The Pharmacology of Synapses

378 Pages·1970·9.272 MB·English

by  J. W. Phillis and G. A. Kerkut (Auth.)

THE PHARMACOLOGY
OF SYNAPSES
BY
J. W. PHILLIS
Department of Physiology, Monash University,
Clayton, Victoria, Australia
PERGAMON PRESS
Oxford ' London · Edinburgh · New York
Toronto · Sydney · Paris * Braunschweig
Pergamon Press Ltd., Headington Hill Hall, Oxford
Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, New York 10523
Pergamon of Canada Ltd., 207 Queen's Quay West, Toronto 1
Pergamon Press (Aust.) Pty. Ltd., 19a Boundary Street, Rushcutters Bay,
N.S.W. 2011, Australia
Copyright © 1970 J. W. Phillis
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 or otherwise,
without the prior permission of Pergamon Press Ltd.
First edition 1970
Reprinted 1974
Library of Congress Catalog Card No. 71-102093
Printed in Great Britain by Biddies Ltd, Guildford, Surrey
ISBN 0 08 015558 8
FOR SIR JOHN C. ECCLES
PREFACE
THE invitation from Professor G. A. Kerkut to write this book came at a
particularly opportune time. The recent development of fluorescent histo-
chemical techniques for the detection of monoamines, and the rapid
progress in neuropharmacology that has followed the development of
microiontophoretic techniques of drug application, have contributed to
the dramatic advances in our understanding of synaptic pharmacology.
Indeed, the present decade may well rival in significance the previous major
era of the 1930's, during which the foundations of chemical transmission
were so brilliantly laid. It has been an exciting experience to observe,
participate in and now to chronicle, the development of neuropharmacology
during the past 10 years.
In this book I have attempted to analyse and record many of the
remarkable developments that have occurred during the past decade.
Reference is also made to earlier work which has retained its significance,
such as the experiments which established that acetylcholine is a trans-
mitter at neuromuscular and ganglionic synapses. In many instances I
have been able, through the generosity of my colleagues, to quote new
developments even before their final publication.
The compilation of this book has been greatly assisted by the appearance
of a number of excellent reviews and symposia. Reference to these sources
has usually been made at the beginning of the relevant sections, and I
would like to acknowledge my debt to the reviewers who have previously
brought the subject together.
It is assumed that the reader of this book will already have some under-
standing of the physiological properties of nerve and muscle cells. Further
knowledge of the electrical properties of excitable cells can be gained from
many sources. However, the accounts in Synaptic Transmission by Pro-
fessor H. McLennan and The Physiology of Synapses by Sir John Eccles
can be considered to be complementary to the present book.
During the writing of this book I have been greatly assisted by my
colleagues I. McCance, A. K. Tebêcis, D. H. York, P. C. Vaughan, G. A.
ix
X PREFACE
Bentley and L. B. Geffen who have criticized chapters and contributed
many valuable suggestions. I also wish to thank Miss D. Harrison and
Miss S. Woolley for their assistance with the illustrations; Mrs. J. Baillie
for her assistance with the bibliography; and Mrs. S. Browne, J. L. Deeker
and Miss C. M. Kinnane for their work in the preparation of the manu-
script.
J. W. PHILLIS
ACKNOWLEDGEMENTS
Grateful thanks are due to the following publishers and their editors
for their generosity in giving permission for reproduction of figures :
Science; The Rockefeller University Press; The Anatomical Society of
Great Britain and Ireland; Ada Physiologica Scandinavica; Macmillan
(Journals) Ltd.; Japanese Journal of Physiology; S. Karger A.G.; The
Williams & Wilkins Co.; Cambridge University Press; The Journal of
Physiology; Elsevier Publishing Company; North-Holland Publishing
Company; American Journal of Physiology; Journal of Neurophysiology ;
Circulation Research.
XI
CHAPTER 1
INTRODUCTION
A. CONCEPTS
The concept that the nervous system is composed of discrete units or
nerve cells was initially proposed by His and Forel and then independently
by Cajal. After Waldeyer suggested the name "neurone" for nerve cells,
the theory of the independence of nerve cells became known as the neurone
theory. It was Cajal who, above all others, established that the functional
connections between nerve cells are effected by close contacts, and not by
continuity in a syncytial network, as proposed in the rival reticular theory
of Gerlach and Golgi. The name "synapse" was given to these functional
connections between nerve cells by Sherrington and it is with the details of
operation of junctions between nerve cells and between nerve cells and
effector cells that this book is concerned.
B. TRANSMISSION ACROSS THE SYNAPSE
The first speculations on the nature of transmission across junctional
regions were put forward during the last century when DuBois-Reymond
suggested that junctional transmission might be either chemical or elec-
trical and thus initiated the two rival hypotheses of chemical and electrical
transmission.
The next significant development occurred in 1904 when Elliott suggested
that sympathetic nerve impulses liberate adrenaline at the junctional
regions on smooth muscle, and a little later Dixon (1906) proposed that
parasympathetic nerve impulses release a muscarine-like substance. In
1914, Dale commented on the fidelity with which acetylcholine reproduced
the actions of parasympathetic stimulation, just as adrenaline did those of
stimulation of the sympathetic system. Dale also noted and differentiated
between the nicotinic and muscarinic actions of acetylcholine.
The experiments of Loewi (1921) demonstrated for the first time the
1
2 THE PHARMACOLOGY OF SYNAPSES
release of a chemical, "Vagustoff" (acetylcholine), during nerve stimula-
tion and showed that the vagus inhibited the heart by means of this release.
Cannon and Bacq (1931) subsequently showed that stimulation of the
sympathetic nerves caused the release of an adrenaline-like substance
which accelerated the heart.
A series of classical investigations (Feldberg and Gaddum, 1934;
Feldberg and Vartiainen, 1934; Dale, Feldberg and Vogt, 1936; Brown,
Dale and Feldberg, 1936), which will be described in more detail in sub-
sequent chapters, established that acetylcholine is the transmitter at skeletal
neuromuscular and ganglionic synapses. In 1935, Dale suggested an exten-
sion of the chemical transmitter hypothesis to account for excitation and
inhibition in the central nervous system.
Despite these findings the electrical hypothesis of synaptic transmission
in the central nervous system continued to have considerable support until
the advent of intracellular recording in 1951. However, the observations
made with this new technique were difficult to reconcile with the theories
of electrical transmission developed by Eccles and other scientists (see
Eccles, 1964), and the concept of chemical transmission at synaptic junc-
tions was generally accepted.
However, since the discovery of a special type of electrically transmitting
synapse in crayfish (Furshpan and Potter, 1959), electrical transmission
has been described at several junctions. These include the giant motor
synapses of the crayfish (Furshpan and Potter, 1959), in which the synaptic
membrane is an efficient electrical rectifier, ensuring one-way transmission.
The septal junctions of the giant axons in the longitudinal nerve cord of
some forms of Annelidae and Crustaceae allow transmission in either
direction, as these low resistance membranes do not possess any rectifying
properties (Kao and Grundfest, 1957).
Both chemical and electrical transmission of excitation have been
demonstrated in the large calciform synapses in the ciliary ganglion of the
chick (Martin and Pilar, 1963a, b).
Electrotonic transmission of excitation between adjacent nerve cells has
been demonstrated in various species. These include the two giant cells in
the segmental ganglia of the leech (Hagiwara and Mori ta, 1962). An exten-
sive study of electrotonic transmission between the spinal electromotor
neurones of Mormyrid electric fish has been reported by Bennett, Aljure,
Nakajima and Pappas (1963). In addition to the electrophysiological
evidence for electrical transmission, the authors noted that there was actual
INTRODUCTION 3
fusion of the dendrites in their histological preparations and not the usual
separation by a 200 Â cleft. At these presumed electrical transmitting areas
there were none of the special features of chemically transmitting synapses,
such as vesicles and mitochondria.
Washizu (1960) has presented another example of electrical trans-
mission, that between motoneurones in the amphibian spinal cord.
Recording intracellularly from an isolated toad spinal cord, he found that
20 % of the motoneurones could be excited by stimulation of either of two
adjacent ventral roots. The responses were not identical as there was always
a latency difference of at least 0 · 6 msec between the two routes of excita-
tion. As there was no prepotential associated with excitation from either
ventral root, Washizu concluded that the later response was probably the
result of ephaptic transmission through dendritic junctions between moto-
neurones. Although subsequent investigations have shown that the
excitation is preceded by a graded depolarization (Kubota and Brookhart,
1962; Katz and Miledi, 1963; Grinnell, 1966), which led Kubota and
Brookhart (1962) to attribute it to a synaptic excitatory action by motor-
axon collateral onto motoneuronal dendrites, it seems that Washizu's
original explanation is more probable (Grinnell, 1966).
An inhibitory synapse, which operates by electrical transmission, has
been described in the Mauthner cells of fish (Furukawa and Furshpan,
1963). By a detailed study with intra- and extracellular recording from
Mauthner cells it has been established that activation of the fine nerve
fibres around the axon hillock region applies a hyperpolarizing current to
the axon hillock, thus effecting an inhibition. It has been suggested that
the intracellular hyperpolarization is a passive result of the generation of
an external hyperpolarizing potential around the axon hillock. This extra-
cellular potential has been attributed to the failure of the impulse to invade
the terminal portions of axons which surround the axon hillock. These
terminals become sources for extracellular current flow to the more
proximal, excited, zones of these fibres.
C. IDENTIFICATION OF CHEMICALLY AND ELECTRICALLY
TRANSMITTING SYNAPSES
A distinction between chemically and electrically transmitting synapses
can be based on their morphological, physiological and pharmacological
properties. Ideally, intracellular electrodes must be inserted into both pre-
4 THE PHARMACOLOGY OF SYNAPSES
and postsynaptic elements, as has been possible with the crayfish giant
synapse (Furshpan and Potter, 1959) and chick ciliary ganglion (Martin
and Pilar, 1963a, b). Where the presynaptic element is very small in rela-
tion to the postsynaptic structure, as at neuromuscular junctions, chemical
transmission is obligatory. At amphibian neuromuscular junctions, the
maximum current that could be provided by the presynaptic element
would fail by a factor of hundreds to produce the transfer of charge of
2-4 x 10"9 coulombs that Fatt and Katz (1951) calculate to occur across
the uncurarized endplate membrane.
However at many junctions where it is technically not feasible to insert a
microelectrode into the presynaptic element, it may be difficult to dis-
tinguish between the two types of transmission. In a recent paper, Rail,
Burke, Smith, Nelson and Frank (1967) discuss the evidence for the genera-
tion of monosynaptic excitatory postsynaptic potentials in motoneurones
by dorsal root afférents presented in a preceding series of papers (Smith,
Wuerker and Frank, 1967; Nelson and Frank, 1967; Burke, 1967; Rail,
1967). They conclude that for distal dendritic input locations, the various
types of synaptic mechanism are virtually indistinguishable, and that for
somatic and proximal dendritic input locations, mechanisms involving
either electrical transmission (through a low resistance electric coupling
between the afferent fibres and the motoneurone) or chemical transmission
would be consistent with their evidence.
The criteria for distinguishing chemical and electrical transmission have
previously been reviewed by Eccles (1964) and will be discussed only to a
limited extent in the present account.
1. Chemical Synapses
In the classical type of chemically transmitting synapse, the arrival of an
impulse at the presynaptic terminal evokes a release of a chemical mediator
which, after diffusion across the synaptic cleft, attaches to receptors on the
postsynaptic membrane. At excitatory junctions, the transmitter increases
the permeability of the postsynaptic membrane to sodium and potassium
ions (Takeuchi and Takeuchi, 1960a), thereby causing a depolarization or
excitatory junctional potential. At inhibitory synapses, the transmitter
increases the permeability of the postsynaptic membrane to chloride and/or
potassium ions, stabilizing and frequently hyperpolarizing the postsynaptic
membrane. Hyperpolarizing potentials are designated as inhibitory junc-
tional potentials.