Download Chemical Nature of Synaptic Transmission in Vertebrates

PHYSIOLOQICAL REVIEWS
Vol. 54, No. 2, April 1974
kinted
in I7.S.A.
Chemical Nature of Synaptic
Transmission in Vertebrates
K. KRNJEVIC:
Department
of Research
in Anaesthesia,
McGill
University,
Montreal,
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...............................................
I. General
Introduction.
......................................................
... Historical.
.............................
B. Identification
of chemical
transmitters.
......................................................
I I. Acetylcholine
...................................................
... Introduction.
.................
B. Acetylcholine
in skeletal
neuromuscular
transmission.
1. How does ACh act?. ..........................................
.....................................
2. Kelease of ACh in muscle.
.....................
C. Acetylcholine
in transmission
to smooth
muscle.
D. Inhibitory
action of ACh on heart ..................................
............................
E. Acetylcholine
in ganglionic
transmission.
.....................................................
1. Release.
2. Actions
of ACh on ganglion
cells. ...............................
.......................
F. .4cetylcholine
in central
nervous
transmission.
1. Excitatory
action of ACh. ......................................
2. Central
inhibitory
actions
of ACh .................................
G. Other
evidence
indicating
cholinergic
transmission
in CNS ............
..........................................
H. Acetylcholine
receptors.
.............................
1. Cation
movements
and L4Ch system.
III.
Amino
-4cids. ......................................................
.......................................................
A. General.
..........................................
B. Inhibitory
amino acids.
1. r-Aminobutyric
acid. ..........................................
.....................................................
2. Glycine.
..........................................
C. Excitatory
amino acids.
1. Excitatory
actions
of dicarboxylic
amino acids. ....................
........................................
2. Other
relevant
evidence
....................................................
IV. Catecholamines.
...................................................
*4. Introduction.
..........................
B. Catecholamines
in peripheral
transmission.
........................
1. Norepinephrine
actions
on smooth
muscle.
..............................
2. Catecholamine
actions
on ganglia.
..............................
C. Catecholamines
in CNS transmission.
............................................
1. Depressant
actions.
2. Excitatory
actions
of catecholamines
in CNS ......................
3. Function
of catecholamines
in CNS. .............................
Monoamines .................................................
V. Other
..................................
.4. 5-Hydroxytryptamine
(serotonin)
.................................................
1. Introduction.
.................................
2. Is 5-HT
a central
transmitter?.
............................................
B. Imidazole
derivatives.
...................................................
1. Histamine.
.......................
2. Imidazole
acetic acid and other derivatives.
Canada
April
VI.
VII.
SYNAPTIC
Some Other
Putative
Transmitters.
...................................
A. ,4denosine
derivatives
(adenosine-5’-triphosphate)
....................
1. In CNS ......................................................
2. At periphery.
................................................
B. Ergothioneine
...................................................
C. Polypeptides....................................................
1. Substance
P. .................................................
2. Other
polypeptides............................................
3. Antidiuretic
hormone.
.........................................
Some Special
Aspects
of Chemical
Transmission.
........................
-1. Chemical
transmission
in retina.
...................................
B. Chemical
transmission
at sensory
endings.
..........................
1. Carotid
body chemoreceptors.
..................................
2. Electrical
receptors.
...........................................
..................................
C. Presynaptic
actions
of transmitters
1. Acetylcholine.
................................................
2. Presynaptic
action of neurotransmitter
amino acids. ................
.........................
3. Other
agents acting presynaptically.
D. Denervation
supersensitivity.
......................................
1. Muscle
fibers.
................................................
2. Denervation
supersensitivity
of nerve cells. ........................
E. Role of glial cells. ...............................................
General
Consideration
about Synaptic
Transmission.
....................
A. Origin
and nature
of chemical
transmitters.
.........................
...........................................
B. Electrical
transmission.
C. Chemical
differentiation
in nervous
system.
.........................
GENERAL
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INTRODUCTION
A. Historical
That nerves may exert their effects by secreting specific agents is a very ancient belief. Until the 18th century,
nerves were thought
to produce
movements
spirits” ;
by conveying
from the brain to muscles a special “nerve fluid” or “animal
according
to a prevalent
opinion,
these “animal
spirits”
were distilled
from blood
by the heat generated
in the heart (cf. 334). When animal
electricity
was discovered and nerves were shown to be electrically
excitable,
it was natural
to suspect
that the “nerve
fluid”
might be identical
with electricity
(53 1, 840, 919). After
all, the discharges
of electric organs were indistinguishable
from electricity,
and
even muscles generated
electrical
currents
that could excite nerve fibers (357,
358, 877, 896). Thus in 1863 Krause (725) placed much emphasis on the resemblance between
the electroplaque
and the muscle end plate-where
he correctly
observed
the nerve ending
outside the muscle fiber membrane-and
suggested
that the muscle fiber was excited by an electric discharge
analogous
to that of the
electric organ.
This idea was accepted
by Hermann
(564) and Kiihne
(776), and later by
many other electrophysiologists
(cf. 83l), reaching
a peak of popularity
in the
middle
1930’s (368). On the other hand, du Bois-Reymond,
who discovered
the
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VIII.
I.
VERTEBKATE
I974
420
K.
KRNJEVIC
Volume
54
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action current
(or “negative
variation”)
of nerves, critically
examined
this hypothesis in a long and somewhat
obscure article in 1874 (359), which is often
cited as the first to propose that the nerve ending excites muscle by secreting
a
chemical
transmitter
(254, 295, 373, 776, 1061). But this interpretation
is misleading: du Bois-Reymond
believed
that the nerve terminal
penetrates
beneath
the
muscle membrane,
and he was really discussing
the mechanism
of intracellular
transmission
between the end plate and the contractile
substance of the muscle.
In his opinion,
the nerve impulse
was a self-propagating
“molecular
reaction,”
of which the “negative
variation”
was probably
only an external
manifestation;
at the end plate this “molecular
reaction”
would spread directly to the immediately
contiguous
contractile
substance.
However,
he added that if the nerve ending
remained
outside the sarcolemma,
the mechanism
of neuromuscular
transmission
could only be electrical.
This article thus can hardly be seriously held as proposing
the chemical
hypothesis in the modern sense. It is significant
that its complex argument has also been quoted in support of the electrical
hypothesis
(564, 83 1).
Junctional
transmission
could not become the subject of meaningful
investigations, or even speculation,
before general acceptance
of the neuron theory (cf. 449,
established
the existence
of a protoplasmic
discontinuity
1021, 1226) securely
across which the neural signal must be carried. At the turn of the century,
there
was little discussion of junctional
transmission;
it was simply and noncommittally
accepted
as an obscure physical
process (cf. 450, 1073, 1086). Thus, although
Elliott
first proposed
in 1904 (395) that adrenaline
(epinephrine),
the active
principle
in extracts of the suprarenal
medulla
(952, 1150), might be the chemical
stimulant
released by sympathetic
nerve endings, and shortly after Dixon
(343)
presented
some evidence
that vagal inhibition
of the heart is mediated
by a specific chemical
and suggested more generally
that “excitation
of a nerve induces
the local liberation
of a hormone
which causes specific activity
by combination
with some constituent
of the end-organ,
muscle or gland”
(344), the new hypothesis was almost completely
ignored
(cf. 77, 292, 532), curiously
enough even by
Elliott himself in his subsequent
publications
(cf. 396). It may have been kept in
the background
by Langley’s
(797) strong advocacy of the idea that specific “receptive substances”
are situated at the junction
between nerve and effector organ,
which are activated
by the arrival
of impulses
at the nerve ending,
and whose
characteristics
determine
the quality
of the effector response. Langley’s
scheme
required
neither
chemical
transmission
nor specific transmitters,
being in some
respects the converse of what has been called ‘CDale’s principle”
(371, 373).
Although
in 1912 Weiland
(1238) had obtained
evidence
that the isolated
gut releases an agent that causes intestinal
muscle to contract [this was later identified by le Heux (8 10) as choline]
chemical
transmission
was really launched
as a
widely
accepted
working
hypothesis
and the subject of systematic
investigations
by Loewi’s
discovery
in 1921 of “Vagustoff’
in fluid perfusing
the frog’s heart
(835). The active substance was shown to be acetylcholine
(ACh) (836), which was
already known to have a particularly
powerful
biological
action (293, 6 16). Acetylcholine was then found in extracts of the spleen (296) and in fluid perfused through
sympathetic
ganglia
(426, 429, 699, 847), and good evidence
was obtained
that
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1974
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ACh is the transmitter
at the junction
between motor nerves and skeletal muscle
(172, 297). Later studies on the sympathetic
postganglionic
transmitter
essentially
confirmed
Elliott’s original
hypothesis,
but the active agent released by adrenergic
nerve endings proved to be norepinephrine
rather than epinephrine
(198, 1057,
1215, 1216).
An electrophysiologist
was one of the first authors to suggest that central synapses may operate by chemical transmission
[ 10 yr before the publication
of Dale’s
well-known
article (294)] : in a review of studies on inhibition
written shortly after
Loewi’s
discovery,
Adrian
(6) in 1924 discussed the possibility
that inhibition
in
the central nervous system (CNS) might be caused by an inhibitory
substance;
he
also noted prophetically
that the increase in cardiac demarcation
current observed
during inhibition
“might
well be due to an altered membrane
permeability
of the
surface membrane
to certain ions.” However,
Adrian clearly favored a mechanism
of inhibition
by a Wedensky
type of block, partly because of his own and Keith
Lucas’ observations
on decremental
conduction
in nerves. Most electrophysiologists
were even more reluctant
to believe that a chemical
process of transmission
could
explain
the rapid transfer of signals in the CNS (368, 369, 404, 460, 475, 842).
A radical change in attitude
came only about 20 yr ago, after the introduction of intracellular
microelectrodes
in studies of synaptic
transmission
in muscle
(424), the CNS (167, 1271), sympathetic
ganglia (938), and intestinal
smooth muscle ( 176). The main considerations
that led Eccles (370) to change his views and
adopt the chemical
hypothesis
are essentially
summarized
by these two questions:
How can a minute
nerve ending generate
enough current
to excite the much
larger postsynaptic
cell? What purely
electrical
mechanism
can account
really
satisfactorily
for postsynaptic
inhibition?
Without
some evidence
as to the nature
of the postulated
transmitters,
a
strong advocacy
of the chemical
hypothesis
of central synaptic
transmission
may
have seemed somewhat
arbitrary.
But it was soon vindicated
by the discovery that
certain spinal cells innervated
by recurrent
branches of motor axons are strongly
excited by ACh and that the synaptic
activation
of these cells is enhanced
by
anticholinesterases
and blocked
by ACh antagonists
(375, 376).
On the other hand, it was clear that ACh could not be the main excitatory
or
inhibitory
transmitter
acting on motoneurons,
though little further
progress was
possible without
more satisfactory
methods of testing active substances. The introduction of the microiontophoretic
technique
(325, 925) in studies of central neurons
(268-269)
was therefore
an advance
of considerable
significance,
since it now
became possible to examine
the effects of even very brief applications
of active
chemicals
to individual
cells, in situ. However,
even as recently
as 1965, one of
the principal
experts in this field was quoted as saying that the main evidence for
chemical
transmission
in the CNS was morphological
( 105 1). But subsequent
shifts of opinion
have led to a wide acceptance
of the idea that excitatory
and
inhibitory
amino acids as well as the better known peripheral
transmitters-ACh
and catecholamines
-are
probably
transmitters
at various
central
synapses, although
there is still only suggestive evidence
available
for most pathways.
The recent great advances in this field thus have resulted from the extensive
422
K.
KRNJEVI(?
Volume
54
use of microelectrode
techniques
(both intra- and extracellular)
as well as from
the enormous
development
and refinement
of biochemical
and histochemical
techniques
permitting
ever more precise investigations
on the cellular
and subcellular
localization
of possible transmitters,
their metabolism
and liberation,
and
the identification
and properties
of essential enzymes or receptors
(46, 80, 113,
202, 229, 291, 403, 464, 513, 549, 582, 621, 661, 710, 717, 902, 1036, 1211, 1264).
They have been greatly helped by the parallel development
of studies on synaptic
transmission
in invertebrates
(446, 48 1, 1160).
of Chemical
Transmitters
The accent in this review is principally
on the different
kinds of transmitters
in vertebrates
and the variety of mechanisms
by which they operate. No attempt
is made to analyze
exhaustively
the transmitter
mechanisms
of all the known
central and peripheral
junctions.
The criteria
by which transmitters
are identified
have often been listed and
discussed in detail: for some recent sensible views on this subject, the reader is
referred
to the articles or monographs
by Werman
(1250), McLennan
(890), and
Phillis
(983). To prove that a substance
is a transmitter
or the transmitter
at a
particular
junction
requires
the demonstration
that its action on the postsynaptic
cell is in every respect identical
with the synaptic action and that it is released in
adequate
amounts by activity of the presynaptic
nerve endings. Such a complete
proof is not available
for any postulated
transmitter,
not even at the neuromuscular
junction
(in vertebrates
or invertebrates),
which approaches
most closely to this
ideal. Although
it is usually
assumed that only one transmitter
is released at a
given junction,
it is conceivable
that two or more substances having significantly
different
actions may be released, in which case the criterion
of identity
of action
(1250) could not be easily applied.
In practice
any substance that is a normal
constituent
of nervous tissue and
has a strong excitatory
or inhibitory
action on nerve or muscle cells is potentially
a transmitter:
the probability
that it is a transmitter
increases with the amount of
supporting
information
about the characteristics
of its action, its metabolism
and
turnover
in the tissue, its liberation
during activity, and the possibility
of blocking
synaptic
transmission
by inactivating
postsynaptic
receptors with either an excess
of the supposed transmitter
or some more or less specific antagonist.
The degree of general acceptance
of a newly postulated
transmitter
depends
not only on the amount
and quality
of the available
information,
but also on
whether
it conforms
to current
views about the characteristics
of transmitters.
Excessive emphasis tends to be given to certain arguments
that later turn out to
be of little or no significance.
For example, many opponents
of the
were convinced
that a chemical
process could never be fast enough
synaptic
transmission
because of the slowness of diffusion
(368).
based on a serious misunderstanding
of the kinetics of diffusion
distances that was not entirely excusable since this topic had been
chemical
theory
to account for
This view was
over very short
very lucidly dis-
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B. Zdent$cation
April
1974
VERTEBRATE
SYNAPTIC
TRANSMISSION
423
II.
-4CETYLCHOLINE
A.
jntroduclion
Ever since Dale’s (293) description
of the effects produced
by choline esters
on various preparations,
it has been customary
to classify the actions of ACh as
nicotinelike
on the one hand, or muscarinelike
on the other. Nicotinic
actions are
typically
quick in onset and short lasting; they are blocked by an excess of nicotine
or by curare and curarelike
agents. By contrast, muscarinic
actions tend to be slow
in onset and prolonged;
they are blocked by atropine
and related compounds.
In general,
the parasympathetic
system acts on its effector organs by muscarinic
transmission,
whereas nicotinic
actions are seen characteristically
at the
skeletal neuromuscular
junction
and in autonomic
ganglia;
but ACh may act in
both ways on the same cell, as in sympathetic
ganglia.
This classification
has also
proved useful for distinguishing
cholinergic
actions in the CNS: however,
as seen
below, many neurons
show mixed effects that are not compatible
with such a
simple scheme. Systematic
studies of nicotinic
and muscarinic
agents (cf. 14, 65,
973, 1085) suggest that the two classes of substances interact
with distinct membrane receptors,
which are activated
by different
portions
of the ACh molecule.
The nicotine
receptors
apparently
react with the carboxyl
side of ACh and the
muscarine
receptors with its methyl side (2 16). The effects produced
by the activated receptor may be either excitatory
or inhibitory.
The character
of the receptor
seems to depend principally
on its situation
(the type of cell on which it is found),
but more than one type of receptor can be present on the same cell: for example,
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cussed by A. V. Hill in 1928 (472). S imilar misconceptions
are no doubt obscuring
our present thinking.
Fortunately
throughout
the animal kigdom nervous tissue appears to contain
relatively
few substances that have powerful,
rapid, and reversible
actions on nerve
cells. And since most nerve cells are not equally sensitive to all naturally
occurring
excitatory
or inhibitory
agents, the task of identifying
possible transmitters
is not
so formidable
as it might have been if every species or class had its own variety of
neurotransmitters.
In fact, certain
substances seem to be used as transmitters
through
all the phyla where chemical
transmission
has been demonstrated
with
any certainty
(446,48 1) : ACh, dicarboxylic
amino acids, short-chain
omega-amino
acids, dopamine,
and 5-hydroxytryptamine
(5-HT)
are the putative
transmitters
in animals as varied as vertebrates,
molluscs,
arthropods,
and annelids.
But the
way in which they are used at different
sites or in different
phyla are strikingly
and unpredictably
varied. Hence, although
it is instructive
to know that a certain
agent is probably
the transmitter
at a given junction,
until there is a better understanding
of the principles
underlying
the chemical
specificity
of various parts of
the nervous
system of different
animals,
one cannot argue by analogy
that the
same agent is necessarily
the transmitter
at other junctions
in the same species or
in a corresponding
system of another
phylum.
424
K. KRNJEVIC
Volume
54
sympathetic
ganglion
cells (380) and spinal Renshaw
cells (283) have both nicotinic and muscarinic
receptors,
whereas depolarizing
and hyperpolarizing
effects
of ACh can be elicited
at different
sites on some neuroblastoma
cells (929). A
change of innervation
can alter the receptor properties
(795).
B. Acetylcholine
in Skeletul Neuromuscular
Transmission
1. How does ACh act?
After the first demonstration
that normal
skeletal muscle can be excited by
close-arterial
injections
of ACh (172), the most significant
developments
have been
the discovery
that ACh greatly
increases the end-plate
membrane
conductance
(424, 1153, 1154). S ince the frog end-plate
potential
or current has a reversal level
close to 0 [actually
at about
- 15 mV, according
to Fatt and Katz (424), de1
Castillo and Katz (323), and Takeuchi
and Takeuchi
(1155)], it was first assumed
that ACh made the membrane
freely permeable
to all ions (424); on closer analysis,
however, the ACh-activated
membrane
was found to be permeable
only to cations,
the ratio of Na conductance
to K conductance
(GNa/GK)
being 1.29 (1155). The
reversal level is similar in frog tonic fibers (184) and possibly in mammalian
muscle
(cf. 51).
No systematic
comparison
appears to have been made between the reversal
levels for the action of applied
ACh and for the end-plate
potential
observed in
the same muscle fiber. However,
the similar values (near - 15 mV) obtained
in
different
experiments
suggest that these two reversal levels are identical,
at least
when ACh is applied to the immediate
junctional
region (323, 364, 424, 433, 855,
115 1, 1152, 1155). The same remarkably
constant reversal level is also seen when
the membrane
receptors are activated
by different
cholinomimetic
agents or when
they are partly blocked by curare (364, 433, 1155). It does not appear to be altered by tetrodotoxin
(433, 677).
These observations
suggest that the activated
ACh receptors do not open up
separate Na+ and IS+ channels.
However,
the end-plate
current
has a different
time course when measured
at membrane
potentials
close to the Na+ equilibrium
level (about +50 mV) or the K+ equilibrium
level (about
- 100 mV) (466), and
under these conditions
it shows a differential
action of procaine
and other local
anesthetics
that prolong
the end-plate
potential
(320, 850, 851). This seemed to
indicate
that independent
channels are responsible
for movements
of Na+ and K+
[like those involved
in the generation
of the spike (574)] and that the Na+ channels
are particularly
sensitive to local anesthetics.
However,
it is more likely that the
interaction
between the receptors
and ACh or procaine
is itself a function
of the
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This has been the most extensively
studied transmission
process, and it is the
only one for which we have almost conclusive
evidence with regard to the identity
of the transmitter
(ACh)
and its mechanism
of action (295, 326, 423, 549, 550,
612, 670, 671, 771).
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1974
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425
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membrane
voltage
(7 19, 720, 856, 857, 1125, 1126). The situation
is quite complex: the effects of different
local anesthetics,
such as lidocaine
and procaine,
are
by no means identical
(320), and it appears that in the presence of local anesthetics
postsynaptic hyperpolarization
reduces the quanta1 content of the end-plate
potential (85 1) as it does in the presence of excess K+ (1156).
The reversal level for the action of ACh is not totally invariable.
An increase
in external
Ca 2f lowers the G&Gg
ratio at the end plate by selectively
reducing
AG,, (1152).
The depolarizing
action of ACh (and other cholinomimetics)
on
extrajunctional
receptors
in normal
muscle (cf. 899, 432) and on all receptors
in
denervated
muscle has a relatively
negative
reversal level (at about
-40 mV),
consistent with a GNa/GK ratio of on1.y 0.60 (433, though cf. 853).
Separate
nicotine
and muscarine
receptors
are not likely to be present in
muscle since curare
and atropine
do not specifically
antagonize
nicotinic
and
muscarinic
agents respectively
(854). It is curious that atropine
makes the reversal
potential
for the end-plate
potential
more positive but leaves unaltered
the reversal level for the action of applied
ACh (855), particularly
since atropine
depresses equally
both types of end-plate
responses (100). A possible explanation
is
that atropine
selectively
reduces the relatively
large AGNs of the junctional
receptors, but has the same action on AG Na and AGK at the extrajunctional
sites. Like
procaine
(85 1 ), atropine
may also cause the release of ACh to become sensitive
to postsynaptic
currents.
A very promising
new technique
has been introduced
recently
by Katz and
*Wiledi (682) for the study of the molecular
events elicited in the end-plate
membrane by ACh. The membrane
potential
changes induced
by single molecules
of
ACh may be revealed
by a spectral analysis of the ‘%hot” noise recorded
during
continuous
applications
of ACh. The results suggest that the voltage fluctuations
are produced
by elemental
increases in conductance
of about 0.1 nmho lasting 1
ms. If this interpretation
is correct, only 1000 molecules
of ACh are needed to
produce
the quanta1
responses observed
electrophysiologically
(see below).
Another, somewhat
unexpected,
feature
of interest is that molecules
of carbachol
appear to evoke much briefer changes in conductance.
According
to more recent
experiments
(Katz and Miledi,
personal
communication)
the elemental
conductance changes produced
by other cholinergic
agonists are also relatively
brief; this
may explain
the lower efficacy of various cholinomimetics
(cf. 65). The failure to
observe any effect of neostigmine
on the duration
of the elemental
action of ACh
shows that this is largely independent
of cholinesterase
activity. How the activated
ACh-receptor
alters the membrane
permeability
is still mostly a matter of speculation (367).
Summary. ACh depolarizes
skeletal muscle by raising the cation conductance
of the end-plate
membrane,
with particular
emphasis on GNa, SO that GNJGK
is
1.3 (reversal
potential
- 15 mV). Extrajunctional
receptors,
whose density may
vary seasonally,
activate
the cation conductance
SO as to give a GNa/GK of only
0.6 (reversal potential
-40 mV). The balance of evidence suggests that ACh does
not open up separate Na+ and K+ channels in the membrane.
According
to studies
of the electrical
noise generated
by ACh, the unitary conductance
change produced
-426
K.
KRNJEVIC
rby single molecules of ACh lasts about 1 ms, independently
tivity; other cholinergic
agonists evoke even briefer unitary
account
for their lower efficacy.
Volume
of cholinesterase
events, which
54
acmay
2. Release of AC% in muscle
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Acetylcholine
is manufactured
by the acetylation
of choline.
This process
requires
a specific enzyme,
cholineace tyl transferase,
found inside certain
nerve
cells and their terminals
(presumably
only, or at least mainly,
in those that are
cholinergic)
and acetyl-CoA,
produced
by mitochondria.
Choline
is a normal
constituent
of extracellular
fluid, from which it is taken up by nerve endings, by a
mechanism
specifically
blocked by hemicholinium.
A further
important
source of
choline
is made available
by the rapid hydrolysis
of released ACh through
the
action of the acetylcholinesterase
highly concentrated
at cholinergic
junctions
[for
extensive recent reviews see Potter (1008) and Hebb (548)]. The ACh stored in
nerve endings
is released continually,
as a spontaneous
process, and at a much
accelerated
rate during
depolarization.
The released ACh can be detected
by
chemical
techniques
or bioassay (total release) or by the changes in potential
that
it evokes at the muscle end plate (quanta1 release).
a) Total release. The original
observation
of a release of ACh induced
by
indirect
stimulation
(297) has been confirmed
repeatedly
(149, 399, 746, 1007,
1142). It has been claimed
that an undiminished
amount of ACh is obtained
by
stimulating
long-denervated
muscle, so that ACh cannot be released mainly from
nerve endings
(543) ; however,
these results could not be confirmed
by several
groups of investigators
who have attempted
to repeat the experiment
(15, 149, 768,
1134).
The isolated phrenic nerve-diaphragm
preparation
has been particularly
useful for studies of release, because it is thin enough to permit reasonable
oxygenation
and quick outward
diffusion
of ACh, the total number
of nerve endings is known,
and there is plenty of information
about its electrophysiological
properties.
Using
classical methods of bioassay, Krnjevic
and Mitchell
(746) were able to show that
the mean quantity
of ACh released per impulse by a phrenic nerve ending has the
same order of magnitude
as the minimal
amounts of ACh previously
found necessary to produce
depolarizations
comparable
to end-plate
potentials
(743, 898).
The validity
of these observations
was confirmed
by Potter (1007), who exposed
phrenic
nerve-diaphragm
preparations
to labeled choline
and obtained
similar
yields of [14C]ACh when he stimulated
the phrenic
nerve, and also by Schmidt
et
al. ( 1076), who developed
a technique
combining
pyrolysis
and gas chromatography to prove that the released material
is indeed ACh.
Such good quantitative
agreement
between
ACh release and the amounts
required
at the junction
seemed to complete the evidence that ACh is the mediator
of neuromuscular
transmission.
Unfortunately,
on closer examination,
it is clear
that some of these observations
cannot yet be explained
by such a simple interpretation.
For example,
the leakage of ACh in resting muscle (908, 1007, 1142) is
much too great to be accounted
for by the quanta1 release causing the spontaneous
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miniature
end-plate
potentials
(see below) (828). Mitchell
and Silver (908) further
observed
that this leakage is very much less sensitive than the quanta1 release to
changes in external
Kf concentration
(and also responds differently
to a lowering
of temperature)
and that it is very little diminished
after chronic denervation
(see
also 1007, 1142), when quanta1 release is practically
abolished
(904). Although
the
quanta1
release may not contribute
more than l-2 % to the observed
leakage,
ACh is evidently
coming from the region of the nerve terminal,
since there is no
significant
release of ACh from the noninnervated
area of the muscle fibers (908).
This agrees with the fact that ACh and cholineacetyltransferase
are concentrated
at the junctional
area, both in the normal and the denervated
muscle (552, 1007).
The appreciable
amounts of enzyme that are found after denervation-sufficient
to
account for the observed ACh release -are
presumably
located in Schwann
cells
(cf. 537, 828, 904).
The high rate of leakage in resting muscle may take place from the terminal
by a diffuse, nonquantal
flux, which might be practically
undetectable
electrically
but could have a significant
effect on the sensitivity
of the end plate to ACh (683).
Alternatively,
ACh may be released -in
a quanta1 or nonquantal
manner-from
the axons of the motor nerve (cf. 832), although
ACh, like other ions, should not
readily diffuse out of the intact nerve trunk (cf. 730, 745). It is unlikely
that much
ACh could escape from the synaptic gap at the end plate without
acting on receptors. The junction
seems to be constructed
remarkably
efficiently
for the maximal
utilization
of any released ACh. The high density of receptors
[3 X 10’ per end
by Katz
plate (66, 1005), which is enough for > lo4 quanta of ACh as estimated
and the minuteness
of the synaptic
gap seem to ensure that
and Miledi
(682)
most of the ACh molecules
would collide with a receptor
site within a few ms of
their release.
If preterminal
or nonquantal
release accounts for a major portion of the ACh
collected
in experiments,
the reasonably
good agreement
between the amounts of
ACh released and the amounts required
for excitaticn
may be fortuitous.
Clearly,
further
evidence is needed on this point.
b) @antal release. Both the spontaneous
and the evoked release of ACh are
manifested
by quanta1 changes in membrane
potential
( 150a, 322, 326, 424, 828).
This is not a peculiarity
of muscle, since the quanta1 character
of transmitter
release
in ganglia and even at some central synapses is now well established
(777). Katz’s
original
hypothesis
that these quanta1 events are caused by the release of packets
of ACh has been confirmed
by subsequent
studies. It appears that these packets
consist of at least 1000 molecules
of ACh. They are released at a very low-and
usually random-rate
even from resting nerve endings;
however,
the probability
of release is enormously,
though
transiently,
increased
when an impulse reaches
the terminal
(326, 6 12, 669-67 1, 870). The frequency
of release is progressively
raised (along a steep logarithmic
slope) when the terminal
is depolarized,
whether
by an applied current or by excess K +*: this has led to the proposal
that the release
triggered
off by an action potential
is the direct result of the sharp, transient
depolarization
(829). The important
observation
that K+ potentiates the quanta1
release elicited by electrical
depolarization
(830, 1156) has recently been confirmed
428
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54
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and further
analyzed
by Cooke and Quastel (239). Another
interesting
finding
is
that the amount of ACh released at a given end plate is a relatively
simple function
of terminal
size (779). This seems to imply that the terminal
membrane
has a
rather constant density of release sites.
The release of ACh evoked by an action potential
is very much dependent
on
the presence of Ca2+ and is depressed by Mg2+ (321, 326, 440, 612, 637, 676, 678).
Katz and Miledi
(674, 681) have been able to show that end-plate
potentials
are
obtained
only when the nerve impulse
invades the nerve terminal;
the release
process is a separate event that takes place 0.75 ms or later (depending
on the
temperature)
after the arrival
of the spike (or brief focal depolarization)
(675,
679). A similar potentiating
action of Ca2+ can be demonstrated
when the nerve
terminals
are depolarized
by focal stimulation
in the presence of tetrodotoxin
(236,
678) or by excess KS- (236, 612, 794). Th e most plausible
explanation
for these
findings
is that Ca2+ enters the depolarized
nerve terminal,
and triggers off the
process of ACh release. A direct demonstration
of the entrance
of Ca2f into nerve
fibers as a result of depolarization
has been made with squid axons (53, 54). Although in their initial experiments
Miledi and Slater (903) failed to evoke a release
fibers of the squid ganglion,
of transmitter
by injections
of Ca2+ into presynaptic
similar,
more recent experiments
have produced
unequivocal
evidence that intracellular
injections
of Ca 2+ do cause a release of transmitter
(901 a). In addition
to
its immediate
effect in triggering
ACh release, intracellular
Ca2f by a residual
action
probably
contributes
significantly
to short-term
facilitation
of synaptic
transmission
(680, 1017).
The mechanism
of action of Ca 2f has not yet been explained.
The quanta1
release may involve the cooperative
action of four (346) or five molecules of Ca2+
( 1251) in the frog or three in the rat (794); alternatively,
according
to the most
extensive study to date (236), the probability
of release of a quantum
is a continuous function
of the amount
of Ca 2+ forming
a hypothetical
complex
inside the
nerve ending.
The following
simple scheme could explain
these observations.
The probability of release is reciprocally
related to the magnitude
of an internal
boundary
potential generated
by negative
charges fixed at the inner surface of the membrane
(cf. 211). As Ca2+ enters the terminal,
it is bound to the negative
charges;
the
boundary
potential
is progressively
reduced,
and the probability
of release is
correspondingly
raised. A similar mechanism
may account for the increase in K+
permeability
of spinal motoneurons
caused by intracellular
injections
of Ca2+ (740).
It is not clear whether
Mg2+ acts by competing
with Ca2f at sites of entry or of intraneuronal
binding.
Quastel et al. ( 1014) believe that some release may take place independently
of Ca2+ > but their evidence is not very convincing
in view of the large intracellular
stores of Ca 2f (200 > 8 11) that probably
contribute
to the release of ACh (126a) ;
these intracellular
stores of Ca2+ are not readily depleted
even by strong complexing agents (483). It has been suggested that Ca2+ may become fixed to, and so
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1974
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There is no need to discuss here in detail the role of vesicles in cholinergic
transmission.
The suggestion that quanta of ACh are released from vesicles helped
to explain
many features
of quanta1
transmission
(326), and it has not lost its
validity.
However,
it is still not supported
by very strong, direct evidence [though
compare very recent morphological
data (569a)]. Some correlation
has been found
between vesicle counts in nerve endings and efficiency
of release, at least under
some conditions:
for example, after treatment
with black widow spider venom (220)
or after intense activity (6 12). However,
Birks’ (112) finding that vesicle counts can
be greatly changed by the conditions
of fixation raises some doubts about the significance
of such counts. Another
serious difficulty
is that vesicles isolated from
nerve endings have consistently
been proved to contain ACh that exchanges only
verv. slowly with the relatively
free (cytoplasmic)
pool of ACh from which the more
recently
formed
(and therefore
more strongly
labeled)
ACh released
by nerve
stimulation
evidently
originates
(363, 863, 1037). It is significant
that chemical
transmission
becomes fully established
in the embryonic
ciliary
ganglion
before
synaptic vesicles appear in appreciable
numbers
(796). As pointed out by Ginsborg
(490), a quanta1 release could take place even from a nonvesicular
pool of ACh.
Acetylcholine
release has been much studied by observing
changes in amplitude of end-plate
potential
evoked by repetitive
stimulation
of the motor nerve
of the nerve endings (237(cf. 170, 322, 612) or more recently by focal stimulation
239, 677-679).
Although
this technique
can measure neither
the total release nor
the absolute
amount
of ACh acting on the end plate, it is the only direct way of
estimating
changes in the synaptically
effective release. It thus was used by Elmqvist and Quastel
(397) to estimate the total amount
of ACh available
for transmission by recording
end-plate
potentials
in the rat diaphragm
in the presence of
sufficient
hemicholinium
to block the synthesis of new ACh (cf. 113). This was
found to correspond
to nearly 300,000 quanta
[in the frog, a comparable
figure of
450,000 is obtained
by counting
the quanta released by black widow spider venom
(839)]. However,
the rapid fall in quanta1 content observed during tetanic stimulation (398) suggested that only a relatively
small fraction
of this total amount was
readily
available
for release, just as in sympathetic
ganglia
(cf. 113). It may be
noted that if a quantum
consists of only lo3 molecules
of ACh (682), 3 X lo5
quanta per terminal
are equivalent
to only 2-5 % of the ACh actually
present in
the muscle (552).
After a closer look at quanta1
release, Christensen
and Martin
(2 17) have
concluded
that repetitive
stimulation
leads to a reduction
in probability
of release
(assumed by previous authors to remain constant)
as well as in the available
store.
They point out that the probability
consistently
has a finite positive value, as would
be expected of a binomial
as opposed to a Poisson process.
Summary. The manufacture
of ACh in motor nerve endings and its release by
impulses are well established;
both processes are greatly reduced
by denervation
(any residual
release being probably
from Schwann
cells). Although
there is
reasonable,
order-of-magnitude
agreement
between
the amount
of ACh needed
for an appreciable
postjunctional
effect and what is released during motor nerve
stimulation
(in the phrenic nerve-diaphragm
preparation),
the rate of spontaneous
430
K.
KRNJEVIC
Volume
54
C. Acetylcholine
in Transmission
to Smooth Muscle
The structure
and electrical
properties
of smooth muscle have been studied
and reviewed
extensively
(88, 188, 195, 590, 591, 1182). The most characteristic
feature is the functional
coupling
between cells at areas where the separate membranes combine
to form a highly permeable
“nexus”
(337). Like the gap junctions
of the CNS, the nexus can be reversibly
uncoupled
under some conditions-for
The extent to which
the tissue behaves as a
example,
in hypertonic
solutions.
functional
unit is therefore
potentially
variable.
Another
feature of interest is that
an electrogenic
Na-K pump (1179) probably
contributes
significantly
to the resting potential
(205, 782).
The parasympathetic
actions of ACh on different
kinds of smooth muscle are
too complex for a systematic analysis in this review (for reviews cf. 299, 482, 485,
1074). One action, however,
the excitation
of intestinal
longitudinal
muscle, has
been much investigated
in recent years, so that there is substantial
information
for
a comparison
with muscarinic
effects observed in nerve cells.
Parasympathetic
nerves elicit a depolarizing
junctional
potential
that resembles the slow ganglionic
excitatory
postsynaptic
potential
(EPSP) in having a
very long latency and correspondingly
long duration
(484, 485) and in that it is
blocked by atropinealthough
the amount of atropine required
is lOOO-fold greater
than is needed to block the depolarizing
action of topically
applied ACh (485).
The depolarization
induced by parasympathetic
stimulation
or by the application of ACh induces a discharge
of spikes, but, as in most types of excitable tissue,
the spikes tend to disappear
if the depolarization
exceeds a certain level ( 144, 172,
186, 484). At the same time, there is a change in the shape of the spikes, which last
longer because the phase of repolarization
slows down (177, 186). This tends to
promote
repetitive
firing, especially
in pairs of spikes (177).
The action of ACh on this smooth muscle is thus in several respects similar to
its muscarinic
excitatory
action on some central neurons (749, 754). However,
the
most general opinion
is that ACh excites smooth muscle as it does skeletal muscle
by greatly increasing
the membrane
permeability
to cations (89, 144, 177, 178,
186, 570), and perhaps even anions (365). This opinion was originally
based largely
on an analogy
with the mechanism
of excitation
in skeletal muscle. In a recmt
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release is very much greater than would be expected from the electrically
observed
spontaneous
quanta1 release: one possible explanation
is that ACh is also released
by a nonquantal
process. Quanta1
release is a steep (logarithmic)
function
of terminal depolarization
and is independent
of Na+ influx through
the tetrodotoxinsensitive channels.
It is probably
triggered
by an influx of Ca2+, after a delay of
nearly
1 ms, by an action that may be analogous
to the increase in cation permeability induced
by intracellular
Ca 2+. Although
morphological
evidence
suggests
that ACh is released from synaptic vesicles by exocytosis, other experiments
indicate that only the most recently
synthesized
and probably
extravesicular
ACh is
released by stimulation.
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study, Bolton (144) found that ACh or carbachol
causes a maximum
depolarization to -9 mV. This was assumed to be close to the reversal level for the underlying change in ion fluxes, which gave a lOO-fold maximum
apparent
increase in
conductance.
This level was altered
as expected
by variations
in external
Na+
concentration,
but it was very insensitive
to changes of K+ or Cl-. The author
concluded
that the main action of ACh is to increase greatly the membrane
permeability to both Na+ and K+.
The muscarinic
excitatory
action in the gut thus seems to differ fundamentally
from the muscarinic
action on vertebrate
neurons, which is probably
initiated
by a
reduction
in K conductance
(500, 754, 1236). It is possible, however,
that this
difference
is more apparent
than real. The technique
used for measuring
membrane conductance
in the gut is indirect,
being based on the assumption
that the
smooth muscle always behaves as a linear core conductor,
so that the electrotonic
potential
evoked at a distance accurately
reflects changes in membrane
resistance
(144). But the electrical
coupling
through
the nexus connections
may be altered
by the conditions
of the experiment,
as in the comparable
systems of coupled cells
in the salivary epithelium
of insects (833) or in the crustacean
nervous system (965).
Loewenstein
(833) has shown particularly
that a small increase in internal
Ca2+
has a marked
uncoupling
effect. Since the excitatory
action of ACh on smooth
that this might
muscle is associated with an influx of Ca 2f (365), it is conceivable
reduce intercellular
coupling
sufficiently
to lower sharply the space constant and
Similar
complications
may explain
therefore
the apparent
membrane
resistance.
Hidaka
and Kuriyama’s
(570) observation
that the fall in resistance evoked by
ACh precedes depolarization
by about a second. Thus, the possibility
has not been
entirely
excluded
that, as in neurons,
the initial
effect of ACh in the gut is a reduction
in K permeability
[as is suggested by the prolongation
of spikes (cf. 177,
186)].
The depolarization
initiated
by ACh (through
a reduction
in GK) may itself
lead to a marked increase in conductance
to Na+, K+, and even Cl- (and probably
Ca”+). The observations
of a marked increase in 42K efflux from gut muscle under
the influence
of carbachol
(182, 365, 366) are often cited as evidence
that ACh
directly
increases the cation conductance;
however,
this K+ efflux tends to disappear in the absence of external
Ca 2+ (366) and it is very poorly correlated
with the
excitatory
action -according
to Burgen and Spero (I 82), 1000 times more ACh
is required
to augment
Kf efflux than to initiate
a contraction-which
appears to
indicate
a secondary
rather than a primary
increase in K permeability.
It would
seem premature
to decide that the muscarinic
excitatory
actions in smooth muscle,
on the one hand, and on central and ganglionic
neurons, on the other, are totally
different.
Summary. ACh probably
mediates
the parasympathetic
excitation
of smooth
muscle by a muscarinelike
action. According
to studies on intestinal
smooth muscle,
this depolarizing
action of ACh is associated with a large increase in K+ fluxes; but
it is not yet clear whether
a general increase in ionic or cationic
permeability
is
indeed the primary
action or a secondary
effect after depolarization
and the entry
of Ca2+.
432
D. Inhibitory
IS. KRNJEVIC
Volume
54
Action of ACh on Heart
E. Acetylcholine
in Ganglionic
Transmission
1. Release
The concentration
of a large number
of nerve endings in a very small volume
of tissue, which is moreover
readily
perfused through
its blood supply (426, 699,
847), has made the cat’s superior
cervical ganglion exceptionally
useful for investigations on the synthesis, storage, turnover,
and release of ACh (90, 113, 227-229)
(for a study on the amphibian
isolated ganglion
see 940). The released ACh is
normally
not taken up by the nerve endings.
It is hydrolyzed
by cholinesterase,
and about half the choline
thus formed is immediately
absorbed
into the nerve
endings by an active process that is blocked by hemicholinium-3.
This choline is
then resynthesized
into ACh. The most recently
formed
ACh is preferentially
released by stimulation
(227). Even when exogenous ACh is accumulated
(in the
presence of anticholinesterases)
it is probably
not taken up by the nerve endings,
since it cannot be released by preganglionic
stimulation
(683a).
Although
there is evidence
of a slow excitatory
process in ganglionic
transmission (800), the initial excitation
is mediated
by fast EPSP’s (with corresponding
spontaneous
miniature
junctional
potentials)
whose principal
features are similar
to those of the end-plate
potentials
(EPP’s) recorded
in muscle (12 l-l 24, 330, 409,
777, 871,938).
The EPSP’s have a quanta1 composition,
and the number of quanta
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Although
ACh has some complex
actions at various sites in the heart (for
example
138, 817) that cannot yet be simply explained,
the cholinergic
inhibitory
effect of the vagus on atria1 muscle is a well-established
muscarinic
action [readily
blocked
by atropine
(18, 474, 835)] w h ose mode of operation
is quite distinct.
Gaskell’s (474) original
finding that vagal stimulation
increases the atria1 demarcation current
was fully confirmed
by intracellular
recording.
Vagal impulses and
ACh have a clear hyperpolarizing
effect (183, 324). Further
studies by Trautwein
and his collaborators
revealed
a large increase in membrane
conductance
(1188)
and a reversal
level for the inhibitory
junctional
potential
at about - 100 mV
( 1187). These are the characteristics
of a typical chemical
inhibitory
process, such
as is seen in many central neurons
(see below), but it has proved to be quite exceptional
in being generated
solely by movements of K+ rather than Cl-. Trautwein
and Dude1 (1187) were able to show a clear dependence
of the reversal potential
on the external K+ concentration,
as would be expected of a process determined
by
a change in G, (964).
Summary. The inhibitory
effect of the vagus on the heart is mediated
by a
muscarinic
action of ACh. It is manifested
by a fall in membrane
resistance and a
hyperpolarization
with a highly negative
reversal level ( - 100 mV), sensitive to
changes in external
K +. It is therefore
very probably
due to a large increase in
K+ conductance.
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2. Actions of AC% on ganglion
cells
It has long been known that ganglionic
transmission
is blocked by an excess of
nicotine
(799), but there is now a good deal of evidence
that in addition
to the
rapid, nicotinic
mechanism
of cholinergic
transmission
there is a slower excitatory
process that appears to act on muscarinic
receptors, since it is blocked by atropine
(380, 427, 825, 867). Th e nicotinic
and muscarinic
actions of ACh in ganglia are
therefore
considered
separately.
a) Nicotinic actions. Fast ganglionic
EPSP’s can be mimicked
by direct applications of ACh or nicotine
( 12 1, 330, 492). Like the muscle EPP, they reverse at a
level between 0 and - 20 mV (121, 330, 705, 938, 1236). There is only indirect
evidence for a conductance
change during the fast EPSP (12 1), but ACh certainly
causes a large increase in conductance
(492, 706). The ganglionic
response differs
from the EPP mainly in having a substantially
longer active phase, possibly owing
to the absence of postsynaptic
acetylcholinesterase
(12 1, 938). In an illuminating
study of postganglionic
parasympathetic
neurons in the atria1 septum of the frog,
Harris et al. (536) were able to show that, as in muscle, the sensitivity
to ACh is
highest at the synapses, but the maximum
effect of ACh was much less than the
maximum
observed in muscle. Although
the fast excitatory
process in ganglion
is
nicotinic,
the most effective blocking
agents are not curare and its derivatives,
but
hexamethonium
and tetraethylammonium
(909, 97 1).
b) Muscarinic actions. Eccles and Libet (380) found that the slow components
of the ganglionic
response could be blocked with atropine.
Intracellular
recording
later demonstrated
a corresponding
slow EPSP, which is also sensitive to atropine
and is evidently
caused by a muscarinic
cholinergic
transmitter
(824, 825, 1184).
This EPSP has a very long latency (over 100 ms) and it can last for several seconds.
It is evoked particularly
effectively
by repetitive
stimulation.
The fast and slow
EPSP’s are generated
in the same cell and, at least in some cases, by the activity
of the same preganglionic
fibers.
The most interesting
aspect of this slow EPSP is that, like the comparable
muscarinic
excitatory
effect of ACh on cerebral
cortical neurons
(750, 752, 754,
763), it appears to be generated
by a special kind of transmitter
action. This was
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released by an impulse is a function
of the extracellular
Ca2: Mg2 ratio. In the frog
the quanta1 content of an EPSP appears to be in the order of 100, but individual
nerve endings probably
release only 2-3 quanta per impulse (940); in mammalian
ganglia,
only l-2 quanta
may be released by a single preganglionic
fiber, presumably
having several endings on a cell (124).
Summary. Most features of the synthesis, storage, and release of ACh in preganglionic
terminals
are similar
to the corresponding
processes in motor nerve
endings of skeletal muscle. Acetylcholine
is hydrolyzed
after release, and choline:
is taken up for the resynthesis of ACh. The newly synthesized
transmitter
is preferentially released. As in other systems, the release is dependent
on Ca2+ and blocked
but the number
of quanta released
bY Mg 2+; the EPSP has quanta1 characteristics,
per terminal
is very low.
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first suspected when Kobayashi
and Libet
(705) found that the slow EPSP recorded in the frog’s sympathetic
ganglion
is not associated with a decrease in the
membrane
resistance. Moreover,
the slow EPSP was diminished
by hyperpolarization and increased
by depolarization,
and it proved to be readily
blocked by certain metabolic
inhibitors
such as !2,4-dinitrophenol.
These features
seemed to
indicate
a depolarization
caused by a change in the activity of an electrogenic
ion
(possibly
Cl-) pump;
although
neither
ouabain
nor variations
in internal
or external Cl- had much effect on the EPSP (705). In further
experiments
by Nishi
an increase in resistet al. (941) and Kobayashi
and Libet (706) on frog ganglia,
ance was regularly
seen during slow EPSP’s, and there was a linear relation
between the change in resistance
and the amplitude
of this EPSP. Moreover,
the
muscarinic
depolarizing
action of ACh (revealed
after curarization)
had similar
anomalous
properties,
being abolished
or even reversed by strong hyperpolarization. Such a clear increase in resistance is not seen in mammalian
ganglia,
possibly
owing to the greater difficulty
of eliminating
the fast nicotinic
action.
Since the frog ganglion
cells show no evidence of anomalous
rectification,
the
increase
in resistance
during
the slow EPSP, the diminished
amplitude
of the
EPSP with hyperpolarization,
and its reversal at a highly negative
level are all
simply explained
by a reduction
in membrane
conductance
to an ion having
a
very negative
equilibrium
potential
(1236). Since the EPSP proved to be insensitive to changes in Cl- concentration,
Weight
and Votava
(1236) concluded
that a
reduction
in K+ conductance
(G,) was the most likely mechanism,
in agreement
with the independent
observations
on cortical
neurons
(500, 752, 754).
Arguing
against this idea, Libet (826) has pointed
out that the slow EPSP,
when it is reversed, has a much shorter time course than normal and, further,
that
this EPSP is highly susceptible
to block by metabolic
inhibitors.
An asymmetrical
reversal of synaptic potentials
is by no means uncommon
(cf. 38, 240 691) and it
can be explained
partly by a nonuniform
distribution
of the currents
or ions injected into the cell and partly by a voltage-sensitive
interaction
between transmitter and membrane
receptors
(cf. 7 19, 856, 857). Another
possibility
is that the
EPSP is followed
by a third, even slower synaptic process, having a different
mechanism (1237). Studies on cortical cells have shown that applications
of 2,4-dinitrophenol probably
cause a sharp increase in G ]Ec,which blocks the muscarinic
depolarizing
mechanism
particularly
effectively
(498, 500): a similar
action could
well explain the block of slow ganglionic
EPSP’s by metabolic
inhibitors.
According to Weight and Votava
(1237), the reversal level of the slow EPSP can be varied
by changing
the extracellular
K+ concentration,
as would be expected if the underlying process is indeed a fall in GK.
Summary. Ganglion
cells differ from skeletal muscle fibers in having well-defined functional
nicotine
and muscarine
receptors.
The former are responsible
for
the early fast EPSP evoked by preganglionic
stimulation.
When activated
they
cause a sharp rise in conductance
and depolarization-with
a reversal level between 0 and - 20 mV-presumably
due to a large increase in GNa and GK. These
nicotine receptors are readily blocked by hexamethonium.
The muscarine
receptors
are responsible
for the slow EPSP (lasting
several seconds), which is associated
April
1974
VERTEBRATE
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TRANSMISSION
435
with a rise in resistance, and has a highly negative reversal level, sensitive to changes
in K+. The simplest explanation
for these unusual features is that activation
of the
muscarine
receptors causes a fall in GI(.
F. Acetvlcholine
in Central Nervous
Transmission
1. Excitatory
action of ACh
a) Nicotinic actions. 1) ON RENSHAW
CELLS.
The main characteristics
of the excitation
of Renshaw
cells by activity of the recurrent
branches of motor fibers are
the very brief latency of onset of the discharge
and its very high frequency,
even in
response to a single stimulus
(375, 376, 452). The initial
peak frequency
is commonly in the order of 1000 set-l and is relatively
independent
of the intensity
of
the stimulating
volley, an increase of which tends mainly to prolong
the discharge
of the cell. This synaptic action can be almost completely
blocked by certain ACh
antagonists,
especially
by dihydro-beta-erythroidine
(376) and mecamylamine
(I 195).
Microiontophoretic
studies with ACh and related compounds
(117, 268, 269,
282) have shown that ACh has a very quick and rapidly reversible
excitatory
effect
on Renshaw
cells, which can be obtained
also with nicotine
and other nicotinic
agents; however,
the action of nicotine
is somewhat
slower in onset and it lasts
much longer, presumably
because nicotine
is not broken down by cholinesterases
[in the presence of anticholinesterases,
the effect of ACh is markedly
prolonged
(269)]. The most potent blocking
agents, in addition
to those mentioned
above,
are hexamethonium
and tetraethylammonium
(283). Tubocurarine
and related
agents are not only relatively
ineffective
as blockers, but they may even increase
excitability.
It is evident
that in their pharmacological
characteristics,
Renshaw
cells are
much more like sympathetic
ganglion
cells than muscle end plates (cf. 65); a
common
cholinergic
innervation,
by the very same motoneurons,
therefore
does
not preclude
quite distinct
postsynaptic
receptor
properties.
A further
similarity
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Many authors suggested that ACh might act as a transmitter
in the CNS as
well as at the periphery,
before any direct evidence became available
(cf. 294, 295,
425, 1265), although
Dale (295) was careful to emphasize
the importance
of ob-.
taining sound evidence before making any serious claims. The earliest suggestions
were prompted
mainly by the finding
of ACh and cholinesterase
in various parts
of the CNS and the observation
of changes in activity
induced
by injections
of
ACh. The first really decisive progress in the study of central transmitter
mechanisms came with the demonstration
that recurrent
branches of motoneurons
are
probably
cholinergic
and that they excite certain
interneurons
(Renshaw
cells)
by a nicotinic
action not unlike that seen in skeletal muscle (376). The evidence
for the existence of distinct Renshaw cells was recently comprehensively
reviewed
by Willis (1268).
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between ganglion
cells and Renshaw cells is that both also have well-differentiated
muscarinic
receptors.
So even in this case -which
is the paradigm
of the applicability of Dale’s principle
to central synapses (37 1, 373)-the
characteristics
of the
transmission
process are by no means fully determined
by the nature of the presynaptic fibers.
It is generally
presumed
that here, as in other nicotinic junctions,
the mode of
operation
of ACh is by an increase in membrane
permeability
to cations. But since
only very limited
intracellular
recording
has been possible from Renshaw
cells,
there is no reliable
evidence
about the membrane
potential
and conductance
changes induced
either by ACh or by the synaptic action.
The fact that the initial spikes evoked by a ventral root stimulus can be driven
at very high frequencies
and that they are not abolished
by even the strongest
postsynaptic
blocking
agents
has led to the suggestion that the initial firing may be
caused by electrotonic
transmission
(1252). The demonstration
by Quastel
and
Curtis ( 1013) that a prolonged
application
of hemicholinium-3
(HC-3)
blocks the
first spike does not prove conclusively
that even the first spike must be generated
by
ACh, since HC-3, in addition
to depressing
the synthesis of ACh (cf. 113), can
block impulses
in nerve fibers (454). On the other hand, there is no compelling
reason for supposing
that one should be able to block completely
every chemically
mediated
synaptic transmission
by specific antagonists.
The cholinergic
nature of the recurrent
branches of motor fibers is also indicated by evidence that antidromic
stimulation
of the ventral roots causes a release
of ACh in the spinal cord (778, 907), although
these observations
did not exclude
the possibility
that ACh was released from some other neurons or even from the
motoneuronal
cell bodies or ventral
root fibers (1072).
2) OTHER
CENTRAL
NICOTINIC
ACTIONS.
Since the introduction
of the microiontophoretic
technique,
ACh has been tested on a large number
of cells of many
different
kinds in all parts of the CNS. Many have proved sensitive to ACh [for
systematic reviews, see McLennan
(890) and Phillis (983, 984)], but so far almost
none has given responses strictly comparable
to those of Renshaw cells. The excitations are practically
never so rapid and so quickly
reversible,
although
some unusually sharp responses have been observed in the lateral geniculate
of the cat (988)
and in the brainstem
of the rat (155). In several areas the actions of ACh can be
reproduced
with nicotine,
and it is sometimes blocked quite effectively
by dihydrofl-erythroidine
-for
example,
in the medulla
( 1066), the lateral geniculate
(26 1,
988), the thalamus
(29), the cerebellum
(880), and the supraoptic
nucleus of the
hypothalamus
(63, 350, 351). Although
the most striking excitatory
actions of ACh
in the cortex are muscarinic
(see below), some nicotinic
excitations
have been observed in the cingulate
gyrus (732) or in very superficial
layers (1136). Nicotinic
excitations
as a rule have not been very easily reproduced
and authors are apt to
disagree
over the supposed
efficiency
of various
blocking
agents (cf. 253, 880).
Furthermore,
in almost no instance has it been possible to block convincingly
a
given synaptic input with a nicotine
antagonist.
One therefore
cannot with great
confidence
point to any central pathway,
other than the motor fiber collaterals,
as
very probably
cholinergic
and nicotinic.
Nevertheless,
it is clear that many cells in
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the CNS have comparatively
well-defined
nicotine-type
receptors,
which are predominantly
excitatory
when activated:
it would seem rash to dismiss them all as
nonspecific
and of no functional
significance,
particularly
in view of the difficulty
of stimulating
selectively
all the various pathways
that may be afferent to a given
cell.
Stlmmary. Although
some nicotinic
excitatory
actions of ACh have been observed in most regions of the CNS, the only well-defined
system is that of the spinal
motoneurons’
axon collateral,
the Renshaw cell synapse. The characteristic
feature
is a quick excitation
by nicotinic
agonists, which is rapidly
reversible
and is prevented by ganglionic
blocking
agents. Tubocurarine
and related compounds
are
not useful ACh antagonists
in the CNS, because they strongly excite many neurons.
b) Muscarinic
excitation. A relatively
slow and prolonged
excitatory
action of
ACh and other muscarinic
agents, blocked by atropine
and hyoscine, is seen with
many central neurons,
not infrequently
even neurons that show a nicotinic
effect
(983). An almost pure muscarinic
excitation
is seen in the cerebral
cortex, where
this kind of action was first observed (749, 750). This therefore
is described
in some
detail, since it has been studied rather extensively
and substantial
evidence is available about its likely mode of operation.
1) OF CORTICAL
NEURONS.
Excitatory
effects of intracarotid
injections
of ACh
in the cerveau isole’ preparation
had been described
by Bonnet and Bremer
(145)
and Bremer
and Chatonnet
(163),
who noted that they could
be blocked
by atropine.
But more
precise
information
about
the site and mechanism
of action of ACh could not be obtained
without
a more direct
and precise
method
of application.
The first convincing
demonstration
that certain
cortical
cells can be excited by ACh was made with the microiontophoretic
technique
(748,
749, 1115). Th e excitation
is usually slow in onset (not infrequently
being preceded
by reduction
in spontaneous
firing) and it always outlasts the application
by some
tens of seconds. It is seen most clearly with cells relatively
deep in the cortex (below
layers 2 and 3); in the sensorimotor
areas, nearly
all pyramidal
tract cells are
clearly
sensitive to ACh. A systematic
pharmacological
investigation
(750) revealed the remarkably
unambiguous
muscarinic
character
of this action [later confirmed by Crawford
and Curtis (251)].
Further
studies combining
intracellular
recording
with extracellular
iontophoresis (763) made clear that this depolarizing
effect is not associated with the
expected fall in membrane
resistance. This was confirmed
in more detailed
investigations (500, 75 1, 754), in which it was shown that the membrane
resistance tended
to increase during
application
of ACh and that the depolarizing
action had a reversal level close to - 100 mV. Since there was no evidence of anomalous
rectification, these results could best be explained
by a reduction
in Gel or GK (both Cland K+ normally
have an equilibrium
potential
close to - 100 mV), either by a
direct action on the cell membrane
or by an indirect
process of disinhibition.
The
latter could occur if ACh inhibited
adjacent
inhibitory
neurons,
but this should
result in changes in Gel, which are predominantly
responsible
for cortical inhibitory
postsynaptic
potentials
(IPSP’s)
(691, 753). But intracellular
injections
of Cl- causing large positive shifts in Cl- equilibrium
potential
and IPSP reversal level did not
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obviously
change the character
of the response to ACh. It therefore
was concluded
that ACh probably
acts by reducing
GIc.
As supporting
evidence it was pointed
out that Ba2+, which is known to interfere rather specifically
with movements
of K+ in a variety of excitable
tissues (cf.
1257), also tends to excite cortical cells in a rather similar way (753). It should be
noted that tetraethylammonium,
an antagonist
of G, in nerve fibers (574), does
not excite cortical
cells like ACh or Ba2+; its effect seems to be mainly to prolong
the spike (753), either because it blocks the K+ channels only when swept in by an
outward
current
(cf. 39) or because different
K+ channels-having
specific pharconcerned
respectively
in delayed
rectification
and
macological
properties -are
in the G, predominating
during the interspike
intervals
(cf. 233, ‘234); the role of
the additional
channel in the generation
of repetitive
activity has been emphasized,
and it is possible that ACh tends to inactivate
particularly
a similar component
of
G, in cortical neurons.
A significant
aspect of this action of ACh is its tendency
to enhance responses
evoked by other means. This seems to happen in two ways: the reduction
in steadystate GK removes the stabilizing
effect of the outward
K+ current generated
by any
depolarizing
tendency;
the slowing of repolarization
and diminution
of delayed
rectification
may facilitate
repetitive
firing. There is reason to believe that repetitive activity
is essential for the fixation
of memory
traces in neurons or neuronal
circuits and therefore
the elaboration
of conscious processes (cf. 479, 556, 823).
This action of ACh thus could be of special importance
in determining
a certain
kind of cerebral function
rather than the general level of activity.
2) MUSCARINIC
EXCITATION
IN OTHER
PARTS
OF CNS. After
the discovery
of the
muscarinic
excitation
of neocortical
neurons, comparable
responses were obtained
from many other kinds of central neurons, though seldom in such a relatively
pure
form. For example,
slow atropine-sensitive
excitations
have been seen in the ventrobasal thalamus
(29), hippocampus
(118), pyriform
cortex (809), caudate nucleus
(894), cerebellar
cortex (253, 880), lateral
(988) and medial
geniculate
( 1163
1166), and in the medulla
and pons (154). Even Renshaw
cells proved on closer
examination
to have muscarinic
receptors, with properties
similar to those of cortical cells (283). Thus, like sympathetic
ganglion
cells, Renshaw
cells are provided
with at least two kinds of ACh receptors, one rapidly
acting and one slowly acting.
The mixed muscarinic-nicotinic
character
of ACh sensitivity
often observed when
testing different
neurons may be the result of having-variable
amounts of the two
types of receptors
on the same cell.
The ease with which muscarinic
excitations
can be demonstrated
varies greatly
from experiment
to experiment
(cf. 749, 809). This peculiarity
may be partly due
to a specific interference
with the effects of ACh by general anesthetics,
which has
been observed in the cortex (207, 749, 1024), caudate nucleus (132), and thalamus
(986); however,
some authors have failed to detect such a specific action of anesthetics (29, 249, 25 1, 282).
3) BLOCK OF MUSCARINIC
EXCITATION
BY METABOLIC
INHIBITORS,
HYPOXIA,
AND
GENERAL
ANESTHETICS.
Studies on cortical neurons have shown that the excitatory
effect of ACh can be blocked
specifically
but reversibly
by 2,4-dinitrophenol
(DNP) and probably
some other uncouplers
of oxidative
phosphorylation,
as well
A/v-ii
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439
2. Central inhibitory
Central
by Chatfield
actions of ACh
cholinergic
and Lord
inhibitory
pathways
have been postulated
(2 15)] t 0 explain
some effects of topical
[for example,
applications
of
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as by hypoxia
(498, 500, 686). The mechanism
of action of DNP appears to be by
an increase in membrane
permeability
to K+ (498, SOO), which may be caused by a
rise in intracellular
free Ca2+ after the slowing down of mitochondrial
activity
(cf.
ZOO, 81 i). This interpretation
is supported
by recent experiments
in which Ca2f
was injected
in to motoneurons
: this caused a fall in both excitability
and membrane resistance that could be ascribed mainly to a rise in GX (43 1, 740).
Although
it is not immediately
evident
why a rise in internal
Ca2+ should
enhance GK, a simple explanation
may be that Ca2+ neutralizes
a negative boundary potential
at the inner surface of the membrane
(cf. 211) and in this way reduces
the effective transmembrane
potential
that normally
keeps the membrane
cationic
conductance
at a relatively
low level. If this is correct one might expect the membrane properties
to be altered in a similar way by a rise in internal
free Ca2+, membrane depolarization,
or a reduction
in external
Ca2+, since all of these would
reduce the effective transmembrane
potential
(cf. 453). It seems significant
that
all three lead to a fall in excitability
associated with a high GK.
Variations
in metabolism
must change the efficiency of Ca2+ sequestration
by
mitochondria
and thereby
the level of neuronal
excitability.
General
anesthetics
depress mitochondrial
activity ( 10 15, 1016), and therefore narcosis may be brought
about at least partly through
this mechanism
(737, 738). If cerebral
muscarinic
pathways
play a special part in determining
conscious processes (see above), they
would indeed be particularly
susceptible
to depression
by an increase in G,. Although
there is as yet no direct evidence
that anesthetics
specifically
raise GK in
central
neurons,
their effects on the pattern
of firing and sensitivity
to ACh of
cortical neurons can be remarkably
similar to those of DNP orhypoxia
(207).
If other types of muscarinic
transmission
also operate
by lowering
GK, one
would also expect them to be rather sensitive to DNP. This appears to be true for
sympathetic
ganglia
(705, 941), but not for the spinal Renshaw cells (270).
&mmary.
The most common
excitatory
action of ACh in the CNS has muscarinic
characteristics;
it is relatively
slow in onset and very prolonged
and is
readily blocked by atropine.
Some neurons (e.g. Renshaw cells) resemble peripheral
ganglion
cells in having
both nicotine
and muscarine
receptors
and show corresponding
fast and slow responses. According
to intracellular
studies in the cortex,
the depolarizing
effect of ACh is associated with a rise in resistance and it has a
reversal level close to the expected value of K+ equilibrium
potential.
The mechanism of depolarization
is probably
a reduction
in GK, which may also explain
the
characteristic
repetitive
afterdischarges.
This interpretation
receives some support
from the comparable
excitatory
action of Ba2+, a general blocker of GX. The repetitive firing induced
by ACh may be of importance
for the laying down of memory
traces (and possibly consciousness).
This action of ACh is particularly
susceptible
to depression
by general anesthetics
and other inhibitors
of mitochondrial
activity,
which permit intracellular
free Ca 2+ to accumulate
and so cause a rise in G,.
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atropine
on evoked cortical potentials.
Substantial
evidence has now accumulated
from microiontophoretic
experiments
that ACh can depress the firing of certain
neurons.
The first demonstration
of such an effect was made by Randic
et al. (1024),
who observed
a depression
of some cortical
cells by ACh that could not be explained
simply as a current
artifact,
especially
since it was abolished
by atropine.
Although
an indirect
action -through
the excitation
of a neighboring
inhibitory
cell-could
not be excluded,
this was unlikely
in view of the predominance
of depressant effects in the superficial
layers of the cortex, where excitation
by ACh is
seldom seen (248, 251, 749, 1024). Comparable
depressant
effects have been noted
in several subsequent
studies (418, 754, 809, 891, 993, 994). Phillis and his collaborators (65 1, 993; see also 617, 1209) h ave found that stimulation
of several areas of
the brainstem,
as well as of the cortex itself, may cause a characteristic
very prolonged inhibition
of the superficial
cortical cells depressed by ACh. The inhibition
and the effect of ACh are both blocked by atropine
(and, curiously
enough,
by
strychnine),
and Phillis therefore
believes that there must be a cholinergic
inhibitory pathway
acting mainly on cells in the upper layers of the cortex. This inhibitory system appears to be at least partly intracortical,
since the characteristic
inhibition
can be elicited even in chronically
isolated slabs (65 1).
The significance
of this postulated
inhibitory
system is not clear at present.
Even in the superficial
layers only a small percentage
of neurons are strongly depressed by ACh (754,891,
1024, 1121). N evertheless, it seems that cells that tend to
discharge
spontaneously
in high-frequency
bursts are consistently
very sensitive to
this action
(K. KrnjeviC,
personal
observations).
There
is some evidence
that
neurons of this type may themselves have an inhibitory
function
( 1034, 1130). It
therefore
is possible that cholinergic
systems afferent
to the cortex facilitate
the
activity of deeper cortical
(pyramidal
type) neurons both by direct excitation
and
by disinhibition.
A further
point of interest is that even those central neurons that are mainly
excited by ACh are not infrequently
initially
depressed (29, 749, 984, 1065, 1166),
especially
when ’ %pon taneous’ ’ firing is at a very high rate (498).
Most other regions of the CNS also contain
cells that are depressed by ACh
(29, 63, 132, 154, 285, 988, 1163, 1166, 12 13, 1235). In general these depressant
effects are most easily blocked
by atropine
and other muscarinic
antagonists
(63,
154, 285, 854, 994, 1024). Thus, with some exceptions
(984, 994, 1166), the inhibitory action of ACh has a rather clear muscarinic
character.
This is seen especially
well when a given cell has both nicotine
and muscarine
receptors:
for example,
hypothalamicneurosecretory
cells (63, 35 1) are excited by nicotinic
agents and
inhibited
by muscarinic
ones; the excitation
is blocked by the nicotine
antagonist
dihydro-beta-erythroidine
and the inhibition
by atropine
(63). In the medulla
and
pons, excitatory
actions of ACh show a mixed nicotinic-muscarinic
character,
but
inhibitions
are purely muscarinic
(153, 154).
So far a clear change in membrane
permeability
has not been observed during
the depressant
action of ACh on central neurons (754), but one cannot yet dismiss
the possibility
that this effect is similar to the muscarinic
actions that operate by
April
1974
VERTEBRATE
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441
G. Other Evidence Indicating
Cholinergic
Transmission
in CNS
The presence of ACh-sensitive
neurons is necessary but not sufficient evidence
of cholinergic
transmission.
However,
there is plenty of supporting
information
about the presence of ACh, acetylcholinesterase
(AChE),
and cholineacetyltransferase (ChAc)
(the enzyme needed for acetylation
of choline)
in many regions of
the CNS ( 18 1, 196, 254, 425, 430, 547, 549, 550, 554, 560, 659, 848, 977, 1062,
1263). In several areas the AChE and ChAc activities
are well correlated
: for example, they are both at an exceptionally
high level in the striatum,
the interpeduncular
nucleus,
and the hippocampus
(766, 820, 1137), and both tend to
diminish
in parallel after lesions that cut off the presumed
cholinergic
input to the
cerebral
cortex (551) or the hippocampus
(820).
But in other areas, such as the cerebellum,
the correlation
is much less satisfactory (660, 820). The commonly
used histochemical
techniques
that demonstrate
AChE-containing
cells and fibers (480, 709, 7 12, 766, 767, 8 19, 953, 1088, 1089,
1095-1097)-though
convenient
for selectively
tracing
certain pathways-cannot
by themselves
give proof of cholinergic
transmission.
The release of ACh is obviously
an important
aspect of cholinergic
transmission, which has now been demonstrated
unequivocally
in various areas, particularly at the surface of the cerebral hemispheres
(73,8 1, 208, 230,361,562,635,655,
849, 906, 977, 982, 1148), even in the absence of anticholinesterase
( 1110). It increases with the amount
of cerebral
activity
and with the degree of arousal but
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raising GK, such as vagal inhibition
of the heart (1 187) and secretory potentials
in
salivary glands ( 1079). Alternatively,
the relevant
receptors
may be an .alogous to
those responsible
for the atropine-sensitive
hyperpolarizing
action of ACh seen with
some neuroblastoma
cells in tissue culture (929, 975) and even in L cells that are of
fibroblastic
origin (928). This response reverses at a highly negative potential
and
therefore
at first sight appears to be analogous
to the vagal inhibitory
effect, but
there is some evidence that it is associated with a rise rather than a fall in resistance
(929).
Summary. Depressant
effects of ACh have been seen in many regions, and they
may be shown even by cells predominantly
excited by ACh. They appear to be
exclusively
muscarinic,
but it is not known whether they are caused by a rise in Gx
or by some other mechanism.
General conclusions about membrane efects of ACh. At least three different
actions of
ACh have been identified
in vertebrates:
a rapid nicotinic
excitation,
caused by a
general increase in cation permeability;
a slow muscarinic
excitation,
probably
caused by a specific reduction
in K permeability;
and a muscarinic
inhibition,
caused by a specific increase in K permeability.
These three mechanisms,
operating
singly or in various combinations,
may account for most of the observed actions of
ACh. It is of interest that muscarinic
actions seem to operate principally
on K+
conductance,
except perhaps in the gut, and that more generally
all the identified
actions of ACh in vertebrates
probably
lead to changes in cation permeability
exclusivelv.
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diminishes
during sleep [except during REM sleep (635)] and particularly
in deep
anesthesia.
Acetylcholine
is released particularly
effectively
by stimulation
of the
reticular
formation
(208, 655, 977, 982).
Acetylcholine
is found in synaptosomes
extracted
from the brain (33 1, 1262,
1264). Suspensions
of such synaptosomes
release ACh when they are stimulated
by
electrical
pulses or excess K+ (309). Yamamura
and Snyder
( 128 1) have further
shown that synaptosomes
possess a high-affinity,
Na-sensitive
mechanism
for the
uptake of choline.
These observations
thus are in reasonable
agreement
with the idea that
cholinergic
pathways
from the phylogenetically
older regions of the brain (e.g.
mesencephalic
reticular
formation,
hypothalamus,
striatum,
and septum)
have a
facilitatory
(“arousing”)
action on the neocortex
of the cerebral hemispheres
(459,
733, 766, 767,977,
1088, 1116, 1118, 1129, 1148) as well as on several of the sensory
relay nuclei (e.g. 164, 876, 984, 988, 1166).
Although
this relatively
simple picture may well be correct, it has not yet been
possible to prove in a really convincing
way that the arousal system is essentially
cholinergic.
The difficulty
is partly because there is no certain method of stimulating this pathway
selectively
and exclusively
and partly because its fibers appear to
be very small and diffusely distributed,
so that the responses evoked by stimulation
have a long latency and are not well synchronized.
Moreover,
the effects of ACh
antagonists
have not been easy to interpret:
for example,
atropine
causes a marked
increase in the release of ACh from the cortex (849). It is still not known whether
this is due to the removal
of an inhibitory
feedback
from ACh-sensitive
cortical
neurons to the reticular
formation
(361; cf. 457, 565) or whether atropine
enhances
ACh release by a direct action on the cholinergic
nerve endings (1003). The operation of such an inhibitory
feedback may help to explain the relative inefficiency
of
atropine
as an inducer
of sleep (156, 1264), although
an even more important
factor may be that these cholinergic
synapses, like those in the bladder
( 18) and
the colon (488), are blocked only by very high doses of atropine.
The situation
is
not made any simpler by the fact (noted above) that many central neurons appear
to have mixed nicotine
and muscarine
receptors and that reticular
stimulation
also
has a marked inhibitory
action on many cortical neurons (cf. 609, 703, 992, 1120,
1129), although
if many of these neurons should prove to be inhibitory
interneurons
(cf. 1130), the reticular
arousal system could operate by a push-pull
process. It is
not yet possible to state unequivocally
that there is cholinergic
transmission
even
at such sites of outstanding
AChE
and ChAc activity
as the striatum
and the
ha benuloin terpeduncular
pathway
( 79 1, 890).
A large number of behavioral
studies with drugs have given some indication
of
a significant
involvement
of cholinergic
mechanisms
in sleep and arousal, memory,
learning,
and various other aspects of behavior
(336, 410, 654, 701, 704, 1009).
Phylogenetically
ancient
groups of neurons
synthesizing
and releasing
specific
transmitters
(cf. 17) could be responsible
for distinct aspects of behavior.
Several
basic drives are believed to be generated
in the limbic system and hypothalamus,
which can be considered
as central components
of the autonomic
system. The high
concentrations
of ACh, ChAc, and AChE in this part of the brain seem to indicate
April
1974
VERTEBRATE
SYNAPTIC
TRANSMISSION
443
H. Acetylcholine
Receptors
There has been a marked upsurge of interest in the macromolecular
membrane
components
with which ACh is presumed
to interact
when it causes excitation.
The very localized
action of ACh in muscle and the fact that it is not sensitive to
tetrodotoxin
(677) strongly
suggest that ACh does not act at the sites of Na+ entry
during the action potential
(574).
Specific
identification
is the essential problem
in the isolation
of receptor
macromolecules.
How can one be certain that the material
in question
is the functional receptor
in situ?
0ne approach
is to bind to the receptor
a slowly reversible
or irreversible
antagonist
that can act as a label. But attempts at identifying
or separating
ACh
receptors
by using curare have not been very successful (210, 385, 1229), mainly
because curare tends to bind to membranes
rather unspecifically.
A recently discovered irreversible
and more specific antagonist,
cr-bungarotoxin,
has been used to
much greater effect for labeling
or isolating
the probable
receptor
protein
from
electric
organs and muscle (66, 101, 2 14, 420, 902, 1005). Another
technique,
affinity
labeling,
utilizes some characteristic
reaction
to tag the receptor:
for example, by alkylating
selectively
thiol groups released from the disulfide
bond that
is typically
closely associated with the ACh binding
site (658). An interaction
between the macromolecule
and ACh itself can be revealed
more directly
by the
XhlR
spectrum
of ACh (664, 666) or by equilibrium
dialysis (389). Acetylcholine
(and other)
receptors
have been the subject of several recent extensive
reviews
(333, 1026, 1027, 1105).
A possible criticism
of these studies is that they do not necessarily
prove that
the macromolecules
in question control ionic movements.
In an attempt to provide
some relevant
evidence,
Parisi et al. (967, 968) h ave incorporated
into artificial
membranes
a “receptor”
proteolipid
extracted
from electric organs and have obtained some evidence of a transient
increase in membrane
conductivity
on applying
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the presence of some important
cholinergic
pathways.
But the evidence obtained
so far from behavioral
studies has been too indirect
and often insufficiently
rigorous
to identify
with any precision
the postulated
cholinergic
synapses or their mode of
operation.
The relatively
tenuous neural links between such ancient regions and
the more recently
developed
neocortical
areas-the
site of the more highly
evolved
intellectual
functionsare certainly
consistent
with the manifest
autonomy of different
aspects of behavior.
Summary. There is much indirect
evidence for cholinergic
activity in the CNS,
such as the presence of ACh and enzymes involved
in its synthesis and hydrolysis,
and it is clear that ACh is released, probably
from cholinergic
nerve endings,
in
various
regions of the brain,
e.g. cerebral
cortex, hippocampus,
striatum,
and
hypothalamus.
Studies of the effects of various drugs also indicate a significant
role
of excitatory
or inhibitory
cholinergic
pathways
in various
aspects of behavior,
such as arousal and wakefulness,
drinking,
aggression,
etc. But so far no specific
cerebral pathway
has been conclusively
shown to act by the release of ACh.
444
K. KRNJEVIC
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54
1. Cation mouements and AC/z system
As pointed out above, all the known transmitter
actions of ACh in vertebrates
apparently
involve changes in the permeability
of cations only. Acetylcholine
may
increase both G, and GNa (1155) or GK alone (1187) or it may reduce GK (752, 754,
1236); there is no evidence
that it ever affects anion permeability.
This suggests
that some component
of the ACh system may have a basic and widespread
(perhaps universal)
function
linked to cation movements
through
cell membranes.
An obvious candidate
for such a role is cholinesterase.
The remarkably
wide
distribution
of cholinesterase
activity
throughout
the nervous system (17, 923),
even in what are manifestly
noncholinergic
pathways,
has long been a puzzle. In
many areas there is a good correlation
between ACh content, cholineacetyltransferase activity, and cholinesterase
(especially
AChE)
activity, but often the correlation is very poor -for
example,
in the dorsal root fibers or the cerebellum
(1095).
On the other hand, Nachmansohn’s
(923) hypothesis
that ChE is present in all
nerve fibers because ACh is directly involved
in the conduction
of the nerve impulse
has received little or no support from a variety of experimental
tests (668). Moreover, cholinesterase
activity is found in many organisms,
tissues, or cells where it
cannot be related to neurotransmission
(42, 709, 7 12); obvious examples in vertebrates are the frog skin (707), the kidney (451), the cornea (980), and red blood
cells (709).
There is some indication
that ChE may be linked to the active transport
of Na+
(451, 707, 716), but an alternative
or additional
possibility
(754) is that ChE may
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ACh. By fractionating
the innervated
face of electric organs, Kasai and Changeux
(661, 662) h ave obtained
a suspension of “microsacs”
consisting of membrane
rich
in AChE
and receptive
to ACh (and other cholinomimetics
or ACh antagonists);
after loading the microsacs with labeled ions, they succeeded in showing that ACh
induces a specific increase in cation permeability,
comparable
with the effects observed in intact muscle (for example,
AG&AGK
was 1.20). These relatively
isolated receptors therefore control ionophores
in an approximately
normal way.
The remarkably
similar number
of receptor
and AChE sites at various junctions (661, 1005) lends some support to the notion that subunits of a single macromolecule
are concerned
in these two distinct functions
(86, 8 14, 1287). It is clear
that these subunits must be largely independent
since the ACh receptor property
is
essentially
unaffected
by total block (67, 71) or even removal of the esterase activity. Most of the recent studies have dealt with the “nicotinic”
ACh receptor,
and
there is much less information
about the “muscarinic”
receptors
(422, 970). It has
been suggested that the muscarinic
effects of ACh are mediated
intracellularly
by
guanosine
3,5-cyclic
monophosphate
(478, 808).
Summary. There has been a rapid advance
in studies aiming
to isolate or
identify
in situ functional
membrane
receptors for ACh, partly thanks to the use of
radioactively
labeled
cu-bungarotoxin,
an irreversible
nicotine
antagonist.
Relatively pure protein has been obtained
in solution having many of the binding
characteristics of the nicotine
receptor
in situ.
April
VERTEBRATE
1974
SYNAPTIC
TRANSMISSION
445
III.
AMINO
ACIDS
A. General
Amino acids have only recently come to be considered
as possible neurotranswas discovered
by Ritthausen
in 1866
mitters,
though
glu tamic acid -which
( 1038)has
since the early years of this century
(2) been known as an important
constituent
of nervous
tissue; it is present in the brain in higher concentration
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be directly involved
in the passive movements
of cations (especially
K+), either as a
carrier molecule or by providing
a negatively
charged hydrophylic
channel for the
passage of cations-in
any case, effectively
functioning
as an ionophore.
The
anionic chain of cholinesterase
has binding
sites for curare and atropine
(86, 665667, 1180) that have been proposed
as nonhydrolytic
receptors for ACh. These or
comparable
sites may act as K+ ionophores.
It thus could be significant
that the high ChE activity of motor nerve fibers is
associated with a relatively
high resting membrane
GK in these fibers (102). Similarly the ChE activity observed
in the transverse
tubular
system of muscle fibers
(68, 901) may be connected
with the high apparent
G, of the tubular
membrane
(16, 388, 577). In the CNS the ChE activity of neuroglia
(480, 709) is associated
with a high relative
GIc (329, 775). In red blood cells either PK or PNa (according
to species) can be reduced
by ACh and some related compounds,
and this effect is
blocked by anticholinesterases
(5 16, 589). The GK of many excitable
cells is specifically blocked by tetraethylammonium
and several other quaternary
ammonium
compounds
more or less closely related to choline (40, 574, 753).
The apparently
nonspecific
convulsant
effects of topical applications
of curare
and strychnine
in areas such as the cerebral
cortex (52, 212, 759) may be due to a
reduction
in membrane
GK (cf. 37, 456). Microiontophoretic
applications
of curare
and various related
compounds
(especially
gallamine)
excite many central cells
that are not sensitive to ACh (285, 472, 1066); a striking
feature is a marked
tendency
toward
repetitive
discharges
(472), very similar to the effect of excess
Ba2+ (753), which also lowers GH in a variety of tissues (1256, 1257). Strychnine
inhibits
cholinesterase
activity
(922), and in some peripheral
nerves it prolongs
spikes and reduces afterhyperpolarizations
(24 1,645, 1230).
All these facts are consistent with the possibility
that some anionic portion
of
the cholinesterase
molecule may have a very general, primordial
function
in providing sites of transmembrane
cation movement,
a function
that may well have long
preceded
its adaptation
for the hydrolysis
of free ACh [and perhaps for use as an
ACh receptor
( 1287)].
Summary. The widespread
distribution
of enzymes related to ACh (especially
cholinesterase)
even in neural tissue indicate
some more general function,
unrelated to synaptic transmission.
Various items of evidence are reviewed
that suggest
the possibility
that cholinesterase
may have a primordial
function
in the regulation
of transmembrane
movements
of cations, possibly as an ionophore.
446
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( 10m2 M) than in most other organs. It seemed to be closely involved
in cerebral
metabolism,
as indicated
by its striking effect on the oxygen consumption
and accumulation
of potassium
by isolated brain or retinal slices ( 1174, 1239). The presence of free glutamate
and glycine could also be ascribed to the requirements
of
protein
manufacture.
Gamma-aminobutyric
acid (GABA),
on the other hand,
which was not discovered
as a brain constituent
until 1950 (45, 1044), in vertebrates is found in hardly any other tissues and is not a component
of protein-although
it is by no means a “new”
compound,
being a very common
product
of
widespread
photosynthetic
and other metabolic
reactions
in microorganisms
and
plants (11, 1228). Its relatively
high concentration
( 10e3 M) in the brain suggested
some special function,
presumably
related to neural activity, but there was no clue
as to what this function
might be. Later studies on metabolism
showed that an
appreciable
proportion
of the glucose-utilizing
system of the Krebs cycle in the
brain was partly shunted via a pathway
passing through
GABA.
One function
of
GABA therefore
appeared to be to provide an alternative
route of cerebral metabolism (884, 1040).
The possibility
that glutamate
and GABA might be concerned
in the control
of neuronal
excitability
was first proposed by Hayashi (541, 542). Although
Brooks
et al. (169) had observed a strong excitatory
action of dicarboxylic
acids, including
dicarboxylic
amino
acids, on the brain of winter
frogs, Hayashi’s
experiments
(541) demonstrated
a much more specific and direct excitatory
action of glutamate
on the mammalian
brain. By making injections
of small volumes of glutamate
solutions into the cortex through
a fine metal tube, Hayashi
anticipated
the microiontophoretic
technique
and was thus able to show that glutamate
acted exclusively
on gray matter. In other experiments
Hayashi
(542) discovered
the marked depressant action of GABA
and other short-chained
a! ,o-amino
acids. Although
his
method of evaluating
the depressant
power may seem crude by later standards-it
was based on the effectiveness
of a given agent in reducing
convulsions
evoked by
various
excitants -nevertheless
it enabled
him to describe
quite accurately
the
relative
potencies
of the short-chained
CY+-amino
acids. His conclusion
that the
most effective depressants are those with five or six carbon atoms in the main chain
and that compounds
with more than seven carbon atoms have little or no depressant activity has been confirmed
by practically
all subsequent
investigators.
However, Hayashi
did not think that either glutamate
or GABA
was likely to be a
natural
transmitter,
but suggested that GABA was probably
the parent substance
of both the excitatory
and the inhibitory
transmitters;
his favored
candidate
for
the latter was ,&hydroxy-y-aminobutyric
acid.
At about the same time, by a curious combination
of circumstances,
GABA
was shown to have a strong inhibitory
action on the crayfish stretch receptor
cell;
however,
further
attempts
at finding
the significance
of this action led to a prolonged and singularly
unhelpful
controversy.
Florey’s discovery
(445) that extracts
of mammalian
brain strongly
inhibit
the crayfish stretch receptor
indicated
the
presence in the brain of an unknown
inhibitory
agent, which was named factor I.
A splendid
example
of interdisciplinary
collaboration
between Florey and Elliott
(80) led to the identification
of GABA as the main component
of brain that could
April
I974
VERTEBRATE
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TRANSMISSION
447
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account for its factor I activity.
The authors therefore
suggested that GABA may
be an inhibitory
transmitter
in mammals,
even though they had very little evidence
that GABA inhibits
neuronal
activity in the mammalian
brain.
However,
serious consideration
of GABA as an inhibitory
transmitter
in mammals proved to be short-lived.
It came under strong attack from several quarters.
On the one hand, it was claimed that, when tested on a variety of excitable preparations, the action of GABA differed
in several essential respects from the action of
factor I (447, 888); an even more serious objection
was that the inhibitory
activity
and the GABA content
could be completely
dissociated,
since it was possible to
make fully potent preparations
of factor I that contained
no GABA
(886, 887).
But in spite of all efforts, the unknown
postulated
inhibitory
agent could not be
identified.
Experiments
on the effects of GABA on neural activity also failed to support its
proposed
role as inhibitory
transmitter
in vertebrates.
Several groups of authors
applied GABA and some related substances to the surface of the cerebral or cerebellar cortex while recording
field potentials
evoked by direct or indirect
stimulation.
They all observed marked effects, but these were interpreted
as inconsistent
with a
general
inhibitory
function
of GABA.
For example,
an elaborate
analysis
by
Purpura
et al. ( 1011) led to the conclusion
that GABA specifically
blocked
axodendritic
excitatory
synapses by a curarelike
action, not associated with changes
in membrane
polarization
or conductance.
Comparable
experiments
by Iwama
and Jasper (627) were interpreted
differently:
GABA clearly had a direct depressant effect, but only on neural elements in the most superficial
layers of the cortex,
because deeper injections
were ineffective.
This conclusion
was also not consistent
with a general inhibitory
role of GABA.
A very different
new technique -release
from multibarreled
micropipettes
by
microiontophoresis
-was
used by Curtis et al. (279) to apply GABA and @-alanine
to single neurons in the spinal cord of the cat. The results were quite conclusive:
all
spinal interneurons
tested were markedly
depressed
by GABA
or fl-alanine.
By
the use of concentric
double micropipettes
the authors also recorded
intracellular
potentials
while applying
GABA extracellularly.
Again very marked effects were
seen regularly:
there was a sharp reduction
in cell excitability
and also in the
amplitude
of synaptic responses evoked by excitatory
or inhibitory
pathways,
but
no sign of a membrane
hyperpolarization.
However,
the depressant
effects of both
GABA
and @alanine
appeared
to be quite impervious
to strychnine,
which had
long been known to block spinal inhibitory
processes (162, 958). Citing the lack of
hyperpolarization,
the resistance to strychnine,
and the depression
of both EPSP’s
and IPSP’s,
Curtis et al. (279) firmly
concluded
that GABA
could not be the
inhibitory
transmitter
in the spinal cord nor probably
in the brain.
Thus arose a wide consensus that, in the vertebrate
CNS, GABA has a nonspecific (modulator?)
depressant
action and that the natural
inhibitory
transmitter(s) must be some other substance(s)
(110, 250,258,
372, 392,888).
Similarly,
any speculation
that glutamate
might be a significant
excitatory
transmitter
for some time was strongly
discouraged
by the results of experiments
that suggested, on the one hand (101 l), that glutamate
has a slowly reversible
de-
448
K.
KRNJEVIC
Volume
54
B. Inhibitory
Amino Acids
1. y-Aminobutyric
A) ACTION
ceptions [cf. the
in every part of
action of GABA
of the CNS (see
transmitter.
acid
0N NERVE CELLS IN DIFFERENT
PARTS OF CM. With almost no exfirst sensory cells in the lamprey’s
spinal cord (872)], all neurons
the CNS of vertebrates
have been found sensitive to the inhibitory
(259, 279, 735, 748, 1065). Since GABA is found in every region
below), GABA is likely to be the most extensively
used inhibitory
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pressant action in the cortex and, on the other, that its marked excitatory
effect on
spinal interneurons
(280) could not be a specific transmitter
action, because it was
unaffected
by a variety
of enzyme inhibitors
that-it
was argued-would
have
delayed the removal of a genuine transmitter.
In spite of further results confirming
that GABA could account for all the factor I activity of brain extracts (815), the
belief that GABA,
glutamate,
and aspartate
could not be natural
transmitters
(cf. 129) stimulated
a continued
very intensive search for other active compounds,
but no further
agents of comparable
potency have ever been isolated (860, 887,
1059).
However,
after a systematic,
wide-ranging
survey of the chemical
sensitivity
of cortical neurons KrnjevX
and Phillis in 1963 (748; see also 73 1, 732) were convinced that glutamate
and GABA could be natural
transmitters
in the brain. This
opinion
was based largely on observations
of the remarkably
potent, and almost
uniquely
rapid, reversible
and reproducible
actions of these naturally
occurring
compounds,
unequaled
in all these respects by any other agents known to be normally present in the brain. The demonstration
that both GABA and glutamate
are
released from the surface of the cerebral
cortex (633), as well as further
microiontophoretic
studies in different
regions of the CNS (1065), added increasing
support for the notion that GABA and glutamate
might be physiological
transmitters.
Compelling
new evidence came with the demonstration
that GABA has a hyperpolarizing
action on cortical neurons (762, 764) and on neurons in Deiters’ nucleus
(945). It was further
shown that, like the natural
transmitter,
GABA greatly increases the chloride permeability
of cortical neurons; and, under a variety of conditions, the cortical
IPSP and the potential
changes induced
by GABA proved to
have a similar reversal level (352, 762, 764). S’mce strychnine
has little or no specific effect on inhibition
in the cortex (759), the lack of antagonism
between GABA
and strychnine
was no discrepancy.
The principal
remaining
problem,
how to explain
the anti-inhibitory
action
of strychnine
in the spinal cord was solved when Werman
and his collaborators
inhibitory
action of glycine on spinal neurons,
(253, 1255) d iscovered the powerful
specifically
and markedly
susceptible
to block by strychnine
(273-275).
Although
evidence
that glutamate
may be an excitatory
transmitter
is still largely circumstantial (644), this idea has now received a wide degree of acceptance
(259).
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1) CEREBRAL
CORTEX.
The powerful
inhibitory
action of GABA on cortical
neurons, first described
by Krnjevic
and Phillis (73 1, 748), has now been repeatedly
confirmed
(250, 1065). The main characteristics
observed on extracellular
recording are quickness and reversibility,
so that it is very effective even when applied
extremely
transiently
by very brief pulses of iontophoretic
current
( < 1 ms). The
pause in firing elicited by such transient
applications
of GABA is very similar to
the silent period observed
during
natural
inhibition
(cf. 757, 758). The minute
amounts of GABA required
under these conditions
( < lo-l4 mol) provide
further
evidence of its great potency.
A new technique
of combining
intracellular
recording
with extracellular
microiontophoretic
applications
(762, 764) made possible a much more critical
comparison
between the actions of GABA and natural
inhibition
evoked by epicortical stimulation
(757, 758, 822). These experiments
revealed a hyperpolarizing
action of GABA
associated with a marked
increase in membrane
conductance.
LMoreover, both the evoked IPSP’s and the effect of GABA could be reversed to a
depolarization
by injections
of chloride
into the neurons.
Like ACh in muscle,
GABA probably
acts on surface receptors,
since it was ineffective
when injected
intracellularly
(cf. also 340). More complete
tests (352, 690) confirmed
these findings and in particular
showed a highly positive correlation
between reversal levels
for IPSP’s and for the action of GABA over a wide range of membrane
potential.
They also demonstrated
a new phenomenon:
a striking
fall in GABA
potency
during
a prolonged
application,
so that after an initial
lo-loo-fold
increase the
conductance
rapidly
declined
to a very much lower level, which, however, was still
well above the resting level, and showed no further decrement
even after several
minutes.
These observations
provide strong evidence that the action of GABA and that
of the natural
inhibitory
transmitter
in the cortex are identical.
The predominant
effect is a sharp increase in chloride
permeability,
as indicated
by the great ease
with which intracellular
injections
of chloride
reverse the IPSP or the GABAevoked hyperpolarization.
A variety of small inorganic
anions and even some large
organic
anions can substitute
for chloride,
showing
that the inhibitory
current
is
carried through
relatively
unselective
anionophores
(691). It is unlikely
that a flux
of K+ contributes
significantly
to the inhibitory
action, because several agents that
block movements
of Kf have no detectable
effect on IPSP’s (753, 754).
2) DEITERS’
NUCLEUS.
Some cells of this nucleus, situated in the medulla,
are
among the largest in the CNS. This feature makes them unusually
suitable for intracellular
studies of inhibition,
especially
as they receive a direct inhibitory
innervation from the cerebellar
cortex (377, 620). Systematic tests of the effects of GABA
on Deiters’
neurons
by Obata et al. (945) gave convincing
evidence of a hyperpolarizing
action and less direct evidence that this is associated with an increase in
membrane
conductance.
Unfortunately,
probably
owing to their large size, Deiters’
neurons proved to be rather impervious
to injections
of chloride,
which had little
or no effect on IPSP’s or potential
changes evoked by GABA. More direct evidence
of an increase in membrane
conductance
during the action of GABA was obtained
in later experiments
(948) in which a similar reversal level was found for the IPSP
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and for the effect of GABA.
The careful independent
observations
of ten Bruggencate and Engberg
(1172) in all respects confirmed
the findings
of Obata and his
collaborators.
Applications
of GABA
occluded
IPSP’s by causing
a clear and
reproducible
hyperpolarization
and a large increase in membrane
conductance.
Both the effects of GABA and the IPSP’s could be reversed by membrane
hyperpolarization,
and the reversal levels were quite similar.
3) SPINAL CORD. As mentioned
above, the first intracellular
observations
on
the effects of GABA,
by Curtis et al. (279), did not reveal any significant
potential
changes. After the demonstration
of a clear hyperpolarized
effect of GABA on some
other central neurons,
Curtis et al. (275) reexamined
thoroughly
the membrane
effects produced
by depressant
amino acids on spinal motoneurons.
They indeed
found
that here also GABA
tended
to hyperpolarize
the cell membrane
and
greatly reduced the membrane
resistance. Like the IPSP, the effect of GABA could
be reversed by artificial
hyperpolarization.
Both phenomena
had approximately
similar
reversal
levels, and they were both also reversed by injections
of small
univalent
anions but not by large inorganic
or divalent
anions.
These observations
indicate that, as in other parts of the CNS, the main action
of GABA is to increase the membrane
permeability
to small anions. Quite similar
effects of GABA have also been recorded
in the CNS of fish, in Mauthner
cells
(340) and spinal interneurons
(872). Although
GABA tends to depolarize
more
peripherally
situated neurons,
such as those in sympathetic
ganglia
(5, 3 15) and
some sensory ganglia (3 17, 3 18), there is now good evidence that this is also caused
by an increase in membrane
conductance
(944), probably
mainly to Cl- (5).
The almost universal
inhibitory
action of GABA on vertebrate
central neurons
thus appears to be due to the same mechanism -that
is, a pronounced
increase in
chloride
permeability
(275, 352, 690, 762, 764, 948, 1172). The great increase in
membrane
conductance
effectively
clamps the membrane
potential
at a relatively
negative level and so prevents depolarization
by excitatory
influences.
This effect is
fully adequate
to explain the marked inhibitory
action of GABA.
In most respects
the tests described
above have shown excellent
agreement
between
the natural
inhibitory
effect and that produced
by GABA,
except possibly for hyperpolarizations that are often somewhat
less conspicuous
with GABA
than during
IPSP’s
even when GABA produces
much larger increases in conductance
(cf. 352). This
may well be an experimental
artifact,
which could be caused by one or more of
several factors : electrical
coupling
between iontophoretic
and recording
electrodes,
the acidity of the GABA solutions used for iontophoresis,
excessive applications
of
GABA causing a rise in internal
Cl- concentration
or even a different
change in
membrane
permeability
(cf. 774), or activation
of a partly different
population
of receptors,
perhaps
extrasynaptic
receptors
with distinct
properties
(cf. 433);
some divergence
could also be expected if GABA is normally
released from nerve
terminals
in association
with other substances that modify
its action. Finally,
one
cannot totally exclude the possibility
that the main transmitter
is not GABA but
some close, much less stable derivative.
Summary. Investigations
on the action of GABA in several parts of the CNS
have shown a striking similarity
with the effects of synaptic inhibition
: the neuronal
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membrane
resistance
is sharply
lowered,
the transmembrane
potential
becomes
more negative,
and there is a similar reversal level, which can be altered by injections of Cl- (or other small anions) inside the cell. These effects of GABA are seen
even when it is applied
in amounts
< lo-l4 mol: they have a very quick time
course, but there is some evidence of desensitization
during prolonged
applications.
These observations
are fully consistent with the hypothesis that GABA is thenatural
transmitter
released by many inhibitory
neurons
and that it acts by increasing
Gor. A comparable
action is seen even on more peripheral
ganglion
cells.
6) Actions of GABA on other elements of CNS. 1) NERVE FIBERS. There is no evidence that GABA can block conduction
in myelinated
nerve fibers (cf. 279, 471,
885). Of greater significance
is the possibility
that GABA might alter the excitability of the unmyelinated,
terminal
region of the fibers. This could be of great functional
importance,
either by changing
the probability
that nerve endings
are
invaded by afferent impulses or because it might reflect a change in polarization
of
the terminal,
which may determine
the amount of transmitter
released by the nerve
ending
(373) [cf. the neuromuscular
junction,
where there is good evidence
that
transmitter
release is a function
of membrane
depolarization
(237, 829)].
Different
tests of GABA on terminals
have not given entirely consistent results.
The most striking
effect is a strong depolarization
of dorsal root fibers in the
amphibian
spinal cord, first observed by Schmidt
(1077) and repeatedly
confirmed
comparable
depolarization
is
produced
by
by later observers
(64, 30 1, 1170). A
several other amino acids. One possible explanation,
that the action of GABA is
indirect,
has not been entirely eliminated.
The depolarizing
effect is fully seen even
in the presence of high concentrations
of magnesium
(64, 301), indicating
that it is
probably
not mediated
synaptically;
however,
this does not exclude the possibility
that GABA releases a depolarizing
agent from certain cells, e.g. neuroglia.
According to other tests (64), this presynaptic
action of GABA is not sensitive to extracellular chloride,
but is affected by changes in sodium concentration.
On the other
hand, a more recent study (939a) has obtained
strong evidence of an increase in
Ger similar to that seen when GABA is applied to nerve cell bodies. Such marked
presynaptic
depolarizations
have not been observed
in the mammalian
CNS
(cf. 379).
The effects of GABA on terminal
excitability
were examined
by Curtis and
Ryall
(284)) who used a multibarreled
micropipette
for simultaneous
electrical
stimulation
and release of GABA.
The results indicated
a marked
depression
of
excitability.
Comparable
experiments
on afferent terminals
in the cuneate nucleus
by Galindo
(469) raised some doubts about the reliability
of this technique.
There
was evidence
that the stimulating
current
pulses were significantly
diminished
during the iontophoretic
release of GABA.
Davidson
and Southwick
(304) superfused the region of the dorsal column nuclei with solutions containing
GABA and
found mainly
evidence
of an enhancement
of terminal
excitability
[cf. also some
tentative
observations
on the spinal cord by Eccles et al. (379)].
2) EFFECTS
OF GABA
ON NEUROGLIA.
In contrast to the hyperpolarization
and
the very regular,
large increase in conductance
produced
by GABA
in cortical
neurons,
unresponsive
cells in the cerebral
cortex -defined
as cells that generate
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no spikes or synaptic potentials,
either spontaneously
or in response to any kind of
stimulation-consistently
failed to show a hyperpolarization
or a fall in resistance
(762, 763). Indeed,
large applications
of GABA led to a slow and reversible
depolarization,
but without
a change in membrane
resistance.
Such unresponsive
cells were later positively
identified
as neuroglia
by intracellular
staining
(5 18,
692).
These observations
suggested the possibility
that GABA may be actively taken
up into glial cells by an electrogenic
pump and that glia perhaps play a significant
part in the removal
of neurotransmitters
from extracellular
fluid (763). This suggestion has received a good deal of support from recent autoradiographic
studies
of the uptake of labeled GABA and other transmitters
(see below). Since the glial
cell membrane
is probably
selectively
permeable
to K+, and its membrane
potential is determined
by the K+ diffusion
gradient
(cf. 329, 775), if the uptake of
GABA is associated with some depolarization,
this could cause an efflux of Kf from
glia and a slow depolarization
of neighboring
cells and fibers.
Summary. GABA appears to have little effect on nerve fibers, but depolarizes
dorsal roots, especially in the amphibian
spinal cord. This action is probably
mediated also by changes in Gel.
c> Other evidence pointing to transmitter function of GABA. 1) DISTRIBUTION
OF
GABA
IN CNS. The discovery
of GABA in the brain (45, 1044) initiated
numerous
studies on its distribution.
It has been found in all partsof the CNS, but consistently
more in gray matter than white matter (1 I, 76, 107, 390, 417, 458, 5 12, 576, 646,
95 1, 1040, 1046, 1100). Certain areas are strikingly
rich in GABA : for example, the
substantia
nigra and parts of the striatum
(417, 951). The cerebral
GABA content
is by no means constant;
there is some evidence that it is reduced in certain convulsive states (700) [but cf. Elliott (39 l)]. The significance
of the lowered GABA (and
glutamate)
content of human and animal epileptic
cortex is not clear (1205).
2) SUBCELLULAR
DISTRIBUTION
OF GABA.
Although
some isolated nerve cells,
such as Purkinje
neurons of the cerebellum,
have a relatively
high GABA content
(946) it is not certain whether
this reflects a truly high level of GABA inside these
neurons
or a high content
of GABA
in inhibitory
terminals
attached
to their
surface.
The experiments
of Elliott
showed that GABA,
like factor I, is present in at
least two forms in the brain : free GABA, which is released by homogenization,
and
occluded GABA, which is released by more severe treatment
(393, 394). The second
was likely to be intracellular.
According
to subfractionation
studies, most of the
occluded
GABA appears to be situated in nerve terminals
(860, 1244). Even synaptic vesicles can be shown to have small amounts
of GABA associated with them
(769, 784, 860), but most of the GABA content of the brain is probably
in a relatively free form in the cytoplasm
rather than bound to some subcellular
particles
(cf. 391, 860, 1059). Although
GABA may not be greatly concentrated
in nerve
terminals,
the amount
present in cortical
synaptosomes
is sufficient
to produce
significant
inhibition.
This was shown by releasing
GABA
from suspensions
of
synaptosomes
directly
on to cortical cells (769) ; all the inhibitory
effects observed
could be reproduced
semiquantitatively
with an artificial
mixture
of GABA
and
some other amino acids.
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3) METABOLISM
OF GABA
AND
RELEVANT
ENZYMES.
The principal
source of
GABA is glutamic
acid, which is itself readily available
from glucose via the tricarboxylic
acid cycle (76, 39 1, 1043). A surprisingly
large fraction
of glucose given
systemically
is rapidly
converted
to glutamate
and GABA (467, 1222, 1283).
Soon after the discovery
of cerebral
GABA,
Roberts
and Frankel
(1045)
showed that the brain contains significant
amounts of an enzyme that decarboxylates glutamate
to produce GABA. In most parts of the CNS, there is relatively
good
correlation
between
glutamic
decarboxylase
(GAD)
activity
and GABA
content
( 12, 76, 783, 1040, 1043). Another
enzyme removes GABA by transamination
with
a-oxoglutaric
acid, producing
succinic semialdehyde
( 1042, 1068). Both enzymes
are found in most parts of the brain and their properties
have been extensively
studied (76, 1041, 1144). The return to the Krebs cycle is completed
by oxidation
of succinic semialdehyde
to succinate, facilitated
by a specific dehydrogenase
(13,
1098). The tissue content
of GABA
is a function
of the activities
of GAD and
GABA-transaminase,
but the main determining
factor is the amount
of GAD activity ( 104 1, 1043). Glutamic
decarboxylase
has some interesting
properties,
including
a high susceptibility
to inactivation
by anions, such as chloride;
it has been
suggested that changes in cytoplasmic
chloride
content, secondary
to activity
or
any other cause, thus could significantly
influence
the supply of GABA
( 1041).
Glutamic
decarboxylase
has been shown to be present in cerebral
synaptosomes
(448, 1063, 1244), especially
in a fraction
distinguishable
from that of ACh-rich
synaptosomes
by its higher density (448). High 1evels of GAD activity have been
found in regions where there is likely to be a high density of inhibitory
terminalsfor example, in the hippocampus
( 1138) or in the cerebellum
(783, 784).
Attempts
at producing
predictable
changes in inhibition
by interference
with
the enzymatic
removal
of GABA have not been an outstanding
success. Neither
inhibition
nor the action of GABA is greatly altered by various inhibitors
of GABAtransaminase
(cf. 279, 765). In the experiments
of Obata et al. (945) there was
some suggestion of an enhancement
of inhibition
by hydroxylamine.
After administration
of amino-oxyacetic
acid, Gottesfeld
et al. (506) have found in the cuneate
nucleus evidence of a reduced sensitivity
to glutamate
and a progressive
increase in
sensitivity
to GABA, as well as in the duration
of evoked inhibitions.
These changes,
which may be due to a slower removal of GABA,
are less impressive
than might be
expected in view of the very large increase in brain GABA content observed at the
same time. It therefore
is likely that GABA-transaminase
plays a relatively
minor
and probably
only indirect
role in the immediate
removal
of GABA
from the
synaptic region.
4) GABA UPTAKE.
Ever since the first proposal
that GABA may be an inhibitory transmitter
in the brain (393, 748), it has been clear that occlusion
by intracellular
uptake is the most significant
method
of removal
of GABA from extracellular
space.
That brain slices accumulate
amino acids has been known for a long time
(113 1). The first systematic
studies on GABA
by Elliott
and van Gelder
(393)
showed that slices of cerebral cortex, unlike slices of muscle or of some other tissue,
could remove GABA very rapidly
from the medium
in which they were soaked;
this GABA was not destroyed
but was held in an occluded
form, from which it
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could be released again by suitable
treatment.
These experiments
provided
the
first evidence that the mechanism
of removal of GABA, like that of catecholamines
in the autonomic
system, was by active uptake into cells rather than by metabolic
conversion
to an inactive
agent. There were further
studies by Tsukada
et al.
(1191) and Strasberg
and Elliott (1139); the latter pointed
out (cf. also 39 1) that a
certain fraction
of GABA binding
is very dependent
on the presence of Naf, and
they suggested that this might play a particularly
significant
role in the removal
of extracellular
GABA.
Much of this uptake is probably
into nerve endings, since
isolated synaptosomes
also accumulate
GABA, at least partly by a Na+-dependent
mechanism
(3 13, 786, 873, 1208). A ccording
to DeFeudis
and Black (314), there
is a more pronounced
Na+-dependent
uptake of labeled GABA
by certain
subcellular
particles
from the cerebral
cortex and hippocampus
than from other
regions of the brain (including
the cerebellum).
Although
many other amino acids
are also absorbed by brain slices, it appears that only GABA and the other putative
neurotransmitter
amino acids are taken up by a high-affinity
(as well as the more
general low-affinity)
type of uptake process (87). Systematic studies by Iversen and
Neal (625) and Beart et al. (82) have shown that some fairly closely related amino
acids (but not glutamate,
aspartate,
or glycine)
can compete with GABA in this
uptake system. It is of interest that differences
in an animal’s
social environment
can be reflected in the degree of activity of these uptake processes (3 13).
In recent autoradiographic
experiments
it was found
that when slices or
homogenates
of the cerebral
or cerebellar
cortex are incubated
in [3H]GABA,
radioactivity
is preferentially
concentrated
in interneurons
(585) and in some
nerve endings
(623). From other studies, however,
it is evident that there is an
important
component
of GABA
uptake
into neuroglia
(148, 507, 563) that is
consistent
with earlier evidence of a high glial GABA content (864, 1 ZOO).
Summary. GABA is found in substantial
concentration
(> 10m3 M) in all regions
of the CNS. In its subcellular
distribution
it differs from ACh, being found mostly
free in the cytoplasm
and relatively
little in vesicles, but nerve endings
contain
sufficient
amounts for appreciable
physiological
effects. It is produced
from glutamic acid by a specific cytoplasmic
decarboxylase,
which is also widely distributed,
but is in significantly
higher concentration
in areas where inhibitory
neurons are
concentrated.
A specific transaminase,
associated with mitochondria,
accelerates
the catabolism
of GABA.
There is a rapid turnover
of GABA,
shown by its early
labeling
after systemic injection
of radioactive
glucose. Interference
with the GABA
enzymes leads to changes in brain GABA level, and some corresponding
behavioral
manifestations
(convulsions
or drowsiness).
All parts of the CNS have a strong
ability to take up GABA,
by both low- and high-affinity
systems (the latter is Na+
dependent),
GABA being accumulated
in certain nerve endings and also in neuroglia. All those features are consistent with the postulated
transmitter
function.
5) RELEASE OF GABA. There is now substantial
evidence that GABA is released
by neural activity,
especially
in the cerebral cortex and Deiters’ nucleus. The first
tentative
report of this was made by Jasper et al. (633), who described
a continual
leakage of endogenous
GABA from the cerebral
cortex of cats at a variable
rate
apparently
related
to the state of consciousness,
being greater during
sleep than
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during waking.
In a much more extensive study Jasper and Koyama
(634) essentially confirmed
these observations,
although
they could not detect any GABA
under normal
conditions:
but a release was clearly seen in the enct$haZe isole’ preparation, and it was greatly reduced
by stimulation
of the midbrain
reticular
formation; conversely,
the output was much greater after a lesion in the midbrain
reticular formation.
In general there was a reciprocal
relation
between
the release of
GABA,
on the one hand, and the release of glutamate
or acetylcholine,
on the
other. According
to very recent experiments,
the output of GABA from the cortex
is especially
enhanced
by stimulation
of a very localized
region of the central gray
of the midbrain
(724). It thus seems that the rate of GABA release in the cortex
is at least partly
under the control
of ascending
systems possibly related
to the
reticular
ascending
pathways.
A different
approach
was used by Iversen et al. (624). They demonstrated
an
increased
efflux of endogenous
GABA
when the visual cortex was stimulated
electrically
at 200/set;
this type of stimulation
(though
at a much lower rate) has
been shown to elicit a very powerful
inhibition
of cortical neurons (757). Distant
stimulation
of the lateral geniculate
was also an effective way of raising the efflux.
The possibility
that GABA is released from inhibitory
nerve endings was reinforced
by abolition
of the evoked release when the cortex was superfused
with a Ca2+-free
solution. Electrical
stimulation
of suspension of cortical synaptosomes
causes preferential release of GABA as well as excitatory
amino acids ( 15 1).
Studies have also been made of the release of radioactivity
from cortical
slices or intact cortex loaded with [3H]GABA
(533, 624, 1122). The efflux of label
is much accelerated
by electrical
stimulation
and by excess Kf and it is reduced
by a combination
of low calcium and high magnesium.
Comparable
results have
been obtained
from the spinal cord (23 1, 289, 534, 1049).
Although
the evidence
obtained
with labeled GABA is highly suggestive,
it
does not prove that GABA is released as the natural
transmitter.
There is some
reason to think that most nerve fibers can be loaded with a variety of exogenous
compounds
and these may be released by direct stimulation
or even during normal
activity
(cf. 7 18, 930, 93 1, 1176). Bowery and Brown’s
(148) demonstration
that
labeled GABA is taken up by several peripheral
nerves (and even skeletal muscle)
is particularly
relevant : GABA
accumulated
by sympathetic
ganglia
can be released by K+ or by direct electrical
stimulation,
though not by stimulating
the
pre- or postganglionic
trunks or by injections
of carbachol.
Since the uptake was
not markedly
reduced
after preganglionic
denervation,
Bowery
and Brown
reasonably concluded
that GABA is probably
accumulated
by glial cells, from which
it can be released by depolarization.
They rightly
advise great caution
in interpreting
the results of this kind of experiment.
Cerebellar
stimulation
sharply
increases the release of endogenous
GABA
into the fourth ventricle
(947). This confirms the identity
of GABA as the probable
inhibitory
transmitter
released
by Purkinje
cell axons projecting
onto Deiters’
neurons
(620, 945, 946, 948).
Summary. Further
evidence
that GABA
may be a physiological
mediator
of
inhibition
is that it is released in the cerebral
cortex and in the fourth ventricle
by
456
K.
KRNJEVIC
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5&
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inhibitory
neural activity.
Comparable
observations
on the release of exogenous
GABA
are suggestive,
but less convincing
evidence
since many compounds,
including
GABA,
are taken up and released by a variety of cells and fibers and even
satellite cells.
6) ANTAGONISTS
OF GABA.
In crustaceans
the action of GABA is rather specifically
and predictably
antagonized
by picrotoxin (cf. 1039). By contrast, in vertebrates such an effect of picrotoxin
or any other specific antagonists
has not been
so easy to demonstrate
convincingly.
Thus, Curtis (274, 288) found that picrotoxin did not antagonize
the action of GABA on spinal neurons,
and Krnjevic
et al. (759) could not demonstrate
a specific block of the inhibition
of cortical
neurons by GABA.
The lack of effect in the spinal cord was not entirely surprising,
since postsynaptic
inhibition
there appeared
to be predominantly
strychnine
sensitive (257, 371). However,
when Eccles et al. (379) found that “remote”
or “presynaptic”
inhibition
was depressed by picrotoxin,
they proposed
that GABA may
act as transmitter
of presynaptic
inhibition.
But how could one explain the associated primary
afferent depolarization
and increase in excitability
in view of Curtis
and Ryall’s
(284) claim that GABA
applied
by microiontophoresis
causes a depression of terminal
excitability?
Other authors took a very different
view of the remote inhibition.
Kellerth
(689) found that various forms of afferent stimulation,
which are said to evoke
presynaptic
inhibition,
can in fact be shown to reduce the excitability
of motoneurons and therefore
must be really postsynaptic
inhibitions,
probably
generated
by somewhat
remote dendritic
synapses. Furthermore,
he observed that this kind
of inhibition
was readily
blocked
with picrotoxin.
He estimated
that of all the
varieties of inhibition
that can be evoked on spinal motoneurons
about half are
blocked by strychnine
and the other half by picrotoxin.
The first direct claim that picrotoxin
blocks a GABA-mediated
inhibition
in
the vertebrate
CNS was made by Galindo
(469) based on observations
made in
the cuneate nucleus of the cat. In the last few years there has been increasing
evidence that picrotoxin
antagonizes
the action of GABA at various sites: in Deiters’
nucleus
(948, 1172), spinal interneurons
(402), olfactory
bulb (934), cerebellum
(1273), cuneate (693, 694), hypoglossal
nucleus (ll73),
and even autonomic
(3 15)
and sensory ganglia (3 17, 3 18). Since picrotoxin
also blocks neurally
evoked inhibition in the cuneate (693, 696), Deiters’ nucleus (1172), spinal cord (689), vestibuloocular
pathway
(571),
cerebellum,
(119, 1273), substantia
nigra
(lOlO),
and
cochlear
nucleus
(1232),
there is quite strong inferential
evidence
that many
physiological
inhibitory
pathways
act by releasing
GABA.
The alkaloid
bicuculline was discovered
by Manske
(86 1) and first shown to
have convulsant
properties
by Welch and Henderson
(1246). It has been proposed
as a specific antagonist
of GABA
in all regions of the mammalian
CNS (262).
The results of further
experiments
by the same authors
(263, 264, 271) and also
by other authors
(119, 693-696,
892, 934, 1169, 1273) support
the idea that bicuculline
antagonizes
relatively
specifically
GABA
(and some “ GABA-like”
agents, but not glycine and its relatives)
as well as neurally
evoked inhibition
at
several sites in the spinal cord, brainstem,
and cerebellum.
However,
several inde-
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2. Glycine
a) Action on nerue cells. Glycine
can be considered
as the first of the series of
short-chain
a! ,o-monocarboxylic
amino
acids and therefore
a member
of the
family of inhibitory
amino acids (see 286, 542).
In their comprehensive
survey of the effects of these agents on spinal neurons,
Curtis and Watkins
(286) rated glycine as only a weak inhibitor.
Its inhibitory
potency on cortical
neurons
was also much less than that of GABA and several
other longer chain compounds
(748). A renewal of interest in glycine was prompted
by the discovery that its distribution
in the various quadrants
of the spinal cord was
consistent with that of an inhibitory
transmitter
(36). Werman
and Aprison
therefore repeated
the test of glycine on spinal neurons and found it to be comparable
in potency with GABA (1253-l 255; see also 3 16, 1060). A relatively
high potency
of glycine has been observed in the cuneate nucleus (47 1, 693, 695) and in several
other areas of the brainstem
(307, 610, 1168, 1169, 1172, 1173). To obtain more
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pendent groups of authors (116, 473, 501, 1143) have failed to observe an effective
and specific block of the action of GABA
or inhibition
in the cerebral
cortex.
Curtis and Felix’s (27 1) more extensive report on tests of bicuculline
in the cerebral
cortex describes such weak and inconstant
effects (far short of block) as to provide
substantial
support
for the belief that bicuculline
is not a universally
reliable
antagonist
of GABA-mediated
inhibitions
(501). The variety
of agents apparently
antagonized
[including
such “glycinelike”
compounds
as P-alanine
and taurine
(cf. z%)] confirms the low specificity
of action of bicuculline
in the cortex.
These findings
seem to indicate
that GABA receptors
vary in their susceptibility to block by picrotoxin
and bicuculline.
The GABA receptors in the cerebral
cortex are particularly
insensitive,
but even in other regions of the CNS, the effects
of bicuculline
and picrotoxin
are evidently
not as predictable
as the specific block
of glycine by strychnine
(3 16, 402, 573, 6 10, 999, 1172, 1173). Both picrotoxin
and
bicuculline
may have a direct excitatory
effect on many neurons,
which greatly
complicates
the analysis (501, 759) ; the precise mechanism
of this has not been
studied in vertebrates,
but it may be analogous
to the reduction
of potassium
conductance
caused by these agents in some invertebrate
peripheral
nerve fibers
(456).
Several other convulsants
have also given some indication
that they may
block the action of GABA.
The most interesting
is ben~ylpenicillin,
which has been
reported
to reduce GABA effects and inhibition
both in the cerebral
cortex (222)
and the spinal cord (272, 302).
Summary. Picrotoxin,
bicuculline,
and some related
agents antagonize
the
action of GABA relatively
specifically
in the spinal cord and brainstem,
but much
less effectively
in the cerebral
cortex. They also block some inhibitory
synaptic
actions that are probably
mediated
by GABA.
Their usefulness is limited
because
they may not be competitive
antagonists,
do not act universally
against GABA,
and probably
have some direct excitatory
action.
458
K. KRNJEVIC
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critical
evidence
in support
of their suggestion
that glycine
was an inhibitory
transmitter
in the spinal cord, Werman
et al. (1254, 1255) performed
a systematic
analysis of its effects on the membrane
potential
and conductance
of spinal motoneurons.
These experiments
showed that glycine causes a hyperpolarization
accompanied
by a large fall in membrane
resistance, which could be attributed
to
a pronounced
increase in chloride
permeability.
Further
tests indicated
a similar
reversal level for the action of glycine and for IPSP’s, and the identity
of action of
the two processes was confirmed
by showing
that the reversal potentials
of both
were changed in a similar way by injections
of two foreign anions (cf. 1249). The
authors therefore
concluded
that glycine fulfilled
several of the main requirements
of a putative
inhibitory
transmitter.
These observations
were soon confirmed
by
Curtis et al. (275), who now also found a relatively
high inhibitory
potency of
glycine and similar intracellular
potential
and conductance
changes. Comparable
observations
were also made in spinal interneurons
(1171) and in spinal neurons
grown in tissue cultures (606) g
Further
tests on cortical
neurons
(116, 690) confirmed
the earlier impression
(748) that glycine is only a weak inhibitor
of most cortical neurons : equal iontophoretic
applications
of glycine produced
less than soth
of the conductance
increase evoked by GABA,
and the reversal potential
for the effect of glycine was
usually more positive than the reversal potential
for the IPSP. Cerebellar
neurons
are also much less sensitive to glycine than to GABA
(687).
Sumnzary. Thorough
tests have shown that glycine produces
a hyperpolarization and fall in membrane
resistance of many neurons by an increase in Gor. This
inhibitory
mechanism
is indistinguishable
from that of synaptic
inhibition
and it
appears to be identical
to the action of GABA.
It is best seen in the spinal cord and
brainstem,
where most cells are sensitive to both glycine and GABA,
but is inconspicuous in the cerebral
or cerebellar
cortex.
relevant
evidence.
1) DISTRIBUTION,
METABOLISM,
AND UPTAKE.
Glycine
b) Other
is found in free form not only in all parts of the CNS (33, 35, 1175) but, unlike
GABA,
also in cerebrospinal
fluid, in serum, and generally
in most tissues. It is in
distinctly
higher concentration
in the spinal cord, where its inhibitory
function
is
likely to be most important-particularly
in the ventral gray matter (35, 36, 646);
this is in good agreement
with the recent demonstration
that the interneurons
that mediate
direct inhibition
are situated
rather more ventrally
than had been
proposed
earlier (632). Although
there is a rapid turnover
of glycine in the CNS,
the precise metabolic
pathway
involved
is not entirely
clear; one probable
source
is glucose, via 3-phosphoglyceric
acid and serine. In any case there does not seem
to be any shortage of glycine required
for inhibitory
function.
The supply of glycine is enhanced
by an active uptake by central nervous
tissue : this is especially
efficient with slices of spinal cord and medulla
(926). Like
any other putative
transmitter
amino acid, glycine is taken up by both a lowaffinity and a sodium-sensitive
high-affinity
mechanism
(87), but the high-affinity
uptake process is only present in the spinal cord. These findings
are consistent with
other evidence already discussed that glycine probably
plays only a minor role as
mediator
of inhibition
in the upper regions of the CNS. Labeled glycine is concen-
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trated in the gray matter (926) and, more specifically,
in synaptosomal
fractions
(837). However,
autoradiographic
studies show also a significant
uptake into glial
cells (584, 608). The high-affinity
uptake of glycine is relatively
specific, being
inhibited
by only a few very closely related
amino acids (926). Like the other
amino acid uptake systems, it is not readily
blocked,
but there is a moderate
antagonism
by y-hydroxymercuribenzoate
(926), which
potentiates
the effect of
applied amino acids (266).
2) RELEASE
OF GLYCINE.
Attempts
at demonstrating
a specific release of endogenous
glycine from central nervous tissue have not so far been successful (33).
Labeled
glycine can be released from preloaded
slices of rat spinal cord (534,
599) or from the hemisected
frog spinal cord (1049) by electrical
stimulation
or
excess potassium.
As has already been pointed out, this type of release could be an
experimental
artifact.
3) ANTAGONISTS
OF ACTION
OF GLYCINE.
The first evidence that the action of
glycine is blocked by strychnine
was obtained
by Curtis et al. (274). Since strychnine has long been known
to abolish the inhibition
of spinal reflexes (152, 162,
257, 371, 958), this observation
provided
further
support for the hypothesis
that
glycine is the natural
transmitter
of inhibition
in the spinal cord (36, 1253, 1254).
A clear and remarkably
specific antagonism
(with moderate
doses) has been observed wherever
glycine
has a significant
inhibitory
action: for example
in the
spinal cord (267, 274, 3 16,803) on medullar
reticular
neurons (610, 1168), Deiters’
nucleus ( 1172), and the cuneate nucleus (469, 573, 693, 695). Several strychninelike agents, such as thebaine
and bruceine,
also block the action of glycine (274).
The striking insensitivity
of cortical inhibition
to moderate
doses of strychnine
(168, 252, 759) is evidently
consistent
with the paucity
of glycine-sensitive
cells.
However,
even the presence of a marked sensitivity
to glycine,
as in the cuneate
and Deiters’
nucleus
(693, 695, 696, 948, I 172), may not necessarily
indicate
physiological
inhibition
mediated
by glycine;
so far ncne of the inhibitory
inputs
into these nuclei has been found to be susceptible
to block by strychnine.
The action of strychnine
is by no means entirely
specific. Curtis et al. (274)
have found that strychnine
will block the inhibitory
action of some other closely
related amino acids, particularly
those with a relatively
short carbon atom chain,
such as P-alanine
and taurine,
in contrast to the GABA-like
longer chain amino
acids, whose action is either totally
unaffected
by strychnine
or only when it is
given in exceptionally
high doses. Strychnine
also blocks the depressant
action of
several other compounds,
such as norepinephrine
(NE), ACh, and 5-HT
(983),
as well as some kinds of inhibitions
that probably
are not mediated
by glycine (cf.
14 1, 375, 65 1, 994). There is evidence
that strychnine
lowers the membrane
GK
(37, 456); such an action may well explain some of these less specific antagonistic
or excitatory
effects.
Summary. Glycine
is found throughout
the CNS, as in other tissues; however,
its distribution
in the spinal cord agrees with that expected
of the transmitter
released by the inhibitory
interneurons
activated by IA muscle afferents. Relatively
little is known about its metabolism
and any essential enzymes, but there is clear
evidence of a potent uptake mechanism,
with low- and high-affinity
components,
K. KRNJEVIC
460
Volume
54
especially
in the spinal cord. The only successful release studies so far have utilized
exogenous
labeled glycine. The marked and apparently
competitive
antagonism
of
glycine and some inhibitory
pathways in the spinal cord (and possibly the brainstem)
by strychnine
is further evidence that glycine is probably
the inhibitory
transmitter
of the corresponding
synapses.
C. Excitatory
Amino
Acids
1. Excitatory
actions of dicarboxylic
amino acids
a) L-glutamate.
In small doses, glutamate
predictably
evokes neuronal
firing;
when applied in large amounts,
the excessive excitation
is rapidly
converted
into
a depression
of activity, which may be strictly localized
to the neurons under observation
or may even spread over wide areas of the cortex (spreading
depression).
Because the excitatory
action is so quick and powerful,
it is readily observed only
when very small amounts
of glutamate
are applied
locally from a micropipette.
The most systematic studies therefore
have been made using multibarreled
micropipettes and microion tophoresis : but the effect can be demonstrated
when glutamate is released from a micropipette
by applying
a suitable
pressure (748). The
first systematic
microiontophoretic
study was made on spinal neurons
in cats by
Curtis et al. (280). Comparable
effects were seen in an extensive study of cerebral
cortical
and cerebellar
neurons
in several mammalian
species by Krnjevic
and
Phillis (748). Further
investigations
in practically
every region of the CNS have
confirmed
these observations
and shown that glutamate
can excite central neurons
throughout
the vertebrate
series (153, 259, 644, 983).
i)
EXTRACELLULAR
OBSERVATIONS.
The
principal
characteristics
of the
action of glutamate
are its quick onset and almost instantaneous
cessation. When
brief pulses are used to release glutamate,
the time course of the discharge seems to
correspond
to the expected
time course of change of concentration
in the tissue
(731, 748). U n d er optimal
conditions,
cells can be excited with as little as 10-14lo-l5 mol. The rate of firing elicited by a steady application
can be varied according to the amount
of glutamate
released;
it is certainly
not an all-or-none
action.
Desensitization
is not a very marked feature, so that firing can be maintained
for
prolonged
periods. The pattern
of firing elicited appears to be a characteristic
of
the cell (472). Although
practically
all cells are excited by glutamate,
some functionally
or topographically
distinct
cells can be shown to be significantly
more
sensitive (471, 893, 913).
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The two principal,
naturally
occurring
dicarboxylic
amino acids, L-glutamic
and L-aspartic,
can be considered
together since they both have the same kind of
excitatory
action. As a rule L-glutamate
is somewhat
more powerful,
and of course
it is found in much larger amounts
in the CNS. It therefore
seems likely to play
the more important
role, so the main emphasis here is on glutamate;
however,
much of the evidence pointing
to a transmitter
function
for glutamate
may apply
equally
well to L-aspartate.
April
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Large applications
of glutamate
cause transient,
strong firing and then a disappearance
of activity,
lasting as long as the release of glutamate
continues;
a
brief period of firing may follow the end of the release. This kind of block by inactivation
presumably
explains
the apparent
depressant
effect of topical
applications
(cf. 1011). As van Harreveld
( 1206) first pointed
out, applications
of
glutamate
to the cerebral
cortex readily
elicit spreading
depression
(807, 869);
he therefore
suggested that glutamate
released from cortical
cells may by itself
initiate spreading
depression.
This has recently been questioned
by Do Carmo and
Leao (345), who have obtained
evidence
that glutamate
only causes spreading
depression
if associated with a local mechanical
disturbance.
2) INTRACELLULAR
OBSERVATIONS.
Curtis et al. (280) were the first to show, by
intracellular
recording,
that the increase in membrane
excitability
caused by glutamate is associated with a clear depolarizing
effect. The depolarizing
action could
be maintained
during a 30-s application
of glutamate
with no evidence of marked
desensitization;
it was accompanied
by a reduction
in amplitude
of EPSP’s and
by larger IPSP’s. Intracellular
studies on cortical neurons by Krnjevid
et al. (73 1,
763) confirmed
the depolarizing
effect of glutamate
and showed that it was associated with a marked
fall in membrane
resistance
(763). In other experiments
Curtis
(258) compared
the reversal
levels for the action of glutamate
and of
EPSP’s. He found a consistent difference
between these two, the reversal level for
glutamate
being always more positive than that for the EPSP’s, which he took as
further
evidence
that glutamate
was not the natural
excitatory
transmitter.
The most systematic intracellular
studies of the effect of glutamate
have been
performed
by Zieglgansberger
and Puil on spinal neurons
( 108, 1285). These
authors
showed that motoneurons
and also other spinal
neurons
were readily
depolarized
by glutamic
acid, but cells with a low resistance (particularly
motoneurons)
were not easily made to fire spikes. The depolarization
was regularly
associated with a fall in membrane
resistance. The maximal
depolarizations
were
by 22-30 mV and the maximal
conductance
increase about 75 %. The ratio of
potential
change to conductance
changes is much greater than is observed
when
applying
inhibitory
amino acids (cf. 352, 1255), as might be expected
from a
permeability
change to an ion whose equilibrium
potential
is very different
from
the resting potential.
The potency of glutamate
in producing
conductance
changes
appears to be considerably
less than that of GABA (cf. 352). This does not necessarily mean that glutamate
is intrinsically
less potent;
it may simply reflect the
greater size of most of the spinal neurons
studied.
This is also suggested by the
relatively
slow time course of conductance
increase.
Zieglgtisberger
and Puil (1285) o b served a reversal level for the action of
and 0 mV, but noted that these values were
glutamate
somewhere
between -30
probably
partly falsified by the distribution
of current in the cell and that the true
reversal level was probably
substantially
more positive. In some recent experiments
Curtis et al. (265) showed that the depolarizing
action of a closely related excitant
amino acid, DL-homocysteic,
was not affected by intracellular
injections
of chloride
that reverse IPSP’s, so it is unlikely
that a chloride
permeability
change is involved
in the excitatory
action. Furthermore,
since the depolarizing
effect was not blocked
462
K. KRNJEVIC
by tetrodotoxin,
it cannot be mediated
propagated
action potential.
by the sodium
Volume
channels
responsible
54
for the
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3) MECHANISMOFACTION
OF GLUTAMATE.
The depolarizing
action of glutamate
is evidently
caused by an increase in membrane
permeability
(108, 763, 1285) that
permits an increased
influx of sodium ions. Most of the estimates of the reversal
potential
obtained
so far (108, 265, 1285) h ave been in the range between 0 and
-30 mV. They therefore
are consistent with a substantial
increase in K+ permeability as well as P Na and a AGNa/AGK
ratio comparable
with that observed
when
ACh is applied near the muscle end plate ( 1155).
However,
it would be premature
to conclude
that similar changes in membrane permeability
are produced
by these actions of glutamate
and acetylcholine,
since we have very little information
about the sodium equilibrium
potential
in
motoneurons.
If ENa is not at a very positive level, the effect of glutamate
could
involve mainly Z&.
Although
glutamic
acid has a substantial
chelating
action, it is unlikely
that
its excitatory
effect can be simply ascribed to the removal
of Ca2+ from the neuronal membrane
by a straightforward
chelation.
This is clear from experiments
of
Curtis et al. (277) that showed that much stronger chelators
than glutamate
were
much less effective as excitants.
This was also found to be the case in the cerebral
cortex (748). However,
some central neurons, such as the relay cells excited by hair
afferents
in the cuneate nucleus,
are markedly
sensitive to such relatively
mild
chelators
as citrate and ATP, which excite some of these cells very much like
glutamate
(though
less predictably)
(472). Th ese observations
suggest that the
action of glutamate
may involve the displacement
of Ca2+ from critical sites on the
membrane,
but other factors such as the glutamate
molecules’
shape and charge
distribution
are likely to play at least as important
a role as its chelating
power in
aqueous
solutions.
Some confirmation
of this has been obtained
recently
by in
vitro experiments
with synaptic membranes
from the guinea pig brain that show
that glutamate
and other excitant amino acids specifically
tend to mobilize
membrane-bound
Ca2+ (1159). It therefore
is possible that the permeability
change induced by glutamate
is initiated
by the displacement
of Ca2+ from certain membrane sites that control PNa. It should be noted that, like acetylcholine
and GABA,
glutamate
is only effective as an excitant when injected
outside the cells (cf. 240,
691). Its essential interaction
is clearly with some surface “receptor.”
b) Actions of aspartic acid. In most respects the effects produced
by L-aspartate
are similar to, but often somewhat
weaker than, those of glutamic
acid (277, 748),
though some lateral geniculate
cells respond somewhat
more vigorously
to aspartate than to glutamate
(913). The few intracellular
studies performed
with aspartic
acid have shown the same kind of depolarizing
action (277). There is no evidence
of any mutual interference
between the actions of these two amino acids.
c) Other releuant confounds. Somewhat
comparable
excitatory
effects can be obtained with a variety
of compounds
related
to L-glutamic
acid (287, 288, 748).
D-Glutamic
acid is consistently
much less effective, but its action is similar in time
course, and it does not interfere
with that of L-glutamate.
On the other hand,
D-aspartic
acid is not very different
in potency from L-aspartic.
Curtis and Watkins
April
1974
VERTEBRATE
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463
2. Other relevant evidence
The significance
of the “transmitter-like,”
strong and quickly
reversible,
but
by no means unique,
excitatory
action of glutamate
is very much enhanced
by the
wealth of evidence that glutamate
is not only a naturally
occurring
constituent
of
the CNS, but is also exceptionally
readily
available
through
metabolism
and is
very effectively
accumulated
by central neurons.
a) Presence of glutamate in CNS. Glutamate
is well known as the amino acid
found in highest concentrations
(5-10 pmol/g)
in the brain and other parts of the
CNS. Early reports (1, 2) gave rather high estimates of cerebral glutamate
because
they included
amino acids hydrolyzed
from protein.
The first reliable
measurebetween glutamic
ments of free glutamic
acid in tissues, *with a clear distinction
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(286) showed that one of the carboxylic
groups of glutamate
can be substituted
with a sulfonic
group without
reducing
the excitatory
efficiency;
in fact, this
may give even stronger excitant properties.
Thus, both L- and n-cysteic and -homocysteic acids are more potent than glutamic.
The strongest of the excitant
amino
acids, with a quickly reversible,
glutamatelike
action, is D-homocysteic.
An even more potent but much slower excitation
is seen with the N-methyl
derivatives
of aspartic : N-methyl-D-aspartic
acid may be the strongest depolarizing
agent of the whole group (287). A f ew less closely related compounds
have also
been shown to have strong glutamatelike
excitatory
effects; of these the most
interesting
are the naturally
occurring
ibotenic
acid, commonly
found in certain
mushrooms
(647), and a Lathyrus
neurotoxin
(895a, 1233a; K. Krnjevid
and M.
*&lorris, unpublished
observations),
both of which are significantly
more potent
than L-glutamate.
As originally
emphasized
by Curtis and Watkins (286) the characteristic
excitatory effect is seen only with compounds
having
two negative
charges and one
positive
charge at the correct separation:
hence little or no activity
is observed
when any of these essential requirements
is missing. For example,
the following
compounds,
though
very closely related,
are largely
inactive:
the simple dicarboxylic acids, such as ketoglutaric;
the amide of glutamate,
glutamine;
the longer
chain dicarboxylic
amino acids, amino pimelic
and amino adipic;
and the dipeptide, y-glutamyl
glutamate.
Summary. Very small amounts
(e.g. 10-l* mol) of L-glutamate
and aspartate
excite most central neurons quickly and reversibly;
larger amounts cause inactivation, after transient
firing. This excitation
is associated with membrane
depolarization and a fall in resistance, presumably
due to a rise in GNa, which is not sensitive
to tetrodotoxin.
The reversal level for the action of glutamate
appears to be between 0 and - 30 mV, probably
indicating
an increase in Gg as well as Gm.
There is some evidence that the mechanism
of excitation
is initiated
by a mobilization of membrane-bound
Ca 2+. A comparable
or even stronger
excitation
is also
produced
by several related
compounds
not normally
found in the brain:
the
sulfonic derivatives,
cysteic and homocysteic
acids, N-methyl
aspartic acid (especially potent but slow), ibotenic
acid, and a Lathyrus
toxin.
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acid and glutamine
were made by Krebs et al. (728). This work marked
the
beginning
of modern
investigations
into glutamic
acid and its role in cerebral
function
(cf. 1225, 1240). Studies of free ammo acids in tissues were greatly accelerated and made more precise by the introduction
of continuous
column chromatography
(1158) and of micromethods
that permitted
estimations
in small samples
of tissue (107). Surveys of different
regions of the brain (107, 1100, 1157) show
that glutamate
is present everywhere,
but is in higher concentration
(10 pmol/g)
in
the forebrain
and cerebellum:
in various
parts of the brainstem,
such as the
medulla
and pons, the concentration
is about 50 %I less.
A comparable
lower concentration
is also observed in the spinal cord. However, there are systematic
variations
in distribution
within
the spinal cord that
may indicate
that glutamate
is released by specific pathways
(512). Thus glutamate is the only amino acid consistently
at a higher concentration
in dorsal roots
than in ventral
roots, in agreement
with the possibility
that glutamate
is the
excitatory
transmitter
released
by primary
afferent
fibers (471). On the other
hand, since the ventral
gray matter contains less glutamate
than does the dorsal
gray matter, but has a relatively
high aspartic acid content, it was suggested that
aspartate
might be the transmitter
released by polysynaptic
pathways.
The fact
that a relatively
selective destruction
of spinal interneurons
by ischemia is associated with a well-correlated
loss of aspartic
but not glutamic
acid has been interpreted
as supporting
this hypothesis.
b) Subcellular locali<ation
of glutamate. Glutamic
acid, like most of the other
free amino acids, including
aspartate,
GABA,
and glycine, is widely distributed
in
neuron al cytoplasm
(860, 1059) and there is no evidence of specific sequestration
in nerve endings,
particularly
by binding
to synaptic
vesicles (cf. also 1032).
Nevertheless,
because of the quite high concentration
of glutamate
in cytoplasm,
the amount
of glutamate
held in nerve endings-presumably
by virtue of their
cytoplasmic
content-is
quite appreciable
(860); in fact it is adequate
for substantial excitatory
effects on nerve cells (769).
c) Glutamate uptake. The active absorption
of glutamic
acid by brain slices
was first observed
by Stern et al. (1131), who found that glutamate
can be removed from the bathing
medium
against a very high concentration
gradient.
This
phenomenon
has been confirmed
and studied under various conditions
by many
authors
(e.g. 56, 57, 837, 1149, 1191). The glutamate
uptake into synaptosomal
fractions
has been studied particularly
by Logan and Snyder
(837), who demonstrated a specific high-affinity
uptake mechanism,
which is especially
dependent
on
the presence of sodium ions. Much emphasis has been placed on the existence of
high-affinity
uptake processes as evidence for a significant
synaptic function,
but
some doubts about this interpretation
seem indicated
in view of the presence of
low- and high-affinity
uptake mechanisms
in a variety of nonneural
tissues (218).
Balcar
and Johnston
(57) have studied the susceptibility
of the glutamate
uptake mechanism
to inhibition
by closely related compounds
or other agents.
They were able to show that the uptake was not blocked by tetrodotoxin
nor by
several of the most potent amino acids, such as N-methyl
aspartic and DL-homocysteic, and therefore
concluded
that the uptake was not simply related
to de-
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polarization
and the entry of sodium ions, either through
tetrodotoxin-sensitive
or
-insensitive
channels.
On the other hand, the uptake is not wholly
specific since\
it is strongly
inhibited
by other agents, such as cysteic acid and aspartic acid.
There have been relatively
few studies on the cellular localization
of glutamate
taken up from surrounding
medium.
Studies on the retina suggest that glutamate
and aspartate
may be absorbed by glial cells rather than neurons (382) as in some
invertebrate
preparations
(1067). Glutamate
is also taken up actively
by periph-era1 nerves (311, 1259) but it is not certain whether
this uptake is mainly
into%
sensory or motor fibers (or both), or alternatively
into sheath cells, such as Schwann
cells. In any case, very powerful
uptake mechanisms
are evidently
available
for theremoval of any extracellular
glutamate
in the brain and other parts of the nervous
system.
d) Metabolism
of glutamate. It is clear from the many reviews on the subject
(1185, 1203, 1225, 1240) that cerebral glutamate
is a very active metabolite.
There
is general agreement
that the main source of brain glutamate
is glucose, via the
evident when labeled glucose is adKrebs cycle ( 1050, 1185). Th is is strikingly
ministered
systemically:
a remarkably
high percentage
of the labeled carbon enters
the brain within a few minutes, most of which is incorporated
in a few amino acids,
over half into glutamate
(75, 467, 468, 1222, 1283). As Vrba et al. (1222) pointed
out, the transformation
of glucose into amino acids occurs much more rapidly
in
the brain than in any other organ. Clearly, the main pathway
of glucose metabolism in the brain proceeds through
the synthesis and oxidation
of amino
acids,
particularly
glutamate.
By this kind of experiment
it can be shown that glutamate
is present in at
least two different
compartments
in the brain. One compartment
is very quickly
and effectively
labeled
with systemic glucose and is closely linked
with GABA;
presumably
this is the glutamate
from which GABA is synthesized
by decarboxylation. Another
compartment
of glutamate
is labeled more effectively
by injections
of radioactive
pyruvate
and acetate, or by exogenous glutamate,
and it is particularly closely linked with glutamine
(105, 106, 197, 790, 1055). The cellular
or subcellular
localization
of these compartments
has not yet been worked
out in any
detail.
e) Release of glutamate in CM. There is still only very limited
evidence
that
-or
any other excitatory
amino acid -is
L-glutamate
released by the activity
of
nerve endings in any region of CNS. The most convincing
data are those of Jasper
and Koyama,
who have made some systematic studies of amino acid release from
the surface of the cerebral cortex and have been able to show that it is consistently
correlated
with the state of cortical
activity
(634). The leakage of endogenous
glutamate
into fluid superfusing
the cortex of enct$haZe isole’ preparations
of cats
was greatly
increased
by stimulating
the reticular
formation
so as to evoke electrocorticographic
arousal.
There is some evidence
that labeled
glutamate
is released by electrical
stimulation
of cortical slices (533) or by stimulating
suspensions
of cortical
synaptosomes
(15 l)., With amphibian
preparations
an increase in the
rate of release of both glutamate
and aspartate can be evoked by electrical
stimulation of the isolated hemisected
spinal cord ( 1049) or sciatic nerves (3 12, 126 1).
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Although
the evidence for a significant
release of glutamate
(or aspartate)
is
still hardly very conclusive,
this should not be surprising,
even if L-glutamate
is a
transmitter,
in view of the high tissue capacity for uptake.
f) Antagonists of glutamate and other excitatory amino acids. There is no convincing
evidence
at the present that the action of glutamate
can be specifically
blocked.
A number of possible antagonists
have been proposed
in recent years, but none has
been tested sufficiently
critically
to carry conviction.
Many agents of course will
block excitation -for
example,
local anesthetics,
such as procaine,
and a variety of
agents that appear to have a similar effect on excitable
membranes
(cf. 278, 748,
75 1). It therefore
is essential that the postulated
antagonist
should produce
no
change in postsynaptic
excitability,
either by a local anesthetic type of action, by a
GABA-like
inhibitory
action, or by any other kind of direct depressant
effect.
The first suggestion
of a specific antagonist
was made by Boakes et al. (139),
who observed a consistent block by LSD 25 of the excitatory
action of glutamate
on
brainstem
neurons susceptible
to excitation
by 5-HT. Since LSD has a quite marked
local anesthetic
action on peripheral
nerve fibers (342), the effects on central
neurons may well be nonspecific
(75 1).
*McLennan
and his colleagues have recently proposed
a number
of glutamate
derivatives
as specific antagonists
of the action of glutamate,
in particular
DL-amethyl glutamate
and L-glutamic
diethyl
ester (528, 529). This claim, however,
has not received much support
from the experiments
of Curtis et al. (265); it is
made particularly
questionable
by the finding of Zieglggnsberger
and Puil (1285a)
that both these agents produce
a large increase in the membrane
conductance
of
spinal motoneurons
and thus appear to block excitation
rather like glycine. Some
previous
suggestions
that L-methionine-Dr,-sulfoximine
and Z-methoxyaporphine
might be specific antagonists
of the excitatory
amino acids have been only partly
substantiated
by recent experiments
(265). Much more thorough
and extensive
testing will be needed to find out whether
another
recently
proposed
specific
blocking
agent, 1-hydroxy-3-aminopyrrolidone
2 (146, 305), is a genuine antagonist and not another GABA-like
agent (276).
Summary. L-Glutamate
is found in high concentration
in cells throughout
the
nervous system, although
with substantial
regional
variations.
In the spinal cord
its distribution
is consistent with the possibility
that glutamate
is released by the
primary
afferent fibers. Its subcellular
localization
indicates
relatively
little bindbut nerve endings
nevertheless
contain
functionally
significant
ing to particles,
amounts.
All nervous tissue examined
has demonstrated
a strong capacity for the
uptake of glutamate;
as in the case of the other putative
transmitter
-amino acids,
there are low- and high-affimty
components
of uptake, the latter being especially
Na+ dependent.
Glutamate
takes part in several important
metabolic
processes and
can be shown to exist in two or more functional
compartments,
which may reflect
its utilization
by various kinds of excitatory
or inhibitory
neurons. There is some
limited evidence that endogenous
glutamate
is released as a result of neural activity
in the cortex, whereas labeled glutamate
has been shown to be released from brain
and spinal cord slices or synaptosomes.
April
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CATECHOLAMINES
A. Introduction
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The presence of catecholamines
in the nervous system has been known for a
long time; in fact the first specific mechanism
of neurotransmission
ever suggested
was an adrenergic
one (395). Ever since, these compounds
have kept busy a rapidly
growing
number
of investigators
(for extensive reviews see 4, 126, 198, 245, 726,
912, 1056, 1057, 1216, 1220).
The most significant
advances
in knowledge
have been the following:
the
transmitter
released by adrenergic
fibers is in fact norepinephrine
(12 16) ; the two
broad classes of adrenergic
effects [thought
to be mediated
by different
agents,
sympathin
E and sympathin
I (cf. 198)] can be accounted
for by two principal
kinds of receptors,
the cy- and ,&types, found on many cells, and having different
sensitivity
to various
agonists and antagonists
(10, 816, 933); reuptake
by the
presynaptic
nerve terminal
is probably
the most important
mechanism
of removal
of NE liberated
at the synapse (47); histochemical
techniques
are now available
that are capable
of showing
the localization
of catecholamines
in various tissues
(202); finally, the development
of a remarkably
effective agent capable of destroying relatively
selectively
neurons rich in catecholamines
has provided
an outstandingly useful tool for studies of the function
of adrenergic
pathways
(859).
Although
it seemed for a time that all adrenergic
junctions
operate
by the
release of NE, the discovery
of dopamine
(DA) in certain nerve cells of the CNS
(201) led to numerous
studies of the hypothetical
dopaminergic
pathways
and of
their chemical
characteristics
(cf. 62, 601, 602, 1113) including,
m.ost recently,
possible dopaminergic
neurons even in sympathetic
ganglia ( 120).
Before considering
in more detail the mechanism
of adrenergic
junctional
action, it may be useful to summarize
the principal
known features of the synthesis,
storage, and release of catecholamines.
The pathway
of synthesis is as follows. The immediate
precursor
of DA,
L-dopa,
is obtained
from phenylalanine
or tyrosine by hydroxylation;
this ratelimiting
step in the synthesis appears to be regulated
by the concentration
of its
products
and it is mediated
by tyrosine hydroxylase,
an enzyme found in soluble
form in neuronal
cytoplasm.
A relatively
unspecific-also
cytoplasmic-decarboxylase converts the amino acid dopa to dopamine.
The accumulation
of DA in
cytoplasm
is limited
by monoamine
oxidase, which converts
catecholamines
to
inactive
compounds.
However,
DA can be taken up by intraneuronal
granulesvariously
known as dense-core,
osmiophilic,
or granular
vesicles-by
a process that
In the storage granules
requires Mg2+ and ATP and can be blocked by reserpine.
DA may be converted
to NE, through
the action of dopamine-P-hydroxylase.
Although
NE is thus synthesized
inside these intraneuronal
vesicles, an efficient
uptake mechanism
makes possible the recapture
of most of the NE released from
nerve terminals,
which
otherwise
would
be disposed
of by the predominantly
extracellular
catechol-o-methyltransferase.
For detailed
evidence
on these various
468
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45
B. Catecholamines
in Peripheral
Transmission
Adrenergic
mechanisms
(acting by the release of NE) have been the most extensively studied.
Until recently
DA was thought
of principally
as a precursor
of
NE, although
DA appears
to be the predominant
catecholamine
transmitter
in
invertebrates
(1247). But there is now growing
interest in the possibility
that DA
may itself be a transmitter,
released by dopaminergic
neurons
(see below).
The
postganglionic
sympathetic
neurons are generally
believed to produce their effects,
whether
excitatory
or inhibitory,
mainly through
the liberation
of NE (485, 983,
1104, 1146, 1215-1217).
1. Norepinephrine
actions on smooth muscle
There is a great deal of information
about smooth muscle, especially
in the
intestine,
where NE has an inhibitory
action. The excitatory
effects are best seen
in vascular
smooth muscle or in the vas deferens. The latter especially
has been
investigated
in great detail (482, 590, 592, 1101, 1146).
a) Excitation. The vas deferens is very rich in NE-containing
nerve terminals.
It is characterized
by the presence on most of the muscle cells of closely apposed
terminal
varicosities,
containing
small and large granular
vesicles (9 1, 188, 1146).
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points, the reader is referred
to the many available
reviews (46-48,
242, 495, 496,
582, 601, 717, 858, 924, 1054, 1216, 1217, 1241, 1242).
In adrenergic
cells NE is probably
stored in both large and small granular
vesicles, but in their terminals
it is present mainly
in small vesicles, apparently
bound to ATP and a specific protein,
chromogranin.
The number
of vesicles in a
terminal
varicosity
is approximately
1000, and there are about 15,000 molecules of
NE per vesicle (25, 188, 477, 582, 1103).
The release of NE and other catecholamines
has also been studied, though less
extensively
(47,495,
525,612,
1056, 1104). A s in other kinds ofjunctions
the release
process depends on the presence of Ca2f and is inhibited
by Mg2f. Although
miniature junctional
potentials
(592) indicate a quanta1 release-which
is consistent with
a process of exocytosis from vesiclesthere is a marked discrepancy
between the
apparent
vesicle NE content and the amounts released. If one assumes that every
nerve impulse liberates
NE from all the terminal
varicosities
of a given fiber, the
mean release per varicosity
(about 400 molecules)
is only about 2.5 % of the estimated content per vesicle (527). Can vesicles release just a small fraction
of their
NE content?
Perhaps the vesicles from which the release takes place contain
untypically
small amounts of NE. Of course NE might not be released directly from
vesicles, but rather from some other compartment
(497), possibly even a cytoplasmic pool. But then how can one explain the surprisingly
wasteful simultaneous
and proportional
release of the normally
intravesicular
proteins,
dopamine-Bhydroxylase
and chromogranin
(48, 1104, 1243) ? The most questionable
assumption is that all varicosities
necessarily
contribute
to the observed release.
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Intracellular
recording
has revealed spontaneous
miniature
activity (193) in many
ways comparable
to that seen in skeletal muscle (cf. 669). Junctional
potentials
are also evoked by nerve stimulation
(192, 780). They are depressed
by phentolamine
and other a-blocking
agents, though
only by relatively
large doses (20,
194, 780).
Since transmission
is not fully blocked
by doses of cY-antagonists
1000 times
greater
than are necessary to abolish the effects of NE, Ambache
and Zar (20)
have argued that transmission
cannot be adrenergic.
However,
this does not necessarily follow. Many of the nerve-muscle
junctions
in this tissue have only a very
small intercellular
gap (2OOA), so the transmitter
liberated
from the terminal
must
be at a very high concentration
(approaching
10m3 M, as in other junctions
of comparable dimensions).
Unless the receptors have a particularly
high affinity for the
blocking
agents, it may well be impossible
to obtain a total block without
using
extremely
high doses of antagonists,
which are liable to produce nonspecific
effects
(cf. 1146). On the other hand, when applied
directly,
NE interacts with a much
wider population
of receptors (probably
including
extrajunctional
ones) : therefore
strong effects are produced
by much lower concentrations
of NE, which are readily
counteracted
by moderate
doses of antagonists.
Neuromuscular
transmission
should
be blocked more easily when the nerve terminals
remain at some distance from the
muscle fibers. This is indeed the case in the vas deferens of very young animals
( 1147) and, in the adult, in vascular smooth muscle, where phentolamine
and other
cy-antagonists
readily block both nerve-evoked
contractions
and the excitatory
effect
of NE (593). The problem
is by no means settled. According
to the most recent
study of Ambache
et al. (19), tyramine,
which releases endogenous
NE, has a
mainly inhibitory
action on the vas deferens that can be blocked by a-antagonists.
These authors
therefore
conclude
that the motor innervation
cannot be noradrenergic.
There is no real evidence
about the mechanism
of the presumed
adrenergic
excitations
(cf. 300, 592, 1114), but it has generally
been assumed that it is similar
to that of the cholinergic
excitation
of skeletal muscle (592). Reversal
potentials
and changes in membrane
conductance
are not easily studied:
owing to intercell
coupling,
junctional
potentials
can be recorded far from their site of origin throughout a region that includes several cells.
b) Inhibition.
There
is a greater
amount
of information
about
membrane
phenomena
accompanying
inhibition
than for excitation.
The smooth muscle of the intestine
shows predominantly
inhibitory
(both cyand /3-) adrenergic
effects (485, 590, 592, 781), but uterine
and vascular smooth
muscle is clearly inhibited
only by P-agents or by NE after blockade
of a-receptors
( 147, 299, 300, 593, 1114). The mechanism
of the inhibitory
action on the intestine
has been studied
particularly
in the taenia coli by Biilbring
and her colleagues
(49, 177-180,
187, 852, 1182). Th ese authors were at first inclined
to believe that
NE primarily
activates metabolism
and an electrogenic
ion pump,
thus causing
hyperpolarization
and inactivation
of the spikes (e.g. 187; cf. 1109). An alternative
hypothesis
was that an increase in metabolism
promotes
Ca2+ binding
in the membrane, thus reducing
I& (178).
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After Jenkinson
and Morton’s
(638, 639) finding
that NE causes a large increase in K fluxes in taenia coli (but little change in fluxes of Na+ or Cl-), Biilbring
and Tomita
(179, 180) made further
experiments
and indeed observed
a large
increase in membrane
conductance
that could be attributed
mainly to a rise in PK
(and, to a lesser extent, in P,r). Since the effect is so dependent
on the external
Ca2+ concentration,
it was suggested that membrane-bound
Ca2+ induces a high
Kf permeability.
They agreed with Jenkinson
and Morton’s
(639) opinion that this
is an a-receptor
action. But when this is selectively
blocked, a P-receptor
action is
revealed,
which also inhibits
the generation
of spikes or contraction,
even of fully
depolarized
muscle. The ,&effect is believed
to be due to an interference
with the
spike pacemaker
potential
and, presumably,
the influx of Ca2+ (639).
Catecholamines
would thus affect membrane
Ca2+ in two ways. In the a-mode
they would promote
membrane
binding
of Ca2+, which somehow enhances movements of K+. This effect is perhaps comparable
to the potentiation
of G, caused by
intracellular
injections
of Ca2+ in spinal motoneurons
(740) ; in both cases the critical step may be an interaction
between Ca2+ and the inner surface of the cell membrane. In the P-mode catecholamines
would immobilize
membrane-bound
Ca2+ or
reabsorb free Ca2+ and so prevent depolarization
and generation
of the pacemaker
potential
(180, 852). It is of interest that comparable
a- and @-membrane
effects
are seen with liver cells (544, 545). According
to the observations
of Kao et al.
(619, 657) the P-adrenergic
action causes a hyperpolarization
without
changing
membrane
conductances,
apparently
by increasing
the negative
level of &;
this
was thought
to indicate
a primary
metabolic
effect, which enhances the intracellular accumulation
of Kf.
The initial
mechanism
of the P-action
is widely believed
to be mediated
by
activation
of a membrane
adenyl cyclase and the consequent
formation
of cyclicAMP
(CAMP)
(161, 354, 575, 1052). The further
steps, however,
are not clear.
Cyclic-AMP
is known to promote
the phosphorylation
of various enzymes, especially those concerned
with glycolysis in muscle. The P-inhibitory
action could then
be explained
in several ways. The increased
supply of glucose could accelerate
outward
pumping
of Na+ (and therefore
also initiate
an “electrogenic”
hyperpolarization).
Alternatively,
CAMP could directly,
or through
some metabolic
reaction,
alter Ca2+ levels in or near the membrane
(cf. 179, 180). Finally,
CAMP
could regulate
specific ion permeabilities
by phosphorylating
a membrane
protein
concerned
in ion movements
(688). However,
as pointed out by Daniel et al. (300)
and Polacek and Daniel
(1002), there is little real evidence that CAMP mediates
changes in membrane
properties
evoked by P-receptor
actions. A fall in &
(which
may or may not be secondary
to changes in Ca 2f binding)
may be a direct effect of
the catecholamine.
The hypothesis
that NE activates an electrogenic
pump has not
had much support recently
(147, 300).
Summary. Both excitatory
and inhibitory
adrenergic
innervations
have been
described.
The motor
innervation
of the vas deferens
and of vascular
smooth
muscle may operate by the release of NE, but the evidence
is not conclusive,
particularly
for the vas deferens, where junctional
transmission
is not readily blocked
by NE antagonists.
The mechanism
of excitation
has not yet been elucidated.
April
1974
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Inhibitory
actions are more common
and they have been analyzed
in much more
detail. They appear to have two components.
The first, which is blocked by cu-antagonists, is associated with an increase in membrane
conductance,
probably
due
to a rise in GK. The second is blocked by P-antagonists
and is not associated with a
conductance
increase;
its mechanism
has been variously
explained
as involving
stronger
binding
of Ca 2f to the membrane,
a reduction
in GNa, the liberation
of
CAMP and/or
activation
of Na-K pumping
(probably
not electrogenic).
actions on ganglia
Sympathetic
ganglion
cells show a late inhibitory
effect of preganglionic
stimulation,
the slow IPSP, which is probably
mediated
by a catecholamine
inhibitory transmitter
(380, 705, 706,824,827).
This IPSP has rather unusual properties
:
it is depressed by depolarization
and increased
by moderate
hyperpolarization;
it
is not associated
with a detectable
change in membrane
resistance;
and it is relatively insensitive
to changes in external
K+ or Cl- concentrations
(705, 939).
Nishi and Koketsu
(939) therefore
suggested that this IPSP is generated
by an
Kobayashi
and Libet (705) could not produce
a
electrogenic
Na pump; however,
selective block with ouabain
and therefore considered
the hypothesis
of an electrogenie Na pump very unlikely.
After demonstrating
a close similarity
between the
slow IPSP and the hyperpolarizing
effect of injections
of NE, Kobayashi
and Libet
(706) concluded
that it must be produced
by adrenergic
fibers, although
they could
not explain
its mechanism.
The finding
that the small, intensely fluorescent
ganglion
cells-the
probable
-contain
DA rather
than NE (120) has led
adrenergic
inhibitory
interneurons
Libet and Tosaka (827) to reexamine
the properties
of the postulated
adrenergic
inhibitory
system: DA proved to be as effective an inhibitor
as NE. This action of
which
are blocked
by phenoxybenzamine
but
DA is mediated
by a-receptors,
rather
insensitive
to phentolamine
or P-blockers.
Since a block of dopamine-/3hydroxylase
activity
(which converts DA to NE) potentiates
the IPSP, it appears
that the natural
inhibitory
transmitter
is indeed more likely to be DA. The same
authors made a further,
unexpected
observation:
DA has a remarkably
potent and
prolonged
facilitatory
action on the slow, muscarinic
EPSP.
Kebabian
and Greengard
(688) have now found in these ganglia an adenyl
cyclase that is stimulated
by small amounts
of DA, actz’ng as an a-agent (cf. 1052,
1053). They suggest that CAMP and a protein
kinase phosphorylate
a membrane
protein involved
in ionic permeability.
These authors did not specify what change
in permeability
is actually produced,
but a simple explanation
could be a reduction
in Na+ permeability
(300,400,
1094). This would be consistent with the depression
of the slow IPSP by depolarization
and the absence of large changes in resistance.
Everything
else being equal, the change in membrane
resistance needed for a
given potential
change should be proportional
to the initial membrane
conductance
(G) for the relevant
ion. Hence the resistance would rise much less during an IPSP
generated
by a fall in G Na than during an EPSP of comparable
amplitude
caused by
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2. Cutecholamine
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C. Catecholaminesin CNS Transmission
There is a continual
large output of literature
dealing with the presence, synthesis, degradation,
uptake, and other aspects of the metabolism
of catecholamines
in the CNS and its possible relation
to cerebral function
and general behavior
(for
some reviews see 126, 133, 465, 495, 497, 622, 697, 983, 984, 1197, 12 16, 124 1).
However,
since much of this cannot yet be related to specific mechanisms
of synaptic transmission,
the present discussion is concerned
mainly with evidence demonstrating
clear effects of catecholamines
on central neurons,
especially
where they
appear to be related to synaptic mechanisms.
Both excitatory
and inhibitory
effects of catecholamines
have been observed.
As a rule the main catecholamines
have comparable
actions, but the order of
potency or direction
of action may vary greatly in different
regions and perhaps
under different
conditions,
e.g. of anesthesia. No attempt is made to enumerate
the
relative potencies at various sites, but in general norepinephrine
appears to be more
active in the spinal cord, lower brainstem,
and cerebellum,
whereas dopamine
is
often the more effective agent in various parts of the forebrain.
Dopamine
is considered in greater detail when dealing with areas such as the striatum,
where it is
present in particularly
large amounts
and where it is believed
to be playing
an
especially
important
transmitter
role.
1. Depressunt actions
a) General. The most commonly
observed actions are depressant.
They have
been seen in the lateral geniculate
(260, 989), cerebral
cortex (75 1), hippocampus
(118), pyriform
cortex (809), hypothalamus
(137), olfactory
bulb (1064), striatum
(132,567),
thalamus
(986), medial geniculate
(1164), spinal cord (401), red nucleus
(687, 1090, 1091, 1279), and midbrain
(308), medulla
( 140, 153, 247) ; cerebellum
reticular
formation
and superior
colliculus
( 114 1).
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a fall in GK, because the resting G&GK
is likely to be only about Ho. It might be
difficult
to demonstrate
conclusively
such a small resistance change with certainty.
In support of this scheme, McAfee
and Greengard
(879) have recently
obtained
some evidence that both DA and monobutyryl
CAMP hyperpolarize
the ganglion
cells and that these effects and the slow IPSP are potentiated
by theophylline,
which speeds up the accumulation
of CAMP in the ganglion,
probably
by inhibiting
phosphodiesterase
activity.
Summary. There is strong histochemical
and pharmacological
evidence
that
the slow IPSP evoked by preganglionic
stimulation
is mediated
by small interneurons releasing either NE or (more likely) DA. This inhibitory
action is mediated
by a-receptors;
it is associated with no marked change in resistance, and the IPSP
The mechanism
of action has been ascribed
to
is depressed
by depolarization.
activation
of an electrogenic
pump or a reduction
in GNa. There is some evidence
that the NE/DA
receptor is an adenyl cyclase and that CAMP mediates the change
in excitability.
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These blocking
effects have a variable,
though
often relatively
quick, time
course, but they are seldom as sharp as the inhibitory
actions of o-amino
acids (see
above). Although
attempts have been made to correlate
the sensitivity
of various
cells with the presence of pathways
postulated
to be catecholaminergic,
largely on
the evidence of specific histofluorescence
(cf. 291, 465), such correlations
have not
been very conclusive.
For example,
Hongo and Ryall (598) did not find sympathetic
preganglionic
neurons to be particularly
sensitive to NE, even though they appear to receive a
rich innervation
from descending
NE-containing
fibers. More recent findings have
raised some doubts about a proposed
adrenergic
inhibitory
system in the olfactory
bulb ( 1065). The extensive studies of Lundberg
and his associates, while providing
strong inferential
evidence for the involvement
of a descending
adrenergic
pathway
in the control of spinal activity, have not yet succeeded in demonstrating
the precise
site of adrenergic
regulation
(9, 103, 401). There is well-documented
evidence that
the hypothalamus
contains
particularly
large amounts
of NE (29 1, 1196, 12 11,
12 12), that direct applications
of NE in the region of the hypothalamus
lead to
changes in body temperature
(428) or in behavior
[especially
eating (cf. 443, 520,
8 12, 905)], that NE is released in the hypothalamus
(1123), and that when applied
by microiontophoresis
NE excites some hypothalamic
neurons
(137, 727, 917) ;
nevertheless
no adrenergic
pathways
have been demonstrated
in the hypothalamus
with any certainty
or even a high degree of probability.
6) Norepinephrine
in cerebellum. Bloom and his collaborators
believe that they
have obtained
good evidence for the operation
of an adrenergic
inhibitory
system
in the cerebellar
neocortex.
Yamamoto
(1279) was the first investigator
to observe a depressant
action of
NE applied
microiontophoretically
on neocerebellar
neurons in the cat. A depression of the spontaneous
firing of Purkinje
cells has been seen by many later authors
(502, 503, 578, 687, lOgO>, but it is not clear whether the same kind of depressant
mechanism
operates in all species: the effects of NE are quite rapid in the rat, being
approximately
synchronous
with its application
(578), whereas in the cat they are
slow and prolonged
and somewhat
less obvious (687, 1279).
Norepinephrine
is not as strong an inhibitor
as GABA;
the typical effect is a
partial depression
of firing, even when NE is given in amounts several times greater
in potency between
than doses of GABA (578, 687). Th ere is no marked difference
NE and other catecholamines,
although
the action of NE is diminished
more effectively by a P-antagonist
(MJ-1999)
than by other adrenergic
blocking
agentsmost of which, however,
are not readily
tested on cerebellar
neurons
because of
“local anesthetic”
effects (578). According
to the same authors, monononspecific
amine oxidase (MAO)
inhibitors
enhance the action of applied NE.
Does this depressant
effect of NE bear any relation to an adrenergic
inhibitory
innervation
of the cerebellar
cortex? The histofluorescence
technique
of Hijkfelt and
Fuxe (583) has revealed in the cerebellar
cortex of the rat a widespread
plexus of
rather sparse, NE-containing
nerve fibers and terminals
that probably
originate
outside the cerebellum,
presumably
in the brainstem.
According
to further studies
(954), the cells of origin are all in the nucleus of the locus coeruleus,
situated in the
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floor of the fourth ventricle.
Using a combination
of histofluorescence
and electronmicroscopic
and radioautographic
techniques,
Bloom et al. (135) have shown that
some terminals
on Purkinje
cells contain
or take up NE and that these terminals
tend to disappear
after treatment
with 6-hydroxydopamine.
But the vesicles in
these terminals
are neither flattened
[as might be expected of inhibitory
fibers (143,
979, 1194)] nor of the small or large granular
type characteristic
of adrenergic
terminals
(cf. 188, 477, 1103). It is curious that, in the cerebellum,
large granular
vesicles are seen most commonly
in the terminal
of the powerfully
excitatory
climbing fibers (802).
The morphological
observations
thus are not very consistent. But Siggins and
Hoffer and their coworkers
(580, 1093) h ave obtained
some further
evidence supporting
the hypothesis
of an inhibitory
projection
from the locus coeruleus : discrete
electrical
stimulation
of this nucleus apparently
causes a widespread
inhibition
of
cerebellar
Purkinje
neurons (but having a very much slower time course than the
effects of NE). This inhibition
is said to be potentiated
by inactivation
of cyclic
nucleotide
phosphodiesterase
[which would augment
tissue levels of CAMP, the
supposed
mediator
of the action of NE (see below)]
and blocked specifically
by
drugs that may interfere
with the supply of NE, such as reserpine
and cr-methylpara-tyrosine,
or the production
of CAMP (prostaglandins)
or that destroy noradrenergic
pathways
(6-OH-dopamine)
(580).
On the other hand, observations
of the general behavior
and motor activity of
rats treated with sufficient
6-OH-dopamine
to eliminate
permanently
most of the
cerebellar
NE have not revealed
any prolonged
marked impairment,
even when
the lesions are made in very young animals (127, 626, 1162). The contribution
of
the supposed adrenergic
inhibitory
system to cerebellar
function
therefore
is not
very clear.
Summary. The most commonly
observed
effect of NE (and other catecholamines)
in most parts of the CNS is depression
of firing.
Though
variable,
it is
usually quick and reversible,
but is seldom as striking
as the action of inhibitory
amino acids. Attempts
to correlate
NE sensitivity
with histochemical
evidence of
adrenergic
innervation
have not been very successful, with the possible exception
of a proposed
adrenergic
projection
from the locus coeruleus to the neocerebellum.
In the rat particularly,
cerebellar
Purkinje
cells are quite sensitive to NE, which
appears to inhibit
firing by a P-action. There is some evidence that stimulation
of
the locus coeruleus
also inhibits
these cells, but the existence and the specificity
of
the postulated
connection
are not yet fully established.
c) DoFamine in striatum and other parts of CNS. The presence of large amounts of
DA in the brain, especially
in the striatum,
was discovered
by Carlsson (201). It
has been confirmed
by extensive studies of DA and its metabolism
(495, 497, 601603,636,
1197). These indicate the possibility
that DA is a central neurotransmitter.
A substantial
action of DA was first demonstrated
on cortical
neurons
by
Krnjevid
and Phillis (75 1). Several catecholamines,
applied by microiontophoresis,
depressed unit firing, the most potent being DA. Comparable
depressant
actions of
DA were observed subsequently
in some other regions of the forebrain:
the hippocampus ( 118, 566) and particularly
the striatum
(132, 235, 437, 567, 895). Excita-
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tory effects have been seen only rarely, except by York (1282), who observed mainly
excitation
when DA was applied in the putamen.
In various thalamic
nuclei, as in the cerebral cortex, DA is much more potent
than NE (987, 1164, 1167); in the cerebellar
cortex its potency is comparable
to
that of NE (578, 687). By contrast, in the lower brainstem
and the spinal cord DA
is consistently
much weaker than NE (115, 153, 47 1, 611, 1128), though here as
elsewhere its effects are predominantly
depressant.
Thus DA has several of the attributes
of a neurotransmitter,
most likely of
inhibition,
but perhaps even excitation
if York’s observations
on the putamen
can
be confirmed.
The greater
prominence
of DA-containing
pathways
(463, 1197)
and stronger effects of DA in the forebrain
(including
the hypothalamus
and thalamus) suggest that dopaminergic
pathways
are more likely to operate in that area.
Various
specific pathways
have been proposed,
the most extensively
studied being
a possible dopaminergic
connection
between the substantia
nigra and the striatum.
The DA content of the striatum
is greatly reduced
after lesions in the substantia
nigra or at sites between the nigra and the striatum
(28, 84, 505, 586, 910, 1000,
1196), suggesting
the presence of a direct nigrostriatal
pathway.
If this system is
mainly
inhibitory,
its destruction
by disease could result in excessive activity
of
extrapyramidal
pathways
that control
movements
and so account
for various
manifestations
of parkinsonism
(61, 111, 601, 1113). This scheme would explain
the beneficial
effect of treatment
with L-dopa, the direct precursor
of DA (cf. 62,
246, 1196).
With only few exceptions
(442, 708, 1028), classical anatomists
believed
that
only descending
pathways
connect the striatum with the midbrain.
Although
Shute
and Lewis (1087) found evidence
of a direct nigrostriatal
projection
of AChEcontaining
fibers, according
to Oliver et al. (953) these fibers in fact project in the
opposite direction,
from the striatum
to the substantia
nigra. On the other hand, a
recent study of terminal
degeneration
produced
in the caudate of the monkey by
nigral lesions has confirmed
the presence of nigrostriatal
connections
(204);
according
to Golden (504), in the fetus one can readily observe a continuous
system
of nigrostriatal
DA-containing
fibers (which in the adult animal cannot be demonstrated without
pharmacological
manipulations).
It therefore
cannot be doubted
that direct ascending
nigrostriatal
connections
do exist and that at least some of the connecting
fibers contain DA. The presence
of a functional
dopaminergic
pathway
is further
suggested by some evidence that
nigral or caudate stimulation
evokes the release of DA or its metabolites
from the
striatum
(109, 889, 1006, 1221). Unfortunately
the only monosynaptic
nigrostriatal
pathway
for which there is convincing
electrophysiological
evidence-the
slowconducting
nigrocaudate
link carefully
analyzed
by Feltz (435, 438)-has
proved
to be excitatory
and almost certainly
neither
dopaminergic
nor cholinergic
(434,
437), in agreement
with Hull et al.% (615) conclusion
that all inputs into the
caudate
are probably
excitatory.
Hence,
the clear inhibitory
effects of nigral
stimulation
may not be mediated
by direct nigrostriatal
inhibitory
connections.
The substantial
persistence
of this inhibition
after destruction
of the DA-containing
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fibers in the caudate
argues strongly
against a purely
dopaminergic
inhibitory
link (436).
If DA is neither
an excitatory
nor an inhibitory
transmitter
in the caudate,
what is its function
there? One could imagine that it has a general depressant effect
on neuronal
activity
or on the excitations
produced
by other inputs [a kind of
modulating
action (437)]; h owever, some doubt is cast on even this suggestion
by
Buchwald
et al.? (174) observation
that lesions of the nigrostriatal
pathway,
which
cause a large reduction
in striatal DA content, do not alter significantly
the rate of
spontaneous
neuronal
firing recorded in the caudate-although
such lesions appear
to increase spontaneous
firing in the putamen
(950). As suggested by Buchwald
et
al. (174), one must seriously consider
the possibility
that interruption
of a dopaminergic
nigrostriatal
pathway
is not the only or perhaps not even the main factor
responsible
for the manifestations
of parkinsonism.
It is therefore
of interest that
McGeer
et al. (882) have recently shown in parkinsonian
patients a pronounced
loss of glutamic
decarboxylase,
the enzyme responsible
for the synthesis of GABA,
to whose inhibitory
action caudate neurons are particularly
sensitive (434). The
delayed beneficial
effects of large doses of L-dopa may be due to an indirect mechanism, such as a general loading of neurons with dopamine
and its release by pathways that are normally
not dopaminergic
(930).
Summary. In the forebrain,
upper brainstem,
and cerebellum,
the action of DA
is rather consistently
inhibitory,
with a potency equal to or greater than that of NE.
The presence of large amounts of DA in the striatum
and hypothalamus
has been
taken to indicate
the existence of important
dopaminergic
pathways,
especially
an ascending
link between the substantia
nigra and the striatum.
Although
there is
considerable
biochemical,
histochemical,
pharmacological,
and even clinical
evidence for such a pathwayincluding
the demonstration
that nigral stimulation
causes the release of DA or its metabolites
in the striatum
and that most striatal
cells are depressed
by DA-there
is still no convincing
electrophysiological
evidence of the operation
of such a pathway
at the cellular
level.
d) Mechanism of inhibition by NE. It is still not clear how NE depresses excitability. Phillis et al. (990) reported
that NE (as well as 5-HT and histamine)
causes
a hyperpolarization
of spinal motoneurons,
associated with a reduction
in excitability and in the amplitude
of EPSP’s and IPSP’s. According
to Engberg
and
Marshall
(400), this hyperpolarizing
action is accompanied
by an increase in membrane resistance
and is enhanced
by a conditioning
hyperpolarization
and diminished by depolarization
(if large enough,
this can even reverse the effect of NE).
These authors
therefore
conclude
that NE may reduce the ionic permeability,
especially
Z& .
Siggins et al. (1091, 1093) have observed
a similar
pattern
of changes in
Purkinje
cells during applications
of NE-although
the reported
increases in intracellular
negativity
and membrane
resistance seem very much greater than might be
expected
to occur physiologicallyand they concluded
that NE inhibits
these
neurons by inactivating
&a or Pea. This effect was at least partly antagonized
by a
P-blocking
agent. These features
bear a certain
resemblance
to the P-receptor
action in smooth muscle, which is also consistent with a reduction
in membrane
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permeability
to Na+ or Ca 2+ (300). However,
it will be necessary to eliminate
the
possibility
of an indirect or presynaptic
effect reducing
an ongoing release of excitatory transmittei,
as this would give an identical
result.
A very different
mechanism
has been proposed by Phillis et al. (985) to explain
the inhibition
of cortical
neurons. They have found that this action of NE can be
such as lanthanum
and manganese,
and thereblocked by some “Ca antagonists,”
fore suggest that the inhibition
is initiated
by a change in membrane
permeability
in a rise in internal
free Ca2+ and a fall in excitability
to Ca2+, possibly resulting
comparable
to effects produced
by intracellular
injections
of Ca2+ in spinal motoneurons (740).
Without
much more evidence, it is impossible
to decide whether NE can inhibit
central neurons by two distinct mechanisms-one
by reducing
GNa and the other
by an increase in GK, roughly
analogous
to the P- and the a-receptor
actions in the
gut, respectively:
it is also not clear whether
the effects observed in different
parts
of the CNS are essentially of the same nature.
1) ROLE OF CYCLIC AMP. In support of Yamamoto’s
(1279) suggestion
that the
inhibitory
action of NE might be mediated
by CAMP, Siggins et al. (1090, 1091,
1094) and Hoffer et al. (579) have presented
evidence that CAMP inhibits
cerebellar neurons like NE, that inhibitors
of phosphodiesterase
potentiate
the action
of NE, and that Purkinje
cells are particularly
rich in CAMP (134). They therefore
believe that NE acts through
the intermediary
of CAMP. This hypothesis
is consistent with the idea that in many tissues [including
some identifiable
nerve cells
(SSS)] adenyl cyclase acts as a P-receptor
( 161, 300, 575, 1019, 1052, 1053, 1109).
There are several serious objections
to this interpretation.
It is not easy to
understand
how the applied CAMP penetrates
the cell membrane
rapidly
enough
to produce
the effects reported
(cf. 787); if it does penetrate,
how do these effects
lead to a transient
reduction
in membrane
pNB. There is little evidence that CAMP
is directly
involved
in changes in membrane
permeability
of other excitable
tissues
(300, 1002). Furthermore,
adenosine
and some other derivatives
such as AMP
and ATP, which also greatly increase the CAMP levels of the brain tissue (10 18,
1019), were found to have no inhibitory
action on Purkinje
cells (579). There are
serious doubts about the direct relevance
of studies on brain slices, in view of the
demonstration
that NE greatly increases the accumulation
of CAMP by neuroglia
assumption
(579, 688, 879,
(221, 487). 0 ne wonders also about the unquestioning
1091) that methylxanthines
have no other significant
action in tissues than to
inhibit
phosphodiesterase
activity (cf. 1001, 1018, 1019).
It should be noted that Godfraind
and Pumain (502, 503), who tried to repeat
the experiments
on the cerebellum
of the rat, could not obtain a marked depression
of Purkinje
neurons
with CAMP.
Purpura
and Shofer (1012) have seen mainly
excitatory
effects of CAMP in the immature
cerebral
cortex, and Lake and Phillis
(792) observed little or no effect of CAMP on cortical neurons, as well as no relation
between
the inhibitory
potency
of NE in different
species and the amounts
of
CAMP previously
found to be produced
by NE in the cortex of the same animals.
On the other hand, Anderson
et al. (31) have reported
that CAMP depresses neuronal firing in the lower brainstem.
Finally,
the possibility
of a mainly presynaptic
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phenomenon
should be kept in mind in view of the fact that adenosine
and 5-AMP,
which specifically
increase the CAMP content of nerve terminals,
both diminish
the release of ACh from motor nerve endings in muscle (493, 494).
Unless further,
much more critical evidence is presented,
the hypothesis
that
noradrenergic
inhibition
of cerebellar
or other neurons
is directly
mediated
by
CAMP can only be viewed with reservation.
Summmy. There are at present two principal
explanations
for the mechanism
of inhibition
by NE. One is based on preliminary
observations
that NE causes a
hyperpolarization
of spinal motoneurons
and cerebellar
Purkinje
cells associated
with a rise in resistance;
since the hyperpolarization
is reduced
or even reversed
by depolarization,
it can be ascribed to a reduction
in GNa (or possibly G&.
A
second hypothesis
proposes that NE increases Ca2+ influx and therefore
leads to a
secondary
hyperpolarization
by a rise of GX. Strong claims have been made that
the inhibitory
effects of NE and DA in the cerebellum
and sympathetic
ganglia
are mediated
by CAMP, but the evidence is insufficiently
complete for any definitive conclusions,
particularly
with regard to the action of catecholamines
at other
sites in the CNS.
e) Role of prostaglandins.
Prostaglandins
are ZO-carbon fatty acids folded over
in a double chain by an internal
link forming
a cyclopentane
ring. They have a
strong action on smooth muscle and occur naturally
in various tissues (104, 605,
12 14). Since they are not only present in the CNS, but can be shown to be released
from the brain and spinal cord (158, 223, 224, 1022), they have been proposed
as
potential
neurotransmitters
(360, 604, 605).
However,
the exceedingly
slow and prolonged
changes in spinal reflexes apparently
produced
by prostaglandins
(360) hardly indicate
a transmitterlike
action
(cf. also 223). Tests of prostaglandins
E (especially
EJ applied
directly
to nerve
cells have shown either no clear effect, as in the cerebral
cortex (732, 792) and the
cuneate nucleus (223), or, in some other parts of the medulla,
an excitatory
action
characterized
by very rapid desensitization
(44).
According
to S&gins et al. (1092), although
prostaglandins
E have variable
effects on the Purkinje
cells of the rat cerebellum,
they consistently
and specifically
antagonize
the inhibitory
action of NE. This was interpreted
as due to a reduction
in CAMP formation,
and therefore
in keeping
with the hypothesis
that CAMP
mediates the action of NE. However,
this seems a weak argument
without
some
evidence
that prostaglandins
E reduce adenyl cyclase activity in these cells [cf. a
similar argument
used by McAfee and Greengard
(879) with regard to the action
of DA in sympathetic
ganglia],
especially
since the most common
effect of prostaglandins
is to speed up the formation
of CAMP in various tissues ( 104, 1083), including
some nerve cells (486).
Although
it is not clear what general role prostaglandins
would have in synaptic transmission,
the fact that they appear to be widely released during nerve terminal activity
(225, 558, 559, 1023) does suggest a significant
function : perhaps a
postsynaptic
one, leading to the mobilization
of membrane-bound
Ca2+ (225; cf.
also 1030, 103 1, 1083), or a presynaptic
negative
feedback,
limiting
the release
of the neurotransmitter
(557-559,
1146).
April
1974
VERTEBRATE
SYNAPTIC
TRANSMISSION
479
Summary. The available
evidence does not appear to indicate
a simple neurotransmitter
function
of prostaglandins
at central or peripheral
junctions,
but their
evident release in the tissue during activity may be of significance
in the presynaptic
control
of transmitter
release (probably
inhibited
by prostaglandins)
as well as
influencing
excitability
through
changes in Ca 2+ binding
in synaptic membranes.
2. Excitatory
actions of catecholamines
in CNS
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Except perhaps in the putamen
(1282), DA has not been found to have pronounced
excitatory
effects in the CNS. Norepinephrine,
on the other hand, consistently excites many neurons,
especially
in certain
parts of the brainstem.
For
example,
more cells are excited than are depressed by NE in the medulla
or pons
( 140, 153) and in the perifornical
and vendromedial
areas of the hypothalamus
(727). The excitations
seen in the medulla
are unlikely
to be simply disinhibitions,
since they are produced
by relatively
small doses of NE and have a much slower
time course than the depressant
effects evoked by NE in the same area (153).
Even better evidence
of a specific excitatory
action is Yamamoto’s
(1279)
finding
that neurons in Deiter’s nucleus are only excited by NE. Moss et al. (917)
give another example of a neuron-specific
effect in the hypothalamus:
NE inhibits
most neurosecretory
cells of the paraventricular
nucleus
but excites the great
majority
of the other, nonneurosecretory
cells.
Such observations
are most easily explained
by the presence of at least two
kinds of NE receptors in central neurons, one (or two, see above) mediating
inhibition of firing and another responsible
for excitation;
there is at present no evidence
that these receptors
are more readily
blocked by a- or P-blocking
agents (cf. 153,
643, 983).
Are both excitatory
and inhibitory
receptors
to be found on most neurons,
in all parts of the CNS? Some observations
might suggest that the answer is yes.
Thus, although
the predominant
effect of NE is a depression
of firing in most regions of the CNS ( 118, 132, 401, 75 1, 989, 1060, 1141, 1164, 1279) some excitatory
responses have often been obtained
from the same cells. For example,
Krnjevie
and Phillis (75 l), studying
mainly
barbiturate-anesthetized
cats, observed
in the
cerebral
cortex a delayed
but strong excitation
when epinephrine
was applied in
large doses. As smaller doses had a purely depressant
effect, it was suggested that
depression
was probably
the significant
action and that the excitations
might have
been artifacts.
But Johnson
et al. (642, 643) reported
mainly
(slow) excitatory
effects in cats more lightly
anesthetized
with halothane,
or in the unanesthetized
enciphale isol&, and so concluded
that excitation
was the more important
effect,
which was probably
depressed by anesthesia. Although
Johnson et al. (642) thought
they had eliminated
the possibility
of an artifactual
excitation
by an excess of Hf
released simultaneously
from the acid solutions in the micropipette,
Frederickson
et al. (455) have recently found that the incidence
of excitatory
effects (also in the
cat’s cortex) is simply correlated
with the acidity of the NE solutions used. According to these authors,
irrespective
of the degree or kind of anesthesia
used, only
480
K. KRNJEVIC;
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54
3. Function
of catecholamines in CNS
Although
catecholamines
are found throughout
all parts of the CNS, they are
especially
concentrated
in basal areas of the brain (201, 202, 29 1, 465, 582, 597,
1197, 1211, 1212). As Vogt (1211) p ointed out, the hypothalamic
and midbrain
regions of high NE content
agree rather well with the distribution
of sites from
which pressor responses and other manifestations
of sympathetic
activity
can be
elicited
by stimulation.
This area therefore
can be considered
as a central component of the sympathetic
system, and it seems fitting that it should be rich in NE.
A further natural
step is to assume that catecholamines
may be used as neurotransrnitters, just as in the peripheral
sympathetic
system. This idea has been very extensively discussed and on the whole received favorably
(133, 153, 654, 697, 865,
866, 868, 1058, 1075, 1211, 1275).
In addition
to the studies described
above, which show that catecholamines
can influence
neuronal
excitability,
what other evidence supports a possible transmitter role of NE and other catecholamines?
Catecholamines
can be released by direct or indirect
stimulation
of central
nervous tissue (27, 48, 58, 109, 685, 918, 930, 1006, 122 1, 1243). This evidence is
somewhat limited, probably
because of the active presynaptic
reuptake mechanisms
that very effectively
remove catecholamines
from the extracellular
space (47, 621,
685, 1107, 1189, 1217, 1242).
Other arguments
for the involvement
of catecholamines
in CNS function
are
based on the effects produced
by precursors
or antagonists
or other drugs that promote release or block reuptake.
One example
has been studied extensively
by Lundberg
and his colleagues.
They have shown that intravenous
injections
of L-dopa, the precursor
of DA and
NE, cause pronounced
changes in spinal reflexes. The balance of activity between
extensor and flexor motoneurons
or static and dynamic
y-motoneurons
is greatly
altered;
moreover,
there is a changed
distribution
of primary
afferent depolarizations also evoked by volleys in cutaneous nerves and high threshold
muscle afferents
(((flexor
reflex afferents”)
( 103, 63 1, 844). These complex
phenomena
can be
explained
by the activation
of descending
noradrenergic
pathways
(of supraspinal
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depressant
effects are seen if NE is released from solutions at pH 2 4. Stone (1135)
has proposed
that NE causes a constriction
of cortical arterioles,
the neurons being
secondarily
excited by local hypoxia,
but this is unlikely
because cortical arterioles
are rather
insensitive
to local applications
of NE (805). These studies have not
excluded
the possibility
that NE enhances transmitter
release by acting presynaptitally, as it does at some peripheral
junctions
(150, 640, 742).
Summary. Although
some apparent
excitatory
effects of NE may well be technical artifacts
(possibly
resulting
from a simultaneous
release of H+ during
iontophoresis),
certain neurons
in the hypothalamus,
pons, and medulla
are regularly
excited by relatively
small amounts of NE under conditions
that seem to indicate
specific excitatory
receptors
for NE. The mechanism
of this action has not been
investigated.
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1974
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origin) that exert an inhibitory
influence
on certain spinal interneurons.
However,
although
the effects of L-dopa are impressive,
it has not been possible so far to
identify
with any precision
either the postulated
descending
tracts or the target
interneurons.
Putative
dopaminergic
pathways
have been much discussed. As stated earlier,
in spite of the wealth of suggestive neurochemical
evidence, the electrophysiological
evidence for a dopaminergic
nigrostriatal
link is unsatisfactory.
Excessive activity
of dopaminergic
systems has also been implicated
in the etiology of schizophrenia,
on the ground that neuroleptic
drugs specifically
block DA receptors
(cf. chapt. 3
in 142; 878). This hypothesis
is based on rather indirect
pharmacological
considerations
and has not so far received
any support
from direct studies of DAsensitive cells (cf. chapt. 2 in 142).
The activity
of noradrenergic
pathways
is thought
to underlie
emotional
states, particularly
a tendency
to euphoria
or more generally
behavior
leading to
“reward”
(697, 1075, 1123). This is suggested by the effects of such drugs as amphetamine
[which is believed
to promote
the release of NE ( 140, 5 lo)] and antidepressants
[which reduce the uptake of NE by nerve endings and therefore
would
enough.
It has
potentiate
a noradrenergic
activity
(12 17)]. Th’ is 1‘d ea is plausible
received wide acceptance
by students of behavior
and has probably
been a useful
conceptual
framework
for interpreting
and designing
experiments.
Unfortunately,
it still has no more than a very tenuous basis of hard physiological
facts. This should
be kept in mind, as there is a danger that it may be taken too literally
and may
impede rather than stimulate
wide-ranging
studies. Some caution is needed in the
drugs, when even such classical modulators
interpretation
of the effect of “specific”
of adrenergic
function
as reserpine
and MAO
inhibitors
can be shown to affect
markedly
levels of excitatory
and inhibitory
amino acids (1070).
Another
related hypothesis
is that adrenergic
pathways
play an essential role
in the control of hunger and eating (520, 812, 905, 1099, 1112, 1196) as well as in
the maintenance
of a constant body temperature
(428, 921).
Until now the result of investigations
of hypothalamic
neurons have not given
much support
to a simple neurochemical
scheme of coding
of behavior
(727).
Similarly,
the idea that catecholaminergic
hypothalamic
pathways
control
the
release of pituitary
hormones
(1078, 1181, 1275) is supported
by only somewhat
indirect
evidence.
The supposed
participation
of an ascending
noradrenergic
system in the
mechanism
of arousal or the maintenance
of wakefulness
has less substantial
evidence in its favor than is suggested by the enthusiasm
with which it is repeatedly
publicized
(e.g. 648, 653, 654, 9 14). Thus the available
evidence
indicates
an
inhibitory
rather than an excitatory
action of NE in the cerebral
cortex; this is
hardly consistent with an arousing
action, unless it can be shown that the cortical
projection
of NE-containing
fibers [presumably
from the locus coeruleus
(cf. 333a,
954, 1197)] innervates
mainly
inhibitory
neurons.
Alternatively,
the adrenergic
mechanism
may operate
primarily
at the brainstem
level (cf. 153, 157, 1058).
There is little clear evidence of a reciprocal
action between brainstem
adrenergic
and tryptaminergic
centers or pathways
(cf. 247).
Perhaps the most serious argument
against an essential involvement
of norad-
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renergic
pathways
in the control
of wakefulness
is an apparently
normal
pattern
and amount
of motor activity
shown by animals
treated with sufficient
6-OHdopamine
to destroy selectively
most of the central NE- and DA-containing
fibers
(127, 130, 411, 626). In fact, these animals maintain
their body temperature
and
they eat, drink, and put on weight at the same rate as normal
controls
(626, 628,
789, 1069, 1286).
More generally,
there is surprisingly
little noticeable
change in their behavior:
apart from a temporary
disturbance
after injections,
presumably
at least partly
due to a sudden large release of catecholamines,
treated rats soon appear to behave
very much like normal
animals, even when tested by relatively
sophisticated
techniques ( 116 1, 1162); they survive in this condition
for many months, even though
there is no evidence of any recovery of NE-containing
cell jibers ( 127, 626, 628). Similarly,
there is no permanent
change in the behavior
of cats treated with 6-OH-DA,
except
when they are pretreated
with chlorimipramine
(789).
The only suggestive
long-term
changes demonstrated
so far are a possibly
significant
reduction
in feeding evoked by injections
of 2-deoxy-O-glucose
(1286)
and a gradual
increase in aggressive
behavior
(1177), which,
however,
is only
poorly correlated
with the disappearance
of cerebral
NE (1178). Such early postinjection
effects as a reduction
in self-stimulation
(1124) are hardly very significant,
unless they can be shown to be persistent
(cf. 411, 626), especially
since the initial
disturbance
is probably
not related to the destruction
of catecholaminergic
neurons.
(1162).
Much of this evidence seems to indicate
a relatively
nonessential
role of catecholamines
[which would not be very surprising
in view of the low density of NEcontaining
terminals
in most regions;
according
to Lapierre
et al. (799a) in the
cerebral
cortex of the cat such terminals
account for only 1 in lo4 of all synapses]
yet such a conclusion
will not be really justified
until it is certain that even a very
small number
of remaining
catecholaminergic
neurons
may not be sufficient
to
maintain
adequately
whatever
specific function
is mediated
by the NE-containing
neurons. According
to the results of some experiments,
really marked
changes in
behavior
do become evident
when the monoamine-containing
fibers are almost
totally
destroyed
(1196).
Unfortunately,
to obtain
such a drastic effect, 6-OHdopamine
must be injected directly
into the brain and there is a serious risk of nonselective destruction
of all local cells (cf. 999a).
Summary. Central noradrenergic
pathways
have been variously
thought
of as
the central component
of the sympathetic
system, a CCreward” system, an important
element of the cortical arousal mechanism,
or some combination
of these and other
related functions.
However,
in spite of much data showing that NE and other catecholamines
are found in various
fibers, that they are released during activity and
avidly taken up by nerve endings, and that drugs that alter their metabolism
affect
behavior,
it is still impossible
to make definitive
statements about their involvement
in synaptic
transmission
at clearly
identified
sites. Serious questions
about the
significance
of adrenergic
pathways
for normal function
have been raised particularly by the surprising
lack of effects of destruction
of central NE-containing
neurons by 6-OH-dopamine.
April
1974
VERTEBRATE
V.
OTHER
A.
5-Hydroxytryptamine
SYNAPTIC
TRANSMISSION
483
MONOAMINES
(Serotonin)
1. Introduction
2. Is 5-HT
a central transmitter?
The discovery of 5-HT
a> Presence, synthesis, and release of 5-HT. 1) PRESENCE.
in the brain by Twarog
and Page (1193) and Amin et al. (24) was the trigger for
numerous
investigations
of its central function.
Detailed
mapping
of the distribution of 5-HT was done first by biochemical
methods
(406) and later by a histochemical
technique
utilizing
the specific fluorescence
of 5-HT-containing
tissues
that had been treated with formaldehyde
(202). Cell bodies and nerve terminals
rich in 5-HT
thus have been discovered,
forming
relatively
coherent
pathways
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5-Hydroxytryptamine
is a powerful
activator
of some intestinal
smooth muscle, which was discovered
first in extracts of gastric mucosa by Erspamer
(405)
and later, independently,
in serum by Rapport
et al. (1029). According
to subsequent studies [reviewed
by Erspamer
(406) and Page (SSO)], 5-HT in mammals
is
present mainly in the “enterochromafhn”
cells of the gut and in the CNS. Significant amounts of 5-HT are also found in the blood-where
it is taken up by the
platelets -but
this is probably
of gastrointestinal
origin. It is also present, together
with histamine,
in most cells of certain animals such as the rat.
There are large amounts of 5-HT and other indolalkylamines
in amphibian
skin and in a variety of snake venoms. 5-Hydroxytryptamine
has a wide distribution in nervous systems of invertebrates,
where it is probably
both a central and
peripheral
transmitter
(446, 481, 1160, 1192). It is even found in many plants,
including
such fruit as pineapple
and bananas,
but its function
there is quite obscure (406).
There is no evidence that 5-HT is a neurotransmitter
at peripheral
junctions
in
vertebrates.
Its release from the enterochromafhn
cells is unlikely
to be a normal
phenomenon,
so that it is probably
not even a regulator
of gastrointestinal
motility
or secretions (406). A wide variety of peripheral
actions of 5-HT have been reported
(407). The effects on blood vessels are quite complex,
so that blood flow may be
either reduced or probably
more often increased.
Some of the changes are directly
caused by 5-HT, but others may be indirect,
being due to the liberation
of other
agents, such as histamine.
Injections
of 5-HT may produce
marked alteration
in
tissue metabolism,
possibly related
to some reported
alterations
in cellular
permeability.
The physiological
significance
of the excitatory
action of 5-HT on several
kinds of sensory nerve terminals
or fibers (96 1, 1204) is aIso not at all clear : in species where mast cells contain
5-HT,
its release by tissue damage
may reinforce
sensory phenomena,
especially
pain.
484
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quite distinct
from those containing
catecholamines.
The most outstanding
concentration
of 5-HT is in cells situated along the dorsal midline
of the brainstem,
especially
the raphe nuclei, and in fibers traveling
rostrally
along the brainstem
and down the spinal cord; however, there is relatively
little 5-HT in nerve terminals
of the forebrain
and thalamus
(29 1, 463, 465). Further developments,
including
the
use of radioactively
labeled
isotopes and radioautography,
have made possible
electron microscopic
studies of 5-HT-containing
neuronal
elements
(8, 128, 582,
1107), and brain synaptosomes
have been shown to hold substantial
amounts
of
5-HT (33 1, 1264). A specific population
of synaptic vesicles contains 5-HT rather
than catecholamines
(976).
2) SYNTHESIS.
5-Hydroxytryptamine
is synthesized
from the amino acid tryptophan,
by hydroxylation
in the 5 position of the aromatic
ring, and then decarboxylation
(203, 244, 526, 960). The rate-limiting
step appears to be that of 5-hydroxylation,
the required
hydroxylase
being much less abundant
in the brain than
the decarboxylase.
The initial breakdown
of 5-HT occurs through
the action of MAO,
and there
is a subsequent
conversion
to 5-hydroxyindole
acetic acid, which is excreted in the
can be depleted
of 5-HT by reserpine,
preurine ( 125, 244). N erve terminals
sumably
because the drug prevents
the accumulation
of 5-HT in the granular
vesicles, just as it prevents the accumulation
of catecholamines.
Although
6-OHdopamine
can selectively
destroy cells rich in catecholamines
in the rat, it has a
less specific action in the cat, where it also lowers the 5-HT content of the brain
(98 1). The latter may be lowered
fairly selectively
by a comparable
procedure,
intracerebral
injections
of 5,6-dihydroxytryptamine
(74, 243, 298).
The almost total disappearance
of 5-HT from the forebrain
and striatum
after
lesions in the brainstem
(for example,
the medial
forebrain
bundle)
has been
accepted
as evidence
that all tryptaminergic
pathways
originate
in the raphe
nuclei (505, 594). However,
some doubts have been cast on this interpretation
by
the absence of terminal
degeneration,
which is more consistent with a transynaptic
loss of 5-HT and other monoamines
(561, 911).
3) RELEASE.
There is some limited evidence that 5-HT is released in the CNS,
both spontaneously
and as a result of neural activity. 5-Hydroxytryptamine
or some
related compound
was first detected in fluid superfusing
the frog spinal cord (32).
Stimulation
of descending
pathways
is said to promote
the liberation
of 5-HT from
the mammalian
spinal cord (26), and excitation
of rostra1 raphe nuclei augments
the release of 5-HT into the anterior
part of the cat’s lateral ventricle-this
5-HT
is likely to originate
from the caudate nucleus
(594). A spontaneous
release of
5-HT in the monkey’s
superior
colliculus
has been reported
(85). Stimulation
of
the midbrain
raphe nuclei also induces a release of 5-HT (38 1) or 5-hydroxyindole
acetic acid from the cerebral cortex (959; cf. also 175).
Summary. Most of the widely distributed
5-HT-containing
nerve fibers appear
to originate
from the raphe nuclei of the lower brainstem.
5-Hydroxytryptamine
has been shown to be released in various regions of the CNS, including
the cerebral
cortex, striatum,
and spinal cord. The active metabolism
of 5-HT, its rapid uptake
by a mechanism
inhibited
by tricyclic
antidepressant
drugs, and its presence in
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1974
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nerve endings and even in a specific population
of synaptic vesicles are suggestive
evidence of significant
tryptaminergic
transmission.
b) Action of .5-HT in CNS. The results of systemic or intraventricular
injections
of 5-HT in low or moderate
amounts have a mainly sedative effect, though larger
doses may cause strong excitation
[see extensive review by Mantegazzini
(862)].
These observations
are to some extent paralleled
by the results of microiontophoretic
tests on neurons in various parts of the brain and spinal cord. The most
general effect of iontophoretic
applications
is a reduction
in excitability.
This is the
case with neurons in the neocortex
(650, 748, 751), paleocortex
and olfactory
bulb
(131, 809, 1213), archicortex
(118, 566), striatum
(567), cerebellar
cortex ( 136,
687), hypothalamus
(63, 136, 137), and red nucleus (308). Some excitatory
effects
have also been seen, particularly
when applying
relatively
large doses of 5-HT
(748, 751) or as the predominant
response in cats receiving
little or no anesthesia
(642, 1048). But there is some reason to believe that this excitation
may be at least
partly caused by an accumulation
of protons in the tissue when strongly acid solutions (pH < 4) are used for 5-HT release by iontophoresis
(650) [cf. also comparable excitatory
action of acid solutions of catecholamines
(455)].
There is more convincing
evidence
of a genuine excitatory
action of 5-HT
in certain parts of the thalamus,
the brainstem,
and the spinal cord. What seems
particularly
significant
is that under the same experimental
conditions
(anesthesia,
same micropipettes,
etc.) different
types of cells in these regions consistently
give
opposite responses to 5-HT.
Thus, in the lateral geniculate,
some of the nonrelay
cells are excited (107 1),
whereas the relay cells are almost uniformly
inhibited
(984, 989, 107 1, 1167). In a
broad survey of thalamic
neurons, Phillis and Tebecis (987) found that neurons in
the upper and middle
regions were predominantly
inhibited
by 5-HT, but in the
deeper portion
they were often excited. This distribution
paralleled
the superficial
inhibitory
and deep excitatory
effects seen with catecholamines.
Brainstem
neurons
can be excited or inhibited
by 5-HT (159), but more specific tests of selected populations of neurons in the medulla
(43, 611) and the raphe nuclei (247) have shown
some consistent
excitatory
actions : for example,
5-HT regularly
excites reticulospinal neurons
(611).
There are also striking variations
in responses observed in the spinal cord. In
random
surveys of spinal
interneurons,
investigators
have seen either
mainly
depressant
effects (401) or both excitation
and inhibition
(990, 1235). But most
sympathetic preganglionic
neurons are rather clearly excited by 5-HT (3 19), whereas
preganglionic
parasympathetic
neurons
show either no effect or some depression
(1061).
There is little direct evidence about the precise mechanism
of action of 5-HT.
The first studies on the lateral
geniculate
seemed to indicate
that 5-HT blocks
synaptic transmission
more effectively
than cellular
responses to various excitatory
agents, either by a presynaptic
action reducing
transmitter
release or a specific
antagonism
of the natural
transmitter
(260). Later tests in the cortex (748, 75 1)
showed a clear, apparently
nonspecific,
depression
of cell firing, whether
induced
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synaptically
or by applications
of glutamate
or ACh; it was therefore
suggested that
5-HT and inhibitory
amino acids may interact
with the same receptors.
If this
were indeed the case, the inhibition
would be due to an increase in membrane
permeability
to small anions (352, 691, 764, 1255). Although
the hyperpolarization
of spinal motoneurons
induced
by 5-HT (990) is consistent with such a mechanism,
other mechanisms
may well be at work (cf. 400). The recent findings
that Ca
antagonists
abolish the inhibitory
effect of 5-HT in the cortex has led to the suggestion that 5-HT (like NE) increases the membrane
permeability
to Ca2+ (985).
A similar general postsynaptic
depression
can be demonstrated
in the lateral
geniculate
(984, 989, 1071), but the latest experiments
by TebEcis and Di Maria
(1167) indicate
a more specific block of synaptic
transmission
by small doses of
5-HT,
thus supporting
the original
suggestion
of Curtis and Davis (260). This
interesting
action has not so far been observed at any other junctional
site in vertebrates, though
5-HT is said to produce
a specific block of glutamate-mediated
neuromuscular
transmission
in insects ( 1199).
Although
peripheral
actions of 5-HT are blocked
by LSD, brom-LSD,
and
methysergide
(524), there is no general agreement
about any specific antagonists
of
the central actions. A number
of authors have reported
little or no specific antagonism by LSD ( 136, 260, 751, 984, 989, 990), but Roberts and Straughan
(1048)
and Boakes et al. (139) are convinced
that derivatives
of lysergic acid do antagonize
the (mainly
excitatory)
effects of 5-HT they have observed in the cortex and the
brainstem.
According
to TebEcis (1164) strychnine
clearly prevents the inhibitory
action of 5-HT on some thalamic
cells.
Systemic
administration
of LSD, MAO
inhibitors,
or tricyclic
antidepressants (the latter strongly
block the reuptake
of 5-HT)
markedly
and apparently
specifically
reduces the firing of the 5-HT-containing
neurons of the raphe nuclei
(7, 1084). Th ese effects have been interpreted
as due to increased
activity
of a
tryptaminergic
inhibitory
neural
feedback
in which
LSD would
act as agonist
rather
than antagonist
(7), but clearly
other possible explanations
cannot
be
eliminated
without
a great deal more information.
Summary. Specific
populations
of neurons
are consistently
mainly
depressed
or excited by 5-HT, the former effect being probably
somewhat
more common.
Thus, if 5-HT is indeed a transmitter,
it could function
both at inhibitory
and
excitatory
synapses. Various
mechanisms
of action have been proposed,
especially
for the depressant
actions: reduction
of GNa, increase in Gc,, an action similar
to
that of inhibitory
amino acids, or even a block of presynaptic
release of transmitter.
There is also no agreement
about any specific antagonist
of central actions of 5-HT:
LSD and derivatives
do not produce consistent effects.
c) Function of 5-HT in CiW. As soon as 5-HT was discovered
in the brain
(24, 1193), it was proposed
that it might be a neurotransmitter
released by certain central
pathways.
Although
the evidence
discussed so far is consistent
with
this possibility,
it is also by no means conclusive.
The differential
distribution
of
certain nerve cells and terminals
is very suggestive. But then one knows that 5-HT
is present in enterochromaEin
cells and platelets, from which it is not likely to be
April
1974
VERTEBRATE
SYNAPTIC
TRANSMISSION
487
minergic
neurons (cf. also 327). As pointed
out very pertinently
by Oswald
(956),
in a sane and lucid review, everyone
feels like an expert on sleep. This may explain why the most elaborate
and speculative
hypotheses
are so freely developed
in this field on the basis of the flimsiest and most indirect
experimental
evidence.
Summary. On the basis of the evidence reviewed
in the previous sections 5-I-IT
may be released by some central nerve terminals;
although
much of this evidence
is far from conclusive,
tryptaminergic
pathways have been postulated
to play a significant
role in the control of spinal reflex activity, body temperature
through
hypothalamic
projections,
and the initiation
of slow-wave
sleep. Disorders
of such
pathways
are thought
to give rise to hallucinations.
Most of these suggestions cannot yet be considered
as more than useful hypotheses.
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liberated
for purposes of communication,
at least not in the normal
course of
events (406). Evidence
that 5-HT is actually
released by central nerve fibers during normal
activity
is circumstantial
at best. The strong excitation
of peripheral
nerve fibers by 5-HT
(444, 1204) cannot
be related
to a process of junctional
transmission.
It is with these reservations
in mind that one should consider claims
that various functions
are mediated
by tryptaminergic
pathways.
There is some impressive
evidence
for a possible involvement
of 5-HT, released by bulbospinal
pathways,
in the control
(especially
facilitation)
of the discharges of spinal motoneurons
and the transmission
of polysynaptic
reflexes (9, 30,
844). Other studies indicate that 5-HT plays a significant
role in the hypothalamic
control
of body temperature
(83, 85, 428, 594, 921). Many other functions
have
been suggested (for some recent reviews see 34, 960, 1275). There is wide support
for the idea that disturbances
of 5-HT metabolism
and, presumably,
of the carresponding
tryptaminergic
pathways
may be responsible
for hallucinations,
whether
induced
by various drugs or by neural malfunction
in schizophrenia
and
some other mental disorders
(160, 524, 1269, 1274).
A particularly
strongly
promoted
hypothesis
is that tryptaminergic
neurons
of the rostra1 raphe nuclei,
acting in opposition
to the arousing
influence
of a
pontomesencephalic
system of catecholaminergic
neurons,
are mainly responsible
for initiating
the slow-wave
stage of sleep (652654).
The evidence
consists principally
of the following:
lesions of the raphe nuclei [insofar as such lesions are
strictly selective (cf. 1004)] reduce or abolish the need for sleep; and an inhibitor
of 5-HT synthesis, p-chlorophenylalanine
(which
prevents
the hydroxylation
of
tryptophan),
greatly
reduces the amount
of slow-wave
sleep of cats, the effect
being reversed by injections
of 5-hydroxytryptophan.
This much publicized
idea
has received support from some investigators
(e.g. 846, 1198), but not from others:
one obtains
mainly
arousal
by stimulating
the raphe nuclei,
even when using
near-threshold
stimuli
( 1004) ; p-chlorophenylalanine
reduces REM
sleep rather
than slow-wave
sleep in man (1277), and the sedative action of tryptophan
is seen
even when the synthesis of 5-HT is blocked byp-chlorophenylalanine
( 1276). When
the cerebral
5-HT in cats is depleted
by the administration
of another drug, fenAuramine,
there is an increase in slow-wave
sleep (641), SO it is by no means certain
that slow-wave
sleep is only or even mainly determined
by the activity of trypta-
488
B. Imidasole
K.
KRNJEVIC
Volume
54
Derivatives
1. Histamine
2. Imidaeole
acetic acid and other derivatives
Early tests of imidazole-4-acetic
acid on cortical neurons
(751) had shown a
strong inhibitory
effect, comparable
with but usually weaker than that of GABA
[cf. the crayfish stretch receptor
(881)]. Th is observation
was confirmed
and extended
to other central neurons
(3 1, 607, 946, 991). Moreover,
several related
compounds
have proved almost as powerful
as the acetic acid derivative
(499, 739).
Even amyl- and n-propyl
esters of imidazole
acetic acid may have quite a strong
action [in contrast
to esters of GABA,
which are much less active than GABA
@WI *
Roberts and Simonsen
(1047) have shown that imidazole
derivatives
potentiate brain phosphodiesterase
activity
and have therefore
suggested that they may
influence
neuronal
firing through
changes in intracellular
levels of CAMP and
ATP. However,
in their experiments,
1-methylimidazole
acetic acid and imidazole4-carbolic
acid increased
phosphodiesterase
activity almost as much as did imidazole acetic acid. Since the first two agents are only weak inhibitors
of neuronal
firing (499, 607), it is very unlikely
that the inhibition
has anything
to do with
CAMP. A more probable
explanation
is that these inhibitory
compounds
interact
with the membrane
receptors
for GABA
(cf. 31, 263) and therefore
increase the
membrane
permeability
to small anions (691, 764). Although
there is no evidence
at present that these potent imidazole
derivatives
occur in the CNS in really substantial
amounts,
they may be produced
by the metabolism
of histidine
or histamine (cf. 1082, 1106) and therefore
could have a functional
significance.
Summary.
In spite of the presence and release of histamine
in the various parts
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The best known naturally
occurring
imidazole
compound
is histamine.
Its
presence in nerves and release from peripheral
nerve endings was first suggested
and then demonstrated
many years ago (788, 82 1) ; it has therefore
long been
considered
a possible synaptic
transmitter
(cf. 254, 890, 1108), but there is little
real evidence
that histamine
is a significant
transmitter
at any known site. It is
found in variable
amounts
in the brain and spinal cord (515) and also in nerveending fractions of the brain (663). Its action on central nerve cells, which is mainly
inhibitory
(471, 607, 751, 990, 991, 1165), is not particularly
striking when compared with that of the inhibitory
amino acids or, for that matter, that of some
other imidazole
compounds.
The relatively
large amount
of histamine
in dorsal
root fibers and the evidence
that histamine
is released from their peripheral
terminals led Kwiatkowski
(788) to suggest that it might be the transmitter
liberated
by their central endings, but no excitatory
effects of histamine
have been detected
at the first afferent junction
in the cuneate nucleus (47 1). However,
some excitatory actions in the cortex have been described
by Phillis et al. (991).
April
VERTEBRATE
1974
SYNAPTIC
TRANSMISSION
489
of the CNS, its weak, predominantly
inhibitory,
action on some neurons
hardly
indicates
a very significant
role as a synaptic transmitter.
Some other imidazole
derivatives,
including
imidazole-4-acetic
acid, have a much stronger
inhibitory
action, comparable
to that of inhibitory
amino acids and quite likely operating
by the same mechanism.
However,
there is only very indirect
evidence that these
compounds
occur naturally
in the brain or that they are actually utilized
as neurotransmitters.
VI.
SOME
OTHER
PUTATIVE
(Adenosine-5’-
Tri’hosphate)
1. In CNS
When Holton
and Holton
(595) discovered
appreciable
amounts of ATP in
spinal roots, they suggested that ATP may be released as a neurotransmitter
from
both peripheral
and central endings
of sensory fibers. Holton
(596) and Abood
et al. (3) indeed demonstrated
a release of ATP from peripheral
endings excited
antidromically
and also from nerve trunks (as well as muscle). There is no evidence
at present of a specific release of ATP from the central terminals,
but McIlwain
and Pull (883) have observed
a leakage of adenosine
from isolated brain tissue
that is accelerated
by electrical
stimulation.
Tests of ATP on most central neurons have not revealed
a powerful
excitatory (or inhibitory)
action : for example,
neither
in the spinal cord (28 1) nor in
the cerebral
and cerebellar
cortex (75 1) are there any marked effects of ATP applied by iontophoresis.
On the other hand, a number
of cells in the cuneate nucleus
to that of
are strongly
excited by ATP (471), whose potency is often comparable
glutamate,
although
its action tends to be much more prolonged.
This is likely to
be related to the chelating
power of ATP, since ADP is very ineffective,
whereas
citrate is also quite a strong excitant.
2. ,4t periphery
a) Inhibition.
A very different
inhibitory
transmitter
role of ATP in the gut
has been proposed
more recently
by Burnstock
et al. (190). An inhibitory
action
of adenosine
and its derivatives
on smooth muscle has long been known (70, 355,
356, 12 18). Its electrical
characteristics
have been examined
in detail by Imai
and Takeda
(6 18) and Axelsson and Holmberg
(50), who found a direct hyperpolarizing
action on the smooth muscle membrane.
Burnstock
et al. (190) obtained
clear evidence that ATP and several derivatives
of adenosine
are released by transmural electrical
stimulation
that is believed
to have a nonadrenergic
inhibitory
that ATP could be released from the isolated
effect. They showed,
moreover,
Auerbach’s
plexus and that its action was not prevented
by blocking
the intestinal
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A. Adenosine Derivatives
TRANSMITTERS
490
IS. KRNJEVIC
Volume
54
significant
neurotransmitter
mechanism,
even though the term “purinergic”
might
not be quite appropriate.
Summary. Although
it may seem wasteful
to use a high-energy
compound
like ATP as a neurotransmitter,
several features would make it very suitable for
such a function.
Its leakage from active cells seems to be a very widespread
phenomenon -seen
even in plants (806). Its strong anionic
charge can make it react
with divalent
cations attached
to the cell membrane,
causing the membrane
to
contract
and thus possibly
change
significantly
its permeability
characteristics
(cf. 22, 722). As suggested
by Ambrose
(22), ATP could in this way transfer information
between small groups of cells. It should not be surprising
if the same
mechanism
was utilized
for junctional
transmission.
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nerve fibers with tetrodotoxin;
they therefore
concluded
that ATP was probably
the transmitter
released by the intestinal
nonadrenergic
inhibitory
nerve fibers.
This hyperpolarizing
action is thought
to be due to a specific increase in GH (189;
cf. also 1183) ; it is presumably
unrelated
to a chelating
mechanism
since ATP
and ADP are equipotent
in this respect. The substantial
case for ATP (or a close
derivative)
as the general nonadrenergic
inhibitory
transmitter
in the gut is somewhat weakened
by the rather
mixed excitatory
and inhibitory
effects of ATP
seen with most gut preparations
other than the guinea pig taenia coli, which make
it necessary to postulate
the presence of at least two kinds of ATP receptors (190).
b) Excitation. Burnstock et al. (191) have confirmed
Ambache
and Zar’s (20)
observation
that applications
of ATP reproduce
the effects of nerve stimulation
and therefore
propose that the atropine-resistant
synaptic excitation
of the urinary
bladder
is mediated
by ATP or some close derivative.
As further
supporting
evidence they report a block of both types of excitation
by quinidine.
Their observations differ from those of Ambache
and Zar’s (20) in one very significant
respect :
they could not produce
a desensitization
to ATP without
also blocking
the neural
effect.
The possibility
of peripheral
junctional
transmission
by the release of ATP
or related purines from “purinergic”
nerves has been fully discussed by Burnstock
(189). This review lists an extensive series of findings showing that ATP is released
from a variety of tissues and has a marked excitatory
or inhibitory
action on several kinds of smooth muscle and places much emphasis on the presence of adenosine and its derivativesas well as enzymes concerned
in the metabolism
degradation of ATP-in
nerves that appear to be neither cholinergic
nor adrenergic.
Although
this accumulation
of data is quite impressive,
more conclusive
evidence is needed that the postulated
“purinergic”
nerves do not in fact release NE
or ACh, according
to the classical schemes. For example,
questions
have been
raised about the supposed absence of adrenergic
neurons from Auerbach’s
plexus
(99). As pointed
out above, it is not reasonable
to expect junctions
with narrow
gaps to be as readily blocked by antagonists
as the corresponding
effects of topical
applications
of NE or ACh: of course, ATP might be released in conjunction
with
other
transmitters
[cf. its release together
with catecholamines
in the adrenal
medulla
(347)],
but if ATP has a marked
postsynaptic
action, this would be a
A&d
VERTEBRATE
1974
SYNAPTIC
TRANSMISSION
491
B. Ergothioneine
An excitatory
action of cerebellar
extracts (255) has been ascribed by Crossland et al. (256) to the presence of ergothioneine
(897). However,
it is unlikely
that ergothioneine
can be an important
excitatory
transmitter
in the cerebellum,
since cerebellar
neurons are very little affected by direct applications
of this comin the brain does not conform to that of the putapound (756) and its distribution
tive cerebellar
excitatory
factor ( 165).
1. Substance P
This name covers a group of agents that cause strong contractions
of intestinal
smooth muscle, are vasodilators
and sialogogues,
and were first extracted
from
the gut ( 12 18). These polypeptides
(2 13, 12 10) are found in many parts of the
CNS (24, 1284) and in especially high concentration
in the substantia nigra (1284).
Their possible function
as neurotransmitters-especially
at the first synapse in the
afferent pathway
(813)-has
been much discussed (24, 1132, 1284), but there is
only limited
evidence so far (957) that they have a significant
action on neurons
excited by primary
afferent fibers (471). According
to more recent observations
by KrnjevX
and Morris
(747a) pure substance P sometimes has a powerful
action
on cells in the cuneate nucleus; this is probably
a slow depolarization,
which can
lead to inactivation
of cell discharges
rather than overt excitation.
The comparatively slow time course and great variability
of this effect make it unlikely
that
substance P could be the quickly acting excitatory
transmitter
released by primary
afferent fibers (813), but it may well have some other significant
action.
2. Other polypeptides
Excitatory
polypeptides
can be obtained
from cerebrospinal
fluid (439) and
the frog’s skin (408, 957). Whether
these are of significance
for synaptic function
remains to be established.
The possible role of various polypeptides
in neurotransmission has been discussed at some length recently
(129).
3. Antidiuretic
hormone
There
is some
supraoptic
nucleus
If confirmed,
this
action mediated
by
Summary. The
has been shown to
evidence
that the hormone
secreted by the neurons
of the
is also released by their inhibitory
recurrent
branches
(935).
would
be the first example
of a neurotransmitter
inhibitory
a polypeptide.
most promising
other transmitter
candidate
is ATP, which
be released
(as ATP or adenosine)
by stimulation
of the gut,
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C. Polyfeptides
492
K.
KRNJEVIC
Volume
54
VII.
SOME
A. Chemical
SPECIAL
ASPECTS
Transmission
OF
CHEMICAL
TRANSMISSION
in Retina
Because of its comparatively
simple organization
and the fact that it is thin
enough to allow in vitro studies, the retina lends itself to systematic investigations
such as have not been feasible, at least so far, on any other central synapses in
vertebrates.
Over the last few years, they have revealed
some very unexpected
features of the mechanisms
of operation
of central synapses.
The predominant
response of both photoreceptors
and horizontal
cells to
illumination
is a hyperpolarization
associated
with an increase
in membrane
resistance
(78, 79, 656, I 145, 1186, 1248). It appears
that, in the dark, photoreceptors are depolarized
and therefore
release from their terminals
a depolarizing
transmitter
that keeps horizontal
cells and bipolar
cells also depolarized.
On
illumination,
the high membrane
permeability
(presumably
P,,) of the photoreceptor
is reduced.
This allows them to repolarize,
reduces the release of depolarizing
transmitter
from their nerve terminals,
and therefore
leads to a hyperpolarization
of the horizontal
and some bipolar cells (78, 1186, 1190).
The second point of great interest is that only graded potentials
are recorded
from all the cells of the outer layers, including
the bipolar cells. Clear spikes appear
to be generated
only by cells in the inner layer-the
amacrine
and the ganglion
cells (79, 348, 656, 875, 1248, 1270). This is the first convincing
demonstration
of the effectiveness
of local graded potentials
for the transmission
of information
not only within
a given neuron,
but across one or even two synapses.
What evidence do we have about the identity
of the chemical
transmitters
in
the retina? Like most central neurons,
the ganglion
cells are excited by L-glutamate and inhibited
by GABA (942). Glycine also has a clear blocking
action. The
presence of complex
inhibitory
mechanisms
of both strychnine
and picrotoxin
(23, 185).
is suggested by the excitatory
Catecholamines
are also quite
effects
strong
depressants
of ganglion
cell activity
( 1140), whereas cholinomimetics
appear to
have a mainly
facilitatory
action, which has been interpreted
as consistent
with
the presence of nicotinic
synapses (23). The site of these postulated
cholinergic
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peripheral
nerves, and the brain. Although
by no means widely active in the CNS,
it does excite strongly
some relay cells in primary
afferent nuclei and therefore
could be a significant
transmitter
if released by primary
afferent terminals.
Since
ATP and derivatives
depress intestinal
smooth muscle, there is reason to believe
that ATP may be the transmitter
for nonadrenergic
inhibition
in the gut. Some
evidence
suggests that ATP may also be involved
in excitatory
transmission
in
the gut and the bladder
So far none of the physiologically
active polypeptides,
such as substance
P, have shown properties
consistent
with a simple function
as
neurotransmitter,
but there is a possibility
that antidiuretic
hormone
may act as
an inhibitor
in the supraoptic
nucleus.
April
1974
VERTEBRATE
SYNAPTIC
TRANSMISSION
493
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synapses is not clear; it is evidently
neither
on photoreceptors
nor on horizontal
cells (920). Unlike
the horizontal
cells, which are readily
depolarized
by both
L-glutamate
and L-aspartate
(209, 920) and hyperpolarized
by glycine and GABA
(920), photoreceptor
cells appear to be singularly
insensitive
to the usual chemical
transmitters
(920). Because the hyperpolarizing
responses of horizontal
and bipolar cells cannot be easily reversed,
Nelson (929a) has suggested that they are
not due to movements
of a single ion species and, further,
that they may be caused
by changes in the amount of K+ released by the photoreceptors.
The possible involvement
of transmitters
in retinal function
is supported
by
various neurochemical
findings.
Like other parts of the CNS, the retina contains
the usual large amounts
of glutamate,
aspartate,
and GABA,
as well as glycine
(728, 969, 1157). All the enzymes of the GABA
system are present in various
layers of the retina (785). According
to Graham
(51 l), GABA is localized
particularly in the amacrine
cells and horizontal
cells.
A number
of recent autoradiographic
studies have attempted
to localize sites
of uptake of labeled amino acids (particularly
[3H]GABA)
in the retina of several
vertebrate
species (382, 384, 793, 927). Th ere is some disagreement
about the
distribution
of radioactivity.
For example,
according
to Ehinger
and Falck (384)
and Ehinger
(382), labeled GABA and glycine are taken up mainly by amacrine
cells, whereas Lam and Steinman
(793) find that changes in [3H]GABA
uptake
caused by exposure to light are greatest in horizontal
cells. Neal and Iversen (927)
believe that most of the labeled GABA goes into Mtiller
cells (glia); Ehinger and
Falck (384), on the other hand, find that labeled excitatory
amino acids are absorbed particularly
by the Mtiller
cells.
The presence of neurons containing
catecholamines,
particularly
dopamine,
has been demonstrated
by several authors (383, 858) ; they appear to be mainly
in the nuclear
layer. Although
the exceptionally
high choline
acetyltransferase
content of the retina (546) is strong indication
of a cholinergic
mechanism,
it has
been difficult
to obtain consistent evidence for the location
of the presumed
cholinergic
synapses, especially
in view of the widely contradictory
results of histochemical
studies of the distribution
of acetylcholinesterase
(cf. 555, 818, 932).
One can conclude
that there is strong evidence for the participation
of the
conventional
neurotransmitters
in synaptic processes in the retina. The absence of
spike activity
at several synapses in the retina of course would minimize
any significant
contribution
of electrical
transmission.
The high sensitivity
of most horizontal cells and ganglion
cells to L-glutamate
and L-aspartate
makes it quite likely
that one or the other of the excitatory
transmitters
is released by photoreceptors
and some other cells. At least some horizontal
cells and amacrine
cells probably
have an inhibitory
function,
but the evidence
that they act by releasing
GABA
or glycine
is still inferential.
The possible function
of dopaminergic
neurons
is
quite obscure.
Summary. With the exception
of the photoreceptors,
most retinal neurons are
excited by L-glutamate
and aspartate
and inhibited
by GABA and glycine. Catecholamines
also depress excitability,
whereas ACh has a facilitatory
action. There
is also plentiful
evidence
of the presence in the retina
and particularly
of the
494
K.
active uptake of these agents,
various synapses.
B. Chemical
Transmission
KRNJEVIC
some or all of which
Volume
may
well
be transmitters
54
at
at Sensory Endings
1. Carotid
body chemoreceptors
The high sensitivity
of chemoreceptor
afferents
to acetylcholine
and their
close association
with large glomus cells led to several early proposals
that a cholinergic
synapse may be interposed
between the chemoreceptor
elements and the
afferent
nerve fibers (3 10, 108 1, 12 19). This idea has been strongly
advocated
more recently
by Eyzaguirre
and his collaborators,
who have shown that chemoreceptor
activity
can be depressed,
at least to some extent, by magnesium
or by
nicotinic-blocking
agents (4 12, 4 15, 936) and that acetylcholine
is released from
the carotid body (412, 416).
This evidence,
though
very suggestive,
is not conclusive
and doubts have
been raised about the interpretation
(114, 962, 963). The essential counterargument of Biscoe (114) is that the fibers with which glomus cells appear to form synapses are not sensory but efferent fibers, which degenerate
when the glossopharyngeal nerve is cut intracraniallyintracranial
sections are proximal
to the sensory
ganglion
and therefore
should cause a degeneration
of only efferent fibers (“decentralization”),
whereas extracranial
sections are distal to the sensory ganglion,
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Many sensory nerve endings are relatively
easily excited by a variety of neurotransmitter
substances or related
compounds
injected
into their blood supply or
applied directly
(5 14, 96 1, 962). It is not yet certain whether
this is a pharmacological peculiarity
or whether
this indicates, as some have thought
(306, 521, 7 1 1),
that at least some nerve endings are normally
excited by chemical
transmitters
released from specialized
cells acting as transducers.
It seems unlikely,
however,
that a mechanism
of chemical
transmission
is operative
at most sensory endings
since the chemical
sensitivity
of certain receptors
can be blocked by specific antagonists without
blocking
the responses evoked by the natural
mechanical
stimulus. Thus the carotid
sinus baroreceptors
go on responding
to pressure changes
even after their sensitivity
to acetylcholine
has been totally blocked by curarelike
agents (5 14). Similarly,
the chemical responsiveness
may be enhanced
specificallyfor example
by eserinewithout
changing
the threshold
of the mechanical
receptor.
Although
there is only a very remote possibility
that chemical
transmission
is a general feature of sensory endings
(for recent critical
reviews see 962, 963),
there are at least two somewhat
specialized
types of receptors
for which there is
quite strong evidence
indicating
a mechanism
of synaptic
chemical
excitation.
[A further
possible site of chemical
transmission,
at the sensory terminals
of the
eighth nerve (306), is not considered
in any detail here as there is insufficient
evidence for any useful conclusion.]
April
VERTEBRATE
1974
SYNAPTIC
TRANSMISSION
495
2. Electrical
receptors
Strong evidence
has been obtained
by Bennett
and his collaborators
that
electrical
receptors
in fish utilize
a chemical
transmitter
mechanism
(93, 943).
Electrically
sensitive receptor
cells appear to be connected
synaptically
to afferent
fibers. In the ampullae
of Lorenzini
of the skate, the receptor
cells appear to be
electrically
excitable
on one side- the luminal
face that is exposed to applied
currents -and
they probably
release a chemical
transmitter
from the other (serosal) face. There is no direct evidence
about the identity
of this substance,
but,
judging
by the high sensitivity
of the nerve terminal
to L-glutamate,
this could be
the natural
transmitter
(1127).
Summary. Chemical
transmission
is not likely to be a regular feature of sensory
transduction
in all types of sensory receptors,
but certain specialized
receptor cells
may excite the peripheral
terminals
of afferent fibers via a chemical
synapse: for
example,
in the carotid body and the ampullae
of Lorenzini.
C. Presynaptic
Actions of Transmitters
There is now some conclusive
evidence
that transmitters
cant action on nerve terminals,
but it is still not clear whether
quence for normal
synaptic transmission.
can have a signinthis is of any conse-
1. Acetylcholine
The first and most extensively
studied presynaptic
actions are those of acetylcholine,
in muscle and in ganglia.
a) Muscle. The presynaptic
action of ACh was first suggested by the discovery
that anticholinesterases
promote
a repetitive
discharge
of motor terminals
that
can be recorded
antidromically
in ventral
root fibers (441, 874, 1258). The evident possibility
that nerve terminals
might be excited by postsynaptic
electrical
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and so make all fibers degenerate.
Biscoe’s findings
are certainly
incompatible
with the hypothesis
of a sensory synapse; but they have themselves been seriously
questioned.
Hess and Zapata
(569) have repeated
the experiments
and found
that after decentralization
the relevant
nerve fibers and synapses in the carotid
body remained
intact, and there was no change in chemosensory
discharges. They
concluded
that the synapses formed by the glomus cells must be nearly all sensory.
The presence of choline acetyltransferase
activity in the cells rather than the nerve
endings (59) agrees with this interpretation.
However,
Biscoe’s proposal
that the
chemoreceptor
nerve terminals
are directly
depolarized
by changes in Paz, Pco2,
or pH is partly supported
by Eyzaguirre’s
(414) suggestion
that such direct effects
-operating
in parallel
with a cholinergic
junction
between
the chemoceptive
glomus cell and the nerve endingsmay explain
why ACh antagonists
do not
produce
a complete
block of transmission=
496
K. KRNJEVIC?
Volume
54
2. Presynaptic
action
Ofneurotransmitter
amino acids
These have already
been discussed in detail in the section dealing with the
excitatory
and inhibitory
amino acids (see sect. III). Although
depolarizing
effects,
or an increase in terminal
excitability,
have been described
by several authors, the
significance
of these phenomena
for norm.al transmission
is by no means established. This is also true for the specific hypothesis
that GABA is released at axoaxonal
synapses and is responsible
for presynaptic
inhibition.
It appears
that
presynaptic
depolarizing
actions of GABA may operate through
a quite different
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activity
or by excitatory
agents, such as potassium,
released by the postsynaptic
elements
was practically
eliminated
in studies in which the muscle fibers were
largely
cut away, so that the presynaptic
spikes were abolished
and any other
activity reduced
to a minimum
(72, 1025).
In a different
kind of experiment,
Ciani and Edwards
(219) and Hubbard
et al. (613), by making
measurements
of the quanta1 content
of the end-plate
potential,
found
that extrinsic
acetylcholine
significantly
reduces ACh release
from the motor terminals.
Hubbard
et al. further
showed that this effect is associated with an increase in terminal
excitability.
These presynaptic
actions of ACh
are evidently
in the opposite direction
from the potentiation
of transmitter
release
postulated
by Koelle (7 11).
The presynaptic
receptors
for ACh cannot be very different
from the postsynaptic
ones since they are also blocked
by curare. The question
of a possible
presynaptic
component
of the blocking
action of curare has not yet been resolved.
The most recent studies still lead to contradictory
conclusions.
Auerbach
and
Betz (41) could not detect a significant
change in quanta1 release, whereas Hubbard and Wilson (614) found that curare reduces the quanta1 content and further
accelerates the decline in quanta1 content seen during repetitive
activity;
however,
Galindo
(470) b e 1ieves that curare reduces transmitter
release and raises the incidence of presynaptic
failures of nerve conduction.
This long-standing
controversy
is therefore
still not closed.
6) Autonomic ganglia. The studies of Koketsu and Nishi (715), Nishi (937), and
Gingsborg
(491) h ave clearly shown that acetylcholine
can cause a presynaptic
depolarization
and even a transient
block of conduction
in nerve terminals
in
sympathetic
ganglia;
as in muscle, these presynaptic
acetylcholine
receptors
are
nicotinic
and therefore
blocked by nicotine and tubocurarine.
The most conclusive
observations
are those of Pilar (995, 996), who applied ACh while recording
directly from inside the presynaptic
nerve terminals
in avian ciliary ganglia. He thus
obtained
incontrovertible
evidence
that ACh can depolarize
the nerve terminal
and lower its membrane
resistance,
and at the same time reduce the quanta1
content of ACh release. Although
these results are interesting,
it is unlikely
that
they indicate
a very significant
physiological
presynaptic
action of ACh (228).
G) Central neruous system. Apart from some evidence that dorsal root terminals
may be depolarized
by ACh (702, 7 14) and that ACh may have a presynaptic
action in the hippocampal
dentate gyrus (1280), there is very little information
available.
April
1974
VERTEBRATE
SYNAPTIC
TRANSMISSION
mechanism
from that responsible
for central
inhibition
permeability)
and the possibility
has not been excluded
GABA may be mediated
indirectly.
497
(an increase in chloride
that the observed effect of
3. 0 ther agents acting presyna@‘cally
D. Denervation
Supersensitivity
The phenomenon
of postdenervation
receive a good deal of attention.
supersensitivity
(199)
has continued
to
1. Muscle jibers
The principal
aim has been to try and decide whether the spread of the AChsensitive area is caused by the loss of a trophic factor, normally
released from the
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The unmyelinated
terminal
portion
of nerve fibers appears to be particularly
susceptible
to various kinds of agents, ‘both pharmacological
and natural
agents
associated with activity. For example,
there is strong suggestive evidence that even
relatively
small increase in tissue PCO~ may cause a block of nerve conduction
in
activity
a block of conthe region of the terminals
(915, 916). D uring repetitive
duction
on the motor nerve terminals
is frequently
observed
(741, 744) and there
is reason to think that this is caused by the accumulation
of extracellular
potassium
(1025).
The large potentials
that are recorded
in afferent
fibers close to their
terminals
(69, 378, 7 13) may well be caused at least partly by the release and
accumulation
of potassium as a result of nerve activity. Until recently any evidence
that potassium
was indeed accumulating
around unmyelinated
nerve fibers during
activity was obtained
by intracellular
recording
from glial cells (772) or by studies
on isolated
unmyelinated
nerves (698); but with the use of K+-specific
microelectrodes
it has now been possible to show directly
that there are very significant
increases in extracellular
potassium
activity
in the region of afferent
nerve terminals, both in the spinal cord (747, 1224) and the cuneate nucleus (747), whose
time course is very similar
to that of the slow potential
changes recorded
in the
same region and along afferent fibers. Although
the precise significance
of extracellular
changes in potassium
concentration
for synaptic
transmission
is not yet
clear, it is unlikely
that their effects could be totally negligible;
whether
they are
mainly presynaptic
(239, 830, 1156) or postsynaptic
(cf. 929a) remains
to be determined.
Summary. That some presynaptic
terminals
have receptors
sensitive
to the
transmitters
they release has now been incontrovertibly
established,
especially
for
cholinergic
endings in the ciliary ganglion.
It is less certain that t-glutamate
and
GABA
have significant
direct effects on central
presynaptic
terminals.
On the
other hand, the recent demonstration
of an accumulation
of K+ around
active
terminals
may explain previous observations
of slow presynaptic
potential
changes
and perhaps corresponding
alterations
in synaptic efficacy.
498
K. KIWJEVIt?
Volume
54
2. Denervation
supersensitivity
of nerve cells
There is much less precise evidence
about supersensitivity
of peripheral
or
central neurons after denervation.
Although
KufHer et al. (773) were able to show
a spread of ACh sensitivity
in postganglionic
parasympathetic
cells in the frog
heart after denervation,
in view of the relatively
short distance between points of
innervation
on the surface of the cell, it is not certain that this effect would make
a very large difference
to the chemical
sensitivity
of the cell as a whole. There is
reason to think that other factors, particularly
the large reduction
in acetylcholinesterase
activity
after denervation,
play a much greater role in making ganglia
more sensitive to ACh ( 17 1).
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motor nerve terminals
(523, 900, 1223), or whether
it is the result of a loss of
mechanical
activity.
The second possibility
is strongly
indicated
by two kinds of
experiments.
Lomo and Rosenthal
(838) found that chronic
paralysis
caused by
blocking
the motor nerve with a long-lasting
local anesthetic was associated with a
clear spread of ACh sensitivity,
even though neuromuscular
transmission
was not
impaired
by the prolonged
inactivity;
moreover,
the supersensitivity
could
be
prevented
by stimulating
the nerve at a point distal to the site of block. In complementary
experiments,
Vrbova
(1223) and Drachman
and Witzke (349) were able
to reduce greatly
supersensitivity
by stimulating
the denervated
muscle directly
with suitable
electrical
pulses. These findings
strongly
suggest that mechanical
activity
of the muscle is an important
(perhaps
the most important)
stimulus for
the normal
suppression
of gene activity
controlling
the synthesis of new ACh
receptors
[the widespread
sensitivity
after denervation
is not just due to the uncovering
of occluded
receptors;
Fambrough
(419) has shown that the development of ACh supersensitivity
in muscle in vitro is prevented
by inhibitors
of RNA
and protein synthesis].
A significant
role of a trophic factor released by nerve fibers, however,
is indicated by some other observations.
Trophic
factors may be expected to be manufactured
in the motor nerve cell bodies and carried to nerve endings by axoplasmic
transport
(cf. 353, 509, 845, 949, 1245). It therefore
seems significant
that colchitine, one of the agents known to block axoplasmic
transport
when applied locally
to nerve fibers (60, 290, 729), causes a spread of ACh sensitivity
in the corresponding muscles (58 1). According
to these authors,
colchicine
has no effect on nerve
conduction
of neuromuscular
transmission,
and therefore
the supersensitivity
can
only be explained
by the interruption
of a flow of some trophic factor to the muscle.
This claim is not wholly consistent with observations
of several other authors, who
have found
that colchicine
reduces significantly
the efficacy of synaptic
transmission when applied
either to the presynaptic
nerve (684, 978) or the postsynaptic cell or nerve (998, 1080).
A more direct influence
of the nerve terminals
than the induction
of muscular
activity
is also suggested by the observation
that the junctional
region at the end
plate has a higher sensitivity
to ACh and a greater density of receptors
than any
other part of the muscle, even after denervation
(5 1, 433, 538, 649, 898).
April
VERTEBRATE
1974
SYNAPTIC
TRANSMISSION
499
E. Role of Glial
Cells
In his discussion of the functions
of neuroglia,
Lugaro (843) considered
among
other possibilities
that neuroglia
may provide
a form of chemical
insulation,.
especially
in the region of the nerve endings, where he postulated
that unwanted
products
of neuronal
activity were especially
likely to be released. The idea that
neuroglia
may form a useful diffusion
barrier around synaptic
sites has been emphasized
more recently
by some authors. For example,
De Robertis
(332) points
out that neuroglia
do appear to form a continuous
system of cellular
membranes
around
nerve endings
and synapses and therefore
could prevent
the diffusion
of
transmitters
away from sites of release and so prevent an unwanted
action on other
cells.
A more active role was proposed
by KrnjevZ
and Schwartz
(763) : that glia
may be involved
in the removal of transmitter
substances released during
neuronal
activity.
This suggestion
was based on the observation
that cortical
unresponsive
cells-which
are probably
glia, as was subsequently
demonstrated
by intracellular
staining
(5 18, 692, 123 1) -were
depolarized
by applications
of GABA and ACh,
an effect that was not associated with an increase in membrane
conductance
and
therefore
might indicate
an electrogenic
process of active uptake [an alternative
explanation
(804), that the glial cell was depolarized
by potassium
released from
adjacent
cells, does not take into account
the fact that GABA
inhibits
by
increasing
chloride
permeability
and that ACh excites cortical
cells by reducing
potassium
permeability].
There is now rapidly
increasing
biochemical
and auto-
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Very precise tests have not been possible in the CNS, but measurements
of
mean neuronal
sensitivity
in neurally
isolated islands of cortical tissue in cats have
shown no evidence of increased responses to glutamate,
GABA, or ACh applied by
microiontophoresis
(734, 760). With a similar technique,
Spehlmann
et al. (1117,
1119) also failed to see any sign of increased sensitivity
to acetylcholine
in partially
deafferented
cortex. Although
the density of synapses may not be much greater on
mammalian
cortical
neurons
than on the frog’s parasympathetic
neurons
[probably less than 10 % of the surface area is actually
covered by synapses (cf. 232,
536)], when synapses are separated
by distances of 5 pm or less, the responses of‘
the cell may be determined
primarily
by the high-sensitivity
spots. It seems very
likely that much of the apparent
increase in ACh sensitivity
of isolated cortical
tissue can also be ascribed to a marked loss of tissue cholinesterase
(760, 1033).
Another
factor that may cause the apparent
sensitivity
of central nervous tissue to,
increase is a disturbance
of the normal neurotransmitter
uptake mechanisms;
such
an effect is largely
responsible
for the denervation
supersensitivity
of tissues innervated
by adrenergic
nerves (476, 1189).
Summary. Several lines of evidence indicate
that the loss of muscular
activity
promotes
the development
of new ACh receptors,
but a significant
trophic
action
of the nerve fibers has not been eliminated.
In denervated
ganglia
or isolated
portions
of the CNS, a reduced
efficiency
of transmitter
removal
may be more
significant
than the formation
of new receptors in causing supersensitivity.
500
K. KRNJEVIC
Volume
54
VIII.
GENERAL
A. Origin
CONSIDERATIONS
and Nature
of Chemical
ABOUT
SYNAPTIC
TRANSMISSION
Transmitters
One might suppose that in the course of evolution
special substances
were
developed
for the sole purpose of intercellular
communication
and that, as a result
of their release at certain points, specific receptors
were induced
by a process of
adaptation
comparable
to a postulated
mechanism
of antibody
formation
(386,
539, 972). Such a scheme might seem consistent
with the fact that in muscle the
region of innervation
is much more sensitive to the transmitter
released
by the
nerve fibers (ACh)
than is the rest of the muscle fiber (173, 770, 798, 899). This
view of chemical
transmission
has been taken sufficiently
seriously that the widespread actions of certain amino acids in many areas of the vertebrate
CNS have
been considered
as evidence that these compounds
cannot be natural
transmitters
(129, 522, 548).
However,
it is becoming
more and more evident that a chemical
sensitivity
of
the cell membrane
is a quite fundamental
property
that is largely unrelated
to
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radiographic
evidence
that glial cells are indeed sites of uptake of various
neurotransmitters
(382, 563, 584, 608, 864, 927, 955). It may well be a major function
of
neuroglia
to keep the extracellular
spaces of the CNS free of neurotransmitters
and
perhaps other potent agents that might otherwise
interfere
with efficient neuronal
activity.
If neuroglia
are capable
of accumulating
substantial
amounts
of various
neurotransmittersand perhaps even participate
in their synthesis-one
evidently
must consider the possibility
that this uptake process may, under some conditions,
be reversed, so that a significant
release of transmitter
perhaps takes place from
neuroglia.
This could be an abnormal
phenomenon,
resulting
from a tissue disturbance.
Of greater interest
would be a possible release triggered
by adjacent
neuronal
activity.
There are various ways in which such interaction
could take place. An obvious
one would be through
potassium
leakage from active neurons.
Excess potassium
readily
accumulates
in the minute space between neurons and glia (cf. 206, 518,
519, 747, 761, 775, 1224). A n even more direct form of coupling
between neurons
and glia in tissue culture has been reported
by Walker and Hild (1227). Depolarization of the glial cells may conceivably
lead to a discharge
of stored transmitters.
There is evidence that, in denervated
muscle, ACh is released from Schwann
cells
when they are depolarized
by an electrical
current
(328). Another
mechanism
of
coupling
between neurons
and glial cells through
the release of catecholamines
has been recently proposed
by Gilman
and Nirenberg
(487).
Summary. It is increasingly
likely that glial cells are very much involved
in
mechanisms
of chemical
transmission
in the CNS, particularly
in the active uptake
and perhaps metabolism
of excitatory
and inhibitory
transmitters,
and they may
even be sites of transmitter
release, which could play a significant
role in the control of neuronal
discharge.
April
1974
VERTEBRATE
SYNAPTIC
TRANSMISSION
501
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innervation
although
innervation
usually
has a significant
modifying
action.
Chemical
sensitivity
is thus often seen best and most widely at an early stage of
development
and later tends to be repressed to some degree when the cells become
innervated.
A good illustration
of this is provided
by skeletal muscle. The sensitivity
of
muscle fibers to ACh is particularly
high and widely distributed
in the fetus or in
very young animals
(341, 488); in fact, as recent work has shown, it appears at a
very primitive
stage of myogenesis,
long before innervation
(42 1, 944; cf. also 362,
964). When contact is made by a nerve fiber, the ACh-sensitive
area becomes
largely restricted
to the immediate
junctional
zone. But removal of the nerve (5 1,
488, 898) or even prolonged
nerve block (838) rapidly
leads to a reversal to the
more primitive
condition
of widespread
sensitivity.
Even such noninnervated
cells
grown in tissue culture as the mouse neuroblastoma
cells (535, 929) or the fibroblastic L cells (928) have been shown to be sensitive to ACh. These facts demonstrate that sensitivity
to ACh is an intrinsic
property
of many (but not necessarily
all) cells.
On the other hand, ACh or macromolecules
related to the metabolism
of ACh
appear to be involved
in very basic cellular
processes. As pointed
out in section
IIJ,
there is some reason to think that acetylcholinesterase
may provide
sites for
cation movements
through
cell membranes.
Another
possibility
is that ACh and
its related macromolecules
may have a function
in the transport
or accumulation
of raw materials
essential for the synthesis of some membrane
component,
such as
lecithin
or other choline-containing
phospholipids.
A function
of this kind is perhaps indicated
by the fact that ACh markedly
accelerates
the incorporation
of
inorganic
phosphate
in to phosphatidic
acid and phosphatidylinositol
(587, 588,
801), although
the full significance
of this effect is still obscure (540). The presence
of very large amounts of enzymes of the ACh system in the placenta
(553) and the
cornea (1267) may be also related to a comparable
mechanism
of selective transport or of synthesis of new membranes.
In this context, it is perhaps
significant
that regions where new membranes
are being formed at an exceptionally
high rate
because of local injury or some other factors also tend to be sites of relatively
high
ACh sensitivity:
for example,
the musculotendinous
junction
(432, 672), injured
muscle fibers (673), the growing
tips of regenerating
sensory nerve fibers (338),
and perhaps some peripheral
sensory receptors (5 14, 96 1). An interesting
observation is that degenerating
nerve fibers stimulate
the formation
of ACh receptors
(1223), though
it is not clear whether
this effect is mediated
by the release of a
specific chemical
factor or by a physicochemical
interaction.
An essential sensitivity
to excitatory
and inhibitory
amino acids in the vertebrate brain is indicated
by the high sensitivity
to glutamate
and GABA shown by
cerebral
cortical neurons in the newborn
kitten (755) and by cerebellar
neurons in
the newborn
rat before synapses are formed (1272). E ven some cells that lie outside
the CNS and therefore
are probably
never innervated
by GABA-releasing
nerve
fibers such as sympathetic
ganglion
cells (5, 3 15, 944) and dorsal root ganglion
cells (3 18, 944)-which
presumably
have no synapses on them-nevertheless
show
an appreciable
sensitivity
to this inhibitory
amino acid.
Different
synaptic inputs are known to be segregated
on different
regions of
502
IS. KRNJEVIC
Volume
54
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the somadendritic
complex
(377, 841, 1020, 1201, 1202). This is particularly
evident for some inhibitory
inputs that appear to be concentrated
on the soma of
certain cells (232, 373). It is not known at present whether
there is a corresponding differential
sensitivity
of various parts of the cell membrane,
so that for example the region of innervation
by inhibitory
fibers is particularly
sensitive to
GABA-as
might be suggested by the observation
of spots of maximal
ACh sensitivity corresponding
to the synaptic sites on the surface of parasympathetic
ganglion
cells (536). A sharp localization
of GABA sensitivity
on certain
portions
of the
Mauthner
cell was apparent
in Diamond’s
(339) initial
experiments,
but more
precise tests revealed
no significant
difference
in GABA sensitivity
over a large
area of the cell body and dendrite
(340).
In any case it is clear that various cells are not uniquely
sensitive to particular
transmitters.
Most central neurons have proved to be sensitive to several chemical
agents : for example,
notwithstanding
their rather specialized
function,
Renshaw
cells are sensitive to a variety of transmitters
: ACh (both as a nicotinic
and as a
muscarinic
agent), glutamic
acid, GABA, glycine, and probably
some monoamines.
They must have several distinct
chemical
receptors
appropriate
for the different
transmitters,
though it is by no means certain that each Renshaw cell is innervated
by fibers of all the corresponding
types [cf. neurons in the medulla,
which are very
sensitive to both glycine and GABA,
but appear to receive only a GABA-releasing
innervation
(696, 1172)].
In conclusion,
it seems that the chemical
sensitivity
of a given cell is an intrinsic property,
probably
coded genetically
like the specific transmitter
synthesizing capacity
(cf. 17). Why and how these different
sensitivities
originally
developed
are not fully evident,
but one can readily
understand
that the charged
surface of the cell membrane
must be affected by its ionic environment,
particularly by multivalent
ions that tend to interact strongly
with all charged
surfaces.
Practically
all cells appear to have a surface negative
charge (398a), so that any
cation (especially
if multivalent)
would significantly
alter the charge density and
therefore
the conformation
of membrane
macromolecules,
possibly inducing
in this
way various
specific changes in membrane
permeability
and potential
through
which excitability
can be either raised or lowered
(cf. 489, 737). The membranes
of even unicellular
organisms
show some marked
effects of charged
molecules
introduced
into their environment
(22). Since small charged molecules leak out of
cells and the rate of such leakage is likely to be a function
of activity,
the interaction of such small molecules
with adjacent
cells could, from a very early stage of
evolution,
have effectively
provided
a means of intercellular
communication.
Processes of synaptic
transmission
could readily develop from such relatively
distant interactions,
and it may well be that the synaptic transmitters
used by even
the highest organisms
had their origin in this way, not as special molecules
specifically developed
for purposes of communication,
but simply as elements of basic
metabolic
or synthetic
processes common
to large families of cells. Clearly
it is
advantageous
to utilize for transmission
molecules
that are readily
available
from
metabolic
processes widely distributed
in living organisms.
All that is needed for
effective
transmission
is that these molecules
should interact
with certain mem-
April
1974
VERTEBRATE
SYNAPTIC
TRANSMISSION
503
B. Electrical
Transmission
Embryonic
tissues may show a high degree of intercellular
coupling-to
an
as well as
extent quite unsuspected
until recently -so that quite large molecules
electric currents
may readily pass between adjacent
cells (94, 630, 833, 834). This
situation
is ideal for the efficient
distribution
of essential chemicals
during
development,
but it disappears
as the cells differentiate;
most nerve and other cells
in the fully developed
animal
are independent
units, separated
by largely
impermeable
membranes,
even in areas of functional
contact.
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brane groups acting as receptors.
As Watkins
(1233) pointed
out, it is perhaps
significant
that several of the neurotransmitter
molecules
are indeed strikingly
closely related to very common
constituents
of cell membranes.
All the rapidly
acting putative
neurotransmitters
have proved to be relatively
small molecules
(molecular
weights less than 200) of relatively
simple structure,
having
only a few (but well-defined)
charged
groups, typically
with pK’s well
away from seven, so that they are fully ionized at a physiological
pH. Such molecules probably
do not carry a great deal of biological
information.
This is fully
consistent
with the very limited
amount
of information
necessary for synaptic
transmission.
The neurotransmitters
as a rule do not travel more than a minute
distance,
because the synaptic
spaces are small, and therefore
they need specify
neither
their site of origin nor site of action. For practical
purposes all that they
have to embody is a simple yes-or-no
statement.
Much more complex information,
of course, is required
for the establishment
of synaptic connections,
and no doubt
more complex molecules
are involved
in that process.
It is now clear that the genetic information
needed for protein synthesis-and
indeed specifying
the whole organismis transcribed
in terms of 20 simple amino
acids. These building
blocks are thus also units of information,
which are combined
to form polypeptides
and proteins
containing
correspondingly
greater amounts of
information
(387, 629, 1234). It therefore
is appropriate
that the elementary
messages of synaptic transmission
should be mediated
by such amino acids or closely
related
molecules
of comparable
simplicity.
The huge information-handling
capacity
of the brain presumably
resides in the vast number
of cells and synapses
available
and the enormously
varied possibilities
of interconnections
between units
that each contain
relatively
little information.
This system offers a marked
contrast to the storage of genetic information
in single cells in the form of giant macromolecules.
In general the complexity
of molecules
used for the transfer of information
seems to be related
to the complexity
of the message: at one extreme,
synaptic
transmitters
that carry minimal
information
are probably
the simplest molecules
longer chains of polypeptides
make up the releasing
of this type; increasingly
factors or hormones,
which circulate
over relatively
large areas and therefore
must
convey more elaborate
information
to identify
the specific target cells or to initiate
the appropriate
changes in enzyme activity, metabolism,
and ultimately
behavior.
504
K.
KRNJEVIt?
Vohme
54
relatively
few junctions,
where speed of transmission
and
are of particular
importance
(92), although
even at most
mechanisms
also seem to operate (cf. 46 1, 72 1, 796, 87 1).
transmission
is most advantageous
where sharp electrical
sharp synchronization
of these sites chemical
Furthermore,
electrical
signals are generated;
since action potentials
are only necessary for conduction
over relatively
large distances, whereas primitive
nerve cells must have had very limited
dimensions
compatible with efficient signaling
by electrotonic
conduction,
it is very unlikely
that
electrical
transmission
could have been of much use for junctional
transmission
until a relatively
late stage in the evolution
of larger and more complex organisms.
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Only in a small proportion
of cells does one find a type of contact apparently
specialized
to facilitate
cellular
coupling.
At these junctions
the usual synaptic
space is absent: at first this was believed
to be due to partial
fusion of the membranes (966), but subsequent
investigations
have revealed
a narrow
gap (which
can be filled with lanthanum
and horseradish
peroxidase)
as well as a polygonal
system of connections
across the gap, possibly providing
channels for intercellular
currents and diffusion
( 166, 974, 1035).
The first evidence
of functionally
significant
electrical’
transmi .ssion in the
vertebrate
CNS-probably
at synapses of this type-was
obtained
in the medulla
of the goldfish
by Furukawa
and Furshpan
(462): this was seen as an inhibitory
synaptic
potential
of very brief latency,
relatively
insensitive
to the membrane
potential
of the postsynaptic
cell, which could be reproduced
with an anodal current flowing
from an extracellular
micropipette.
Shortly
after Furshpan
(461)
described
an excitatory
PSP with comparable
properties,
also recorded
in the
Mauthner
cell of the goldfish.
It therefore
appeared
that, in addition
to conventional chemical
EPSP’s and IPSP’s, these cells normally
receive significant
electrotonic signals. Other electrotonic
junctions
have been described
in the brain and
the retina of fish (92, 95-98, 656, 721), in the spinal cord of the frog (5 17), and in
the ciliary ganglion
of birds (87 1). In the latter case, where electrical
coupling
is
facilitated
by the presence of exceptionally
large presynaptic
terminals
as well as
effective electrotonic
transmission
develops
relatively
late during
gap junctions,
embryogenesis
or only after hatching
(568, 796, 997).
According
to morphological
evidence
of the presence of gap junctions,
electrotonic
transmission
may be expected
at several sites in the mammalian
CNSparticularly
in the vestibular
nuclear complex,
the retina, and the mesencephalic
nucleus of the trigeminal
nerve (166) and perhaps even in the neocortex
(1102)
and the cerebellum
(1 1 1 1)-but
so far there has been only rather limited
support
from electrophysiological
evidence
(55, 600).
As pointed out by Bennett
(92), electrotonic
transmission
in theory could produce just about all the transmitter
effects needed to operate the.CNS-though
it is
difficult
to see how any electrical
mechanism
could efficiently
generate
the very
long inhibitions
so characteristically
seen in the brain (durations
of > 100 ms).
role in the functional
organization
Since inhibition
in fact has such a predominant
of the CNS (cf. 226, 374, 377) chemical
transmission
may well have had an evolutionary
advantage,
which explains
the relegation
of electrotonic
mechanisms
to
April
1974
VERTEBRATE
C. Chemical Ihferentiation
SYNAPTIC
TRANSMISSION
505
in Nervous System
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Why do different
synapses seem to operate
by distinct
chemical
means? It
would have been simpler (especially
for the investigator)
if only one excitatory
and
possibly one inhibitory
transmitter
were utilized
for all the junctions
throughout
the organism.
Yet it is beyond question
that certain types of cells are consistently
particularly
sensitive to certain agents or tend to release a given transmitter.
Such
differences
are probably
genetically
determined
(cf. 17).
The simplest explanation
is that various aspects of function
and behavior
may
be executed by neurons of a certain genotype,
each type having its own chemical
properties,
which may be related to the function
of the cells or may have arisen
fortuitously.
The chemical
differentiation
of the peripheral
nervous system is well
known (cf. the various divisions
of the autonomic
system). Even in the CNS it is
evident that different
populations
of cells have a distinct chemistry:
not only are
there regional
variations
in the distribution
of monoamines
and other substances,
but the effects produced
at various sites by these agents differ quantitatively
and
even qualitatively,
sometimes in a systematic manner.
For example,
in the spinal
cord glycine plays a very important
inhibitory
role that is rarely seen in some of
the upper regions of the CNS, whereas monoamines
appear to have excitatory
effects in the brainstem
that are not evident in other parts of the brain.
It seems likely that the excitatory
and inhibitory
amino acids are the transmitters released by the large fibers of the rapidly
conducting
pathways in the most
recently developed
part of the CNS, the outermost
portion
that contains the long
tracts of white matter, well-defined
nuclei, and large cells concerned
in the interaction between the organism
and environment
(cf. 1278). The core of the CNS, on
the other hand, is made up of a diffuse network
of small fibers and cells and has
only poorly differentiated
nuclei and tracts. Its function
may well be to control
the internal
state of the organism
(cf. 1278). Cholinergic
and monoaminergic
mechanisms
seem to be particularly
prominent
in this core and the surrounding
intermediate
system that, according
to Yakovlev
(1278), is essentially
responsible
for the outward
expression of the internal
state- what in the higher animals would
correspond
to psychic states. As suggested by many authors, the monoamines
and
ACh may be heavily
involved
in basic drives such as hunger,
thirst, aggression,
mating,
and the related
emotional
states, as well as in other mechanisms
that
maintain
the internal
economy,
presumably
including
sleep. There is a vast literature already
referred
to which discusses the role of possible derangements
of this
system and its chemistry,
in relation
to psychic disorders,
and much use is being
made of drugs that are believed
to exert their effects on the metabolism
of the
corresponding
transmitters.
Of course it could be argued that the more recent,
faster conducting
pathways
have largely taken over the function
of the core-and
this might seem to be indicated
by the surprisingly
insignificant
behavioral
effects
of 6-OH-dopaminebut this would be a very rash conclusion
without
much more
evidence
than is yet available.
An important
technical
problem
arises from the
fact that a diffuse network
of small fibers and cells is not readily
amenable
to
systematic
unit analysis
by electrophysiological
means. Inevitably
the electro-
506
K.
KRNJEVIC
Volume
54
The author
is grateful
to Mrs. L. Simon
for her great assistance
review,
particularly
for typing
the manuscript,
and to the Canadian
for its financial
support.
This review
was essentially
completed
in May 1973.
in the
Medical
preparation
Research
of this
Council
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