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Information to Users INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. A Bell & Howell Information Company 300 North Zeeb Road. Ann Arbor. Ml 48106-1346 USA 313/761-4700 800/521-0600 Order Number 9517043 Serotonergic control of gastrointestinal function LePard, Kathy Jean, Ph.D. The Ohio State University, 1994 UMI 300 N. ZeebRd. Ann Arbor, MI 48106 SEROTONERGIC CONTROL OF GASTROINTESTINAL FUNCTION DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Kathy Jean LePard, B.S., M.S. * * * * * The Ohio State University 1994 Dissertation Committee: Richard C. Rogers, Ph.D. Jackie D. Wood, Ph.D. Robert L. Stephens Jr., Ph.D. Approved by Advisor Department of Physiology To my Husband. ii ACKNOWLEDGMENTS I would like to express my sincere gratitude to the faculty of the Natural Science Division at Huntington College: my undergraduate advisor, Prof. J. Howald, along with Drs. W. Bordeaux, F. Jones, R. Brown, W. Weatherbee and R. Hale, for encouraging my pursuit of science, for academically preparing me for graduate school, but most importantly, for their neverending support and guidance throughout my undergraduate and graduate career. Thanks to my graduate advisor, Dr. Robert Stephens Jr, for his guidance, support and insight during my graduate research. Also, to the other members of my advisory committee, Drs. Helen Cooke, Richard Rogers, and Jackie Wood, for their helpful comments and suggestions. Thanks to the support staff of the Department of Physiology: C. Hagaar, D. Ranft, B. Spink, C. Hairston, R. Lynch and D. Vanek. Also to faculty which have graciously loaned equipment, drugs or provided knowledge: Drs. R. Rogers, J. Rail, P. Ward, C. Heesch, H. Cooke and L. Fisher. Special thanks to our laboratory technician J. Mohammed for her invaluable assistance and National Institutes of Health for funding (NIH DK 42880). iii To my parents, Merle and Maxine Nice, I would like to express my indebtedness for their support, love and encouragement throughout my academic development. Finally, to my husband, Brian. Words cannot express my humble appreciation of your constant faith in me and your unwavering love to me despite the demands of my graduate career. iv VITA March 9, 1967 Born - Logansport, Indiana 1988-1989 Laboratory Assistant, Department of Chemistry Huntington College, Huntington, Indiana Summer 1988 Buckingham Research Fellow Department of Chemistry Miami University, Oxford, Ohio 1985-1989 B.S.S., Huntington College, Huntington, Indiana 1989-1992 M.S.S., College of Medicine, The Ohio State University Columbus, Ohio 1992-1994 Graduate Research Associate The Ohio State University Columbus, Ohio PUBLICATIONS LePard, K.J. and R.L. Stephens Jr. Serotonin Inhibits Gastric Acid Secretion through a 5-Hydroxytryptamine^like Receptor in the Rat. Journal of Pharmacology and Experimental Therapeutics. 1994. 270:1-6. LePard, K.J., S. Gidener and R.L. Stephens Jr. Serotonin Inhibits, but 8-OH-DPAT Stimulates GAstric Acid Secretion through Vagal-Independent Mechanisms. Society for Neuroscience Abstracts. 1994. 20:1376. Stephens JR, R.L., K.J. LePard, J.R. Mohammed and P.E. Ward. Intracisternal Neutral Endopeptidase-24-11 Inhibitors Produce Inhibition in Gastric Acid Output: Independence of Opiate, Bombesin, or Neurotensin-Mediated Mechanisms. Regulatory Peptides. 1993. 46:549-555. v LePard, K.J. and R.L. Stephens Jr. Characterization of Serotonergic Mechanisms Producing Inhibition of Gastric Acid Secretion. 1993. Gastroenterology. 104:A132. LePard, K.J. and R.L. Stephens Jr. Gastrin-Dependent Enterochromaffin-Like Cell Hyperplasia: Effects on Basal and Stimulated GAstric Acid Secretion. Gastroenterology. 1993. 104:A631. LePard, K.J. and R.L. Stephens Jr. Vagally-Mediated Serotonin (5HT) Release Inhibits Gastric Acid Secretion Via Receptors of the 5HT- Family. Society for Neuroscience Abstracts. 1993. 19:962. Shockley,R., K.J. LePard, and R.L. Stephens Jr. Fluoxetine Pretreatment Potentiates Intracisternal TRH Analogue- Stimulated Gastric Acid Secretion in Rats. 1992. 38:121-128. LePard, K.J. and R.L. Stephens Jr. Serotonin (5-HT) Inhibits Gastric Acid Secretion by Nonluminal, Vagal Independent Mechanisms. Society for Neuroscience Abstracts. 1992. 18:1529. McCann, M.J., K.J. Nice-LePard and R.C. Rogers. Dorsal Medullary Injection of Atrial Natriuretic Factor (ANF) Excites Vagal Efferents and Inhibits Gastric Motility. Brain Research. 1991. 549:247-252. FIELDS OF STUDY Major Field: Physiology Studies in: Cardiovascular Physiology Dr. G. Billman Dr. C. Heesch Endocrinology Dr. J. Grossie Gastrointestinal Physiology Dr. J. Rail Dr. R. Stephens Membrane Physiology Dr. J. Grossie Dr. B. Biagi Muscle Physiology Dr. J. Grossie Neurophysiology Dr. B. Stokes Dr. R. Rogers Physiological Laboratory Dr. J. Grossie Renal Physiology Dr. B. Biagi Respiratory Physiology Dr. H. Weiss Biochemistry Dr. K. Richardson Neuroscience Dr. G. Martin Electronic Instrumentation Dr. J.-P. Dujardin Drug Receptor Theory Dr. A. Burkman Statistics Dr. J. Powers vi TABLE 07 CONTENTS DEDICATION ii ACKNOWLEDGMENTS iii VITA . V TABLE OF CONTENTS vii LIST OF FIGURES xiv LIST OF TABLES xvii CHAPTER I. INTRODUCTION I. Historical Aspects 1 II. Regional Distribution of Serotonin in Mammalian Systems 2 A. Central Nervous System 2 B. Gastrointestinal Tract 2 III. Synthesis and Degradation 3 A. Synthesis 3 B. Degradation 4 IV. Localization of Serotonin Receptors 4 A. 5-HT1a Receptors 7 B. 5-HT1p Receptors 7 C. 5-HT2 Receptors 8 D. 5-HT3 Receptors 8 E. 5-HT4 Receptors 8 V. Overview 9 VI. Mechanism of Release of 5-HT from Gastrointestinal Stores: In Vivo Studies 10 A. Introduction 10 B. Release into the Lumen 10 1. Activation of Chemoreceptors 10 2. Central Vagal Control 11 vii 3. Mucosal Mast Cell Degranulation 12 4. Summary (TABLE 2) 13 C. Release into the Portal Circulation 15 1. Activation of Chemoreceptors 15 2. Central Vagal Control 15 3. Splanchnic Nervous Control 17 4. Endocrine Control 17 5. Summary (TABLE 3) 18 D. Release from Enterochromaffin Cells 21 1. Activation of Chemoreceptors 21 2. Central Vagal Control 21 3. Sympathetic Nervous System 22 4. Summary 22 VII. Mechanisms of Release of Serotonin from Gastrointestinal Stores: In Vitro Studies .... 22 A. Introduction 22 B. Release to Mucosal Side 23 1. Nutrients 23 2. Acid in the Duodenal Lumen 23 3. Cholinergic Receptors 24 4. Adrenergic Receptors 25 5. Enteric Neurons 26 6. Intraluminal Pressure 26 7. Summary 26 C. Release to Serosal Side 27 1. Nutrients 27 2. Cholinergic Receptors . 27 3. Adrenergic Receptors 29 4. Enteric Neurons 29 5. Second Messenger Systems 30 a. Cyclic 3 *,5 '-Adenosine Monophosphate (CAMP) 30 b. Cyclic 3',5'-Guanine Monophosphate (cGMP) 30 c. Calcium 30 6. Enzymatic Activity 31 7. Serotonin Receptors 31 8. Summary 32 D. Release from EC Cells or Tissue Segments ... 33 1. Cholinergic Receptors 33 2. Adrenergic Receptors 34 3. Enteric Neurons 34 4. Second Messengers: Calcium 35 5. Summary 35 VIII. Summary: Release of Serotonin 35 A. Release into the Lumen 35 1. Activation of Chemoreceptors 35 2. Central Vagal Control 36 B. Release into the Portal Circulation 36 1. Activation of Chemoreceptors 36 viii 2. Central Vagal Control 36 3. Enteric Neurons 37 IX. Effect of Serotonin on Gastrointestinal Function . 37 A. Exogenous Serotonin 37 1. Gastric Acid Secretion 37 a. In Vivo Studies 37 b. In Vitro Studies 39 2. Gastrointestinal Motility 41 a. In Vivo Studies 41 b. In Vitro Studies 43 3. Gastric Emptying 45 4. Gastrointestinal Blood Flow 45 5. Gastric and Duodenal Lesions 46 6. Vagal Activity 47 a. In Vivo Studies 47 In Vitro Studies 48 B. Endogenous Serotonin 49 1. Gastric Acid Secretion 50 a. Endogenous 5-HT in the Gastric Lumen 50 b. Endogenous 5-HT in the Portal Circulation 50 c. Depletion of Endogenous 5-HT .... 50 2. Gastrointestinal Motility 51 a. Endogenous 5-HT in Mucosal Mast Cells 51 b. Endogenous 5-HT and Enteric Neurons . 52 1) In Vivo Studies 52 2) In Vitro Studies 52 c. Depletion of Endogenous 5-HT .... 52 3. Gastric Emptying 53 a. Enteric Neurons 53 4. Vagal Activity 53 5. Absorption of Nutrients 53 a. Depletion of Endogenous 5-HT .... 53 X. Conclusion 54 CHAPTER II. Serotonin Receptor Subtype Mediating Inhibition of Gastric Acid Secretion 57 I. Overview 57 II. Hypothesis: Intravenous Serotonin Inhibits Acid Secretion by Acting through a Serotonin Receptor . 57 III. Methods 58 A. Animals 58 B. Measurement of Gastric Acid Secretion 58 C. Cannulation of the Splenic Artery 58 D. Protocol for Antagonist Studies 61 ix E. Protocol for Agonist Studies 61 F. Drugs 61 6. Drug Treatments for Antagonist Studies .... 62 H.. Drug Treatments for Agonist Studies .....
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