenosine monophosphate ChAT - Choline acetyltransferase CNS - Central nervous system CT-HRP - Cholera-toxin horseradish peroxidase DBH - Dopamine- 6 -hydroxylase DLH - D-L-Homocysteic acid DMH - Dorsomedial hypothalamic nucleus DMN - Dorsal motor nucleus of the vagus DVMs - Dorsal vagal preganglionic motoneurones EC50 - Effective dose eliciting 50 % of the maximal response Ek - Potassium equilibrium potential EPSCs - Excitatory postsynaptic currents Erev - Reversal potential GABA - Gamma-amino-butyric acid 01 - Gastrointestinal tract ['H] - Tritiated (tritium labelled) h - Hour HRP - Horseradish peroxidase 5-HT - 5 -Hydroxy tryptamine Hz - Cycle.s'^ i.c - Intracistemally IC50 - Concentration blocking 50 % of the maximal response Ih - Non-selective hyperpolarization-activated cationic current i.p. - Intraperitoneal IP3 - Inositol 1,4,5 trisphosphate IPSCs - Inhibitory postsynaptic currents i.v. - Intravenous injection [Klo - Extracellular concentration Ka - Transient current Katp - ATP-dependent current Kd - Equilibrium dissociation constant Ki - Dissociation constant determined by competition ^IR - Inward rectifying current LH - Lateral hypothalamic nucleus min - Minute mRNA - Messenger ribonucleic acid mV - M illivolt [N al, - Extracellular Na^ concentration NA - Nucleus ambiguus NMDA - N-Methyl-D-aspartate nS - Nano-siemens NTS - Nucleus tractus solitarius 8 -OH-DPAT - 8-Hydroxy-2-(di-A-propylamino)-tetralin pA - Pico-amps PBS - Phosphate buffer saline PHA-L - Phaseolus vulgaris leuci-agglutinin PI - Phosphatidylinositol PKC - Protein kinase C PN - Parabrachial nucleus PRV - Pseudorabies virus PSPs - Postsynaptic potentials PVN - Paraventricular nucleus of the hypothalmus s - Second SK^a - Small conductance Ca^^-activated channel SP - Substance P T1 - 1 St thoracic segment T2 - 2 nd thoracic segment TEA - T etraethylammonium TH - Tyrosine hydroxylase TMB - T etramethylbenzidine TRH - Thyrotropin-releasing hormone TTX - Tetrodotoxin VMH - Ventromedial hypothalamic nucleus P - Micro < - Less than > - Greater than TABLE OF CONTENTS Page Title page 1 Acknowledgements 2 Abstract 3 Abbreviations 5 Table of contents 7 List of figures and tables 11 CHAPTER 1 GENERAL INTRODUCTION 14 1.1 Location of vagal motoneurones in the DMN 15 1.1a Early studies 15 1. lb Recent studies 16 1.2 Morphology of DVMs 20 1.3 Outputs from the DMN 22 1.4 Inputs from the DMN 24 1.5 Physiological functions of the DMN 30 1.5a Control of the GI tract by the DMN 30 1.5b Control of the pancreas by the DMN 34 1.5c Control of the heart by the DMN 35 1.5d Is there a topographic organization of physiological functions in the DMN? 38 1.6 Biophysical properties of DVMs 40 1.7 Synaptic activity onto DVMs 45 1.8 5-Hydroxytryptamine is a neurotransmitter in the CNS 45 1.9 Location of 5-HT-containing neurones 47 1.9a Ascending projections of 5-HT-containing neurones 50 1.9b Descending projections of 5-HT-containing neurones 51 1.9c Co-localisation of neurochemicals with 5-HT-containing neurones 52 1.10 5-HT innervation of the DMN 52 1.11 5-HT receptors in the CNS 53 1.12 5-HTi receptors 54 1.12a 5-HTiA receptors 61 1.12b 5-HTib receptors 62 1.12c 5-HTid receptors 63 1.12d 5 -HTje receptors 64 1.12e 5-HTif receptors 65 1.13 5 -HT2 receptors 65 1.13a 5 -HT2A receptors 66 1.13b 5 -HT2B receptors 67 1.13c 5 -HT2C receptors 67 1.14 5 -HT3 receptors 68 1.15 5 -HT4 receptors 69 1.16 5-htg receptors 70 1.17 S-htg receptors 71 1.18 5-ht7 receptors 71 1.19 5-HT receptors in the DMN 72 1.20 Physiological functions of 5-HT in the DMN 73 1.21 The present study 74 CHAPTER 2 METHODS AND MATERIALS 76 2.1 General preparation 77 2.2 Surgical procedures 77 2.3 The recording set-up 79 2.4 Data collection 84 2.5 Data analysis 89 2.5a On-line analysis 89 2.5b Off-line analysis 90 2.6 Drug storage and application 92 2.7 Histological procedures 92 CHAPTER 3 THE EFFECTS OF 5-HT ON DVMs in vitro 94 3.1 Introduction 95 3.1a Electrophysiological effects of 5-HT in the DMN 95 3.1b The present study 95 3.2 Methods 98 3.2a Experimental procedures 98 3.2b Experimental protocol 98 3.3 Results 100 3.3a General properties of DVMs 100 3.3b Effects of 5-HT on DVMs 105 3.3c Dose-dependent effects of 5-HT 110 3.3d Effects of uptake inhibitors 110 3.3e Postsynaptic effects of 5-HT 117 3.3f Ionic mechanisms involved in mediating the effects of 5-HT 122 3.4 Discussion 129 8 3.4a Viability of the preparation 129 3.4b The excitatory effects of 5-HT 130 3.4c Uptake inhibition 133 3.4d Direct effects of 5-HT on DVMs 135 3.4e Ionic mechanisms 135 CHAPTER 4 THE EFFECTS OF SELECTIVE 5-HT RECEPTOR AGONISTS AND ANTAGONISTS ON DVMs in vitro 138 4.1 Introduction 139 4.1a Previous studies on the 5-HT receptor subtypes 139 mediating responses of 5-HT on DVMs 4.1b Selective 5 -HT2a/2c receptor antagonists and agonists 140 4.1c Selective 5-HTg receptor antagonists and agonists 142 4.
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