Table Of ContentThe Serotonin Receptors
The Receptors
Series Editor
David B. Bylund, University of Missouri, Columbia, Missouri
Board of Editors
S. J. Enna, Nova Pharmaceuticals, Baltimore, Maryland
Morley D. Hollenberg, University of Calgary, Calgary,
Alberta, Canada
Bruce S. McEwen, Rockefeller University, New York,
New York
Solomon H. Snyder, Johns Hopkins University,
Baltimore, Maryland
The Serotonin Receptors, edited by Elaine Sanders-Bush,
1988
The alpha-2 Adrenergic Receptors, edited by Lee Limbird,
1988
The Opiate Receptors, edited by Gavril W. Pasternak,
1988
The alpha-l Adrenergic Receptors, edited by
Robert R. Ruffolo, Jr., 1987
The GABA Receptors, edited by S. J. Enna, 1983
The Serotonin
Receptors
Edited by
Elaine Sanders-Bush
Department of Pharmacology and Psychiatry
Vanderbilt University School of Medicine
Nashville, Tennessee
THE HUMANA PRESS • CLIFTON, NEW JERSEY
library of Congress Cataloging in Publication Data
Main entry under title:
The Serotonin receptors.
(The Receptors)
Includes bibliographies and indexes.
1. Serotonin-Receptors. I. Sanders-Bush, Elaine.
II. Series.
QP801.545485 1988 612'.13 88-26646
ISBN-13: 978-1-4612-8912-8 e-ISBN-13: 978-1-4612-4560-5
001: 10.1007/978-1-4612-4560-5
© 1988 The Humana Press Inc.
Softcover reprint ofthe hardcover 1s t edition 1988
Crescent Manor
PO Box 2148
Clifton, NJ 07015
All rights reserved
No part of this book may be reproduced, stored in a retrieval
system, or transmitted in any form or by any means, electronic,
mechanical, photocopying, microfilming, recording, or otherwise
without written permission from the Publisher.
Preface
Serotonin (5-HT) was isolated and chemically characterized nearly
four decades ago, and is now generally accepted to function as a
neurotransmitter and neuromodulatory agent. Early research
focused on the measurement of concentrations, synthesis, and
metabolism of 5-HT, and only recently has the focus shifted to
characterization of 5-HT receptors. Gaddum and Picarelli first sug
gested in 1957 that the effect of 5-HT in the guinea pig ileum is
mediated by two pharmacologically distinguishable receptors;
however, the possibility of dual5-HT receptors was not explored
systematically or successfully until the past decade. It is now clear
that more, perhaps many more, subclasses of 5-HT receptors exist.
The purpose of this book is to provide an up-to-date report on
5-HT receptors. This is a difficult task considering the astonishing
speed at which research in this field is expanding. As the first of
what we can expect to be a steady stream of monographs focusing
on 5-HT receptors, the book confirms that we are in an exciting
time in the history of 5-HT. For those of us who have been work
ing on 5-HT for many years, our dream of equal progress and
recognition with the more extensively studied catecholamines is
finally being realized. We now have a Serotonin Club that held
its first international scientific meeting in 1987, and several more
international meetings are in the planning stages. The recent find
ings that the new, nonbenzodiazepine anxiolytics have prominent
effects on 5-HT receptors has led to a resurgence of interest in the
potential therapeutic value of 5-HT receptor agonists and an
tagonists. The future of research on 5-HT receptors promises to
be exciting.
The publisher and staff of Humana Press have proceeded rapid
ly; this, combined with the cooperation of the contributors, has
resulted in a timely and comprehensive monograph. I want to thank
the individual authors who, recognizing that speed of publication
v
vi Preface
was important, followed through on their commitments and met
the various deadlines. My special thanks are extended to David
Bylund for his advice and support from the beginning to the end
of this endeavor. I also owe a special debt of gratitude to Richard
Glennon, who conceived of and prepared the appendix for this
volume, providing the chemical structures of substances that are
commonly employed as tools to evaluate serotonin mechanisms.
This compilation will serve as a practical and theoretical guide for
both new and established investigators. Readers of the volume
should find it especially helpful as they delve into the complex phar
macology of the 5-HT receptor systems.
Elaine Sanders-Bush
Contents
Pr'eface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
List of Contributors • • . . . . . . • • • • . • . . • • • • . . . xv
Section 1: Historical Perspective
Chapter 1
Historical Perspectives
Samuel S. Wang and Stephen J. Peroutka
1. The Discovery of 5-HT ............................. 3
2. Characterization of Serotonin Receptors .............. 6
2.1. M and D Receptors ............................ 6
2.2. 5-HT and 5-HT Binding Sites .................. 6
t 2
2.3. 5-HT3 Receptors .............................. 10
2.4. Neurophysiological Studies of 5-HT ............ 11
2.5. 5-HT and Behavior ............................ 12
3. Future Approaches ................................ 14
References ........................................ 15
Section 2: Characterization of Serotonin
Receptor Binding Sites
Chapter 2
Biochemistry and Pharmacology of the 5·HT
1
Serotonin Binding Sites
David L. Nelson
1. Introduction ...................................... 23
1.1. Historical Perspectives: The Origins of the
5-HT Binding Site Classification ............... 23
t
vii
viii Contents
1.2. Current Classification and Definitions of
Subtypes of 5-HT Sites ....................... 24
1
2. Radioligand Binding Assays for 5-HTl Sites ......... 25
2.1. [3H]LSD Binding .............................. 25
2.2. PH]5-HT Binding ............................. 26
2.3. 5-HTl Subtype-Selective Radioligands .......... 34
3. Pharmacology of 5-HT Binding Sites ............... 41
1
4. Isolation and Purification of 5-HT Binding Site
1
Subtypes ......................................... 46
4.1. Solubilization of 5-HTl Binding Sites ........... 46
4.2. Affinity Labels for 5-HT Binding Sites ......... 49
1
5. Summary ......................................... 51
References ........................................ 52
Chapter 3
Pharmacology and Biochemistry of the 5·HT Receptor
2
Robert A. Lyon and Milt Titeler
1. Introduction ...................................... 59
2. Current Methods in Radioligand Binding Sites ....... 60
3. Antagonist Radioligands for 5-HT2 Receptors ........ 62
4. Agonist Radioligands for 5-HT2 Receptors ........... 69
5. 5-HT2 Receptor: Site of Action of Hallucinogenic
Drugs ............................................ 75
6. Solubilization, Purification, and Reconstruction of
5-HT Receptors ................................... 76
2
7. Summary ......................................... 83
References ........................................ 84
Chapter 4
Autoradiographic Studies of Serotonin Receptors
J. M. Palacios and M. M. Dietl
1. Inuoduction ...................................... 89
2. Ligands and Conditions for the Autoradiographic
Localization of 5-HT Receptors in the Rat Brain ...... 91
3. Characteristics of 5-HT Receptors in Rat Brain
Examined Autoradiographically . . . . . . . . . . . . . . . . . . . .. 91
4. Distribution of 5-HT Receptors in the Rat Brain ...... 97
4.1. Distribution of 5-HT Receptors in Rat Brain .... 97
1
4.2. Distribution of 5-HT2 Receptors in Rat Brain ... 109
4.3. 5-HT3 Receptors: Apparent Absence from the
Rat Brain .................................... 111
5. Lesion Studies and Possible Localization of 5-HT
Sites in Specific Brain Pathways ................... 112
Contents ix
5.1. Lesions of the Serotoninergic Pathways ........ 112
5.2. Lesions of Chemically Identified Pathways:
The Dopaminergic Nigrostriatal System ........ 116
5.3. The Striatonigral Pathways ................... 117
5.4. Cholinergic Pathways ........................ 117
5.5. Lesions of a Functional Pathway: 5-HT
Receptors in the Visual System ............... 118
6. Serotonin Receptors in Human Brain .............. 119
6.1. 5-HT Receptors in Human Brain .............. 119
1
6.2. 5-HT Receptors in Human Brain .............. 127
2
7. Species Differences in Brain 5-HT Receptors:
A Phylogenetic Approach ......................... 131
8. Conclusions and Future Trends ................... 133
References ....................................... 134
Section 3: Biochemical Mechanisms
of Receptor Action
Chapter 5
5·HT Receptors Coupled to Adenylate Cyclase
Michael De Vivo and Saul Maayani
1. Introduction ..................................... 141
2. Signal Transduction through G Protein Systems .... 142
3. Pharmacological Considerations ................... 144
4. Increases in Cyclic AMP Production Induced
by 5-HT ......................................... 146
4.1. Invertebrate Tissues .......................... 146
4.2. Mammalian Nonneuronal Tissues ............. 150
4.3. Mammalian Neuronal Tissues ................. 153
5. Decreases in Cyclic AMP Production Induced
by 5-HT ......................................... 158
5.1. Inhibition of Basal or Receptor-Stimulated
Cyclic AMP Production by 5-HT .............. 158
5.2. 5-HTIA Receptor-Mediated Inhibition of
Adenylate Cyclase ........................... 160
6. Possible Roles for Cyclic AMP in 5-HT Receptor
Systems ......................................... 164
6.1. Synapsin and Neurotransmitter Release ....... 164
6.2. 5-HT, Cyclic AMP, and the Gill-Withdrawal
Reflex in Aplysia ............................ 165
7. Summary and Conclusions ........................ 166
References ....................................... 168
x Contents
Chapter 6
5-HT Receptors Coupled to Phosphoinositide Hydrolysis
Elaine Sanders-Bush
1. Introduction ..................................... 181
2. 5-HT Stimulated Phosphoinositide Hydrolysis in
Invertebrate Tissues .............................. 184
3. 5-HT Stimulated Phosphoinositide Hydrolysis in
Mammalian Nonneuronal Tissues ................. 185
3.1. Smooth Muscle Preparations .................. 185
3.2. Platelets ..................................... 187
3.3. Choroid Plexus .............................. 187
4. 5-HT Stimulated Phosphoinositide Hydrolysis in
Mammalian Neuronal Tissues ..................... 190
4.1. Cerebral Cortex .............................. 190
4.2. Cultured Cells ............................... 192
4.3. Other Brain Regions ......................... 193
5. Unique Value of Studies of Biochemical Effector
Systems ......................................... 193
References ....................................... 195
Section 4: Correlation of Binding Sites
with Function
Chapter 7
Autoreceptors Regulating Serotonin Release
Derek N. Middlemiss
1. Introduction ..................................... 201
2. Historical Perspective ............................. 202
3. Methodological Considerations .................... 203
3.1. In Vitro Identification of the 5-HT Autoreceptor 203
3.2. In Vivo Identification of the 5-HT Autoreceptor 205
4. 5-HT Autoreceptor Location ....................... 208
5. Drugs Active at the Terminal 5-HT Autoreceptor .... 208
5.1. Agonists .................................... 208
5.2. Antagonists ................................. 209
6. Interactions between the 5-HT Autoreceptor and
Uptake Site ...................................... 213
7. Relationship of the Terminal 5-HT Autoreceptor
to Radioligand Binding Sites ...................... 214
