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Vol. 52, Issue 1, 63-90, March 2000
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
I. Introduction
II. Modulation of Neurochemical Transmission: Role of Receptors and Plasma Membrane Transporters
A. Presynaptic Receptor-Mediated Modulation of Transmitter Release
1. Heteroreceptor-Mediated Control of Transmitter Release.
2. Autoreceptor-Mediated Control of Transmitter Release.
3. Presynaptic Ionotropic Receptors.
4. Presynaptic Metabotropic Receptors.
B. Plasma Membrane Transporters.
1. Characteristics of Transporters.
2. Substrate Selectivity.
III. Nonsynaptic Varicosities
IV. Extracellular Space as a Communication Channel of Nonsynaptic Interaction
V. Nonsynaptically Expressed Receptors and Membrane Transporters of High Affinity as Therapeutic Targets
A. Nonsynaptic Receptors
B. Nonsynaptic Transporters
C. Nonsynaptic Interaction between Neurons without Receptors
VI. Clinical Implications
VII. Summary
Acknowledgments
References
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Abstract |
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Neurochemical and morphological evidence has shown that some neurotransmitters or substances may be released from both synaptic and nonsynaptic sites for diffusion to target cells more distant than those observed in regular synaptic transmission. There are functional interactions between neurons without synaptic contacts, and matches between release sites and localization of receptors sensitive to the chemical signal are exceptions rather than the rule in the central nervous system. This also indicates that besides cabled information signaling (through synapses), there is a "wireless" nonsynaptic interaction between axon terminals. This would be a form of communication transitional between discrete classical neurotransmission (in Sherrington's synapse) and the relatively nonspecific neuroendocrine secretion. Recent findings indicate that in addition to monoamines (norepinephrine, dopamine, serotonin), other transmitters, such as acetylcholine and nitric oxide (NO), may also be involved in these nonsynaptic interactions. It has been shown that NO, an ideal mediator of nonsynaptic communication, can influence the function of uptake carrier systems, which may be an important factor in the regulation of extracellular concentration of different transmitters. This review will focus on the role of nonsynaptic receptors and transporters in presynaptic modulation of chemical transmission in the central nervous system. The nonsynaptic interaction between neurons mediated via receptors and transports of high affinity not localized in synapses has the potential to be an important contributor to the properties and function of neuronal networks. In addition, it will be suggested for the first time that the receptors and transporters expressed nonsynaptically and being of high affinity are the target of drugs taken by the patient.
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I. Introduction |
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Our understanding of chemical
signal transmission between neurons and between axon terminals and
target cells has advanced significantly since Elliott (1904)
, Loewi
(1921)
, and Dale (1934)
first elaborated on the concept that
epinephrine and acetylcholine (ACh)2 are released
from the neuron and may be able to transmit signals toward target
cells. Today, our knowledge of how information is conveyed chemically
from one cell to another has been heavily influenced by textbook data
on the neuromuscular junction (Katz, 1969
), in which the transmitter
ACh is stored in vesicles and released into the junctional gap in
quanta. This system is adopted for very fast signaling: The information
transfer occurs within millisecond time intervals and is able to
transmit messages of several hundred impulses per second. Each synaptic
vesicle releases a quantum of 7000 to 12,000 ACh molecules into
the narrow junctional cleft, raising the local concentration to the
millimolar range (Kuffler and Yoshikami, 1975
; cf. Van der Kloot and
Molgo, 1994
). Under this condition, the receptors receiving the
chemical messages are of low affinity. As far as the structure for
chemical information processing is concerned, since the work of
Ramon-y-Cajal (1893)
and Sherrington (1906)
, much of our current
knowledge comes from studies based on junctional architecture (cf.
Tansey, 1998
). The idea that the transmitter is released in quanta on
the arrival of the action potential is well established and has been
accepted at the neuromuscular junction, but it is not at all clear that this is the case at the autonomic neuroeffector transmission site. In
contrast to striatal muscle, autonomic neuroeffector systems are thus
not organized in units, but the innervation is quite diffuse. The
quantal release is less clearly established in the central nervous
system (CNS), although evidence is presented that this is probably the
case. Accordingly, the brain was considered a telephone network that
receives signals via synapse processing by means of a high
concentration of transmitters through receptors. A chemical signal
transmission system that primarily uses synaptic transmission in the
CNS possesses several characteristics. Because transmitter
concentration in the synaptic gap can be high (~0.01-1 mM), the
receptors expressed on both presynaptic and postsynaptic sites are of
low affinity (MacDermott et al., 1999
). Additionally, once released,
the transmitter is removed from the cleft either enzymatically or by an
uptake system and by diffusion.
One well characterized mechanism by which chemical
neurotransmission can be modulated is the presynaptic modulation of
transmitter release via presynaptic receptors expressed on axon
terminals. Activation of these receptors by endogenous or exogenous
ligands results in inhibition or facilitation of the amount of
transmitters released into the extracellular space by an action
potential (Starke et al., 1977
, 1989
; Westfall 1977
; cf. Starke, 1981
;
Langer, 1981a
; Vizi, 1979
; Muscholl, 1980a
,b
; Kalsner and Westfall,
1990
; Wu and Saggau, 1997
). It is interesting to note that Koelle
(1990)
mentioned in his review that the first concrete evidence of
presynaptic receptors was published in a classic report by Masland and
Wigton (1940)
. These authors claimed that the fasciculation that
follows the intra-arterial injection of ACh or an anticholinesterase
drug into a skeletal muscle reflects the firing of the motor units rather than stimulation of the muscle fibers. The other possibility to
modulate the extracellular concentration of transmitters, once released, is their removal by one of the
Na+/Cl
-dependent
neurotransmitter transporters. The transporter is a plasma membrane
protein that operates by reuptake of the released transmitter. The
tricyclic antidepressants exert their effect on monoamine transporters
by prolonging the time needed for clearance of transmitters from the
extracellular space.
Neurochemical (Vizi, 1980
, 1984
; cf. Vizi and Kiss, 1998
) and
morphological (Descarries et al., 1987
; Oleskevich et al., 1989
; Umbriaco et al., 1995
) evidence has shown that some neurotransmitters may be released from both synaptic and nonsynaptic sites (Fig. 1) for diffusion to target cells more
distant than those observed in synaptic transmission. It has been shown
in the gut and brain that in response to activation of the
noradrenergic neurons, there was an
-adrenoceptor-mediated
inhibition of ACh release from neighboring cholinergic terminals (Vizi
and Knoll, 1971
, 1976
; Vizi, 1974
, 1980b
) without any morphologic
(synaptic) contact between them. These findings indicate that there is
functional interaction (presynaptic inhibition) between neurons without
any morphological contact (cf. Vizi, 1980a
, 1984a
). This was supported by the fact that matches between release sites and localization of
receptors sensitive to the chemical signal are exceptions rather than
the rule (Herkenham, 1987
). Although the disparities between axon
terminals (release sites) and receptors were noted in several reports
(cf. Herkenham, 1991
), Herkenham was the first who studied this
mismatch carefully. Even in the report on substance P receptors (Rothman et al., 1984
), they put forth that mismatches were the rule rather than the exception. The conclusion (Herkenham, 1987
; McLean
et al., 1987
) drawn from this "mismatch" problem was that mismatches reflect on the existence of high-affinity nonsynaptic receptors that are able to mediate "parasynaptic" (Schmitt, 1984
) signal transmission. The nonsynaptic interactions between neurons would
be a form of communication transitional between discrete classic
neurotransmission (in Sherrington's synapse) and the relatively nonspecific neuroendocrine secretion. Recent findings indicate that in
addition to monoamines [norepinephrine (NE), dopamine (DA), and
serotonin(5-hydroxytryptamine, or 5-HT)], other transmitters, such as
ACh (Descarries et al., 1997
) and nitric oxide (NO; Dawson and Snyder,
1994
), also may be involved in these nonsynaptic interactions. NO can
influence the function of uptake carrier systems (Cutillas et al.,
1998
; Kiss et al., 1999
), which may be an important factor in the
regulation of extracellular concentration of different transmitters
(Gainetdinov et al., 1998
; Segovia and Mora, 1998
).
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This review focuses on the role of nonsynaptic receptors and transporters in presynaptic modulation of chemical transmission in the CNS, and I outline some of the potential points at which we might expect the occurrence of nonsynaptic functional interaction between neurons. It should be clear from this review that nonsynaptic interaction between neurons mediated via receptors and transporters of high affinity not localized in synapses has the potential to be an important contributor to the properties and function of neuronal networks. In addition, receptors and transporters expressed nonsynaptically and of high affinity are the target of drugs taken by the patient.
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II. Modulation of Neurochemical Transmission: Role of Receptors and Plasma Membrane Transporters |
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A. Presynaptic Receptor-Mediated Modulation of Transmitter Release
Action potential at the nerve terminal results in an increase in
Ca2+ influx through Ca2+
channels, activating Ca2+ sensors, which in turn
trigger the release machinery to cause vesicle fusion and transmitter
release (cf. Llinas, 1977
). Extracellular Ca2+
concentration
([Ca2+]o)-dependent
release of transmitters [glutamate (Glu): Uchihashi et al., 1998
;
Nakai et al., 1999
; DA: Milusheva et al., 1992
, 1996
; and NE: West and
Fillenz, 1980
) is vesicular (Katz, 1969
)], has a high
requirement for energy, and is very sensitive to the intracellular ATP
level. The
[Ca2+]o-dependent release
can be blocked by tetrodotoxin and subjected to presynaptic modulation
via activation of different presynaptic receptors (Table
1).
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It was not until the late 1960s that the concept of presynaptic
receptors (i.e., receptors on nerve endings, as opposed to postsynaptic
receptors on effector cells) was proposed and the hypothesis was
advanced that presynaptic receptor mechanisms are involved in the
modulation of neuronal ACh and NE release via
- and muscarinic
heteroreceptors (Lindmar et al., 1968
; Vizi, 1968
; Löffelholz and
Muscholl, 1969a
,b
; Paton and Vizi, 1969
).
In 1971, in different laboratories (De Potter and Chubb, 1971
; Farnebo
and Hamberger, 1971
; Kirpekar and Puig, 1971
; Starke, 1971
), NE was
shown to inhibit its own release from noradrenergic terminals via
presynaptic
-adrenoceptors. This was named "negative feedback"
modulation. Later, similar autoreceptor-mediated modulation was
described for other transmitters. It was even shown that there is a
positive feedback modulation when the transmitter released into the
synaptic cleft increases its own release via stimulation of receptors
located on terminals from which the transmitter is released.
The release of transmitter is subjected to presynaptic
receptor-mediated modulation (Langer, 1977
, 1981a
; Nicoll and Alger, 1979
; Vizi, 1979
, 1984
; cf. Starke et al., 1989
) if the release is of
vesicular origin, is
[Ca2+]o-dependent (Table
1), and is associated with axonal conduction. The ligand-gated release
by nicotinic acetylcholine receptor (nAChR) or P2X receptor stimulation
is also [Ca2+]o-dependent
(Sershen et al., 1997
; cf. Wonnacott, 1997
). Because it has been shown
that
2-adrenoceptor activation (Vizi et al., 1995b
) inhibits the release of NE evoked by nAChR stimulation, it seems
very likely that this type of release is subjected to presynaptic inhibition.
There is a
[Ca2+]o-independent
release that is not associated with neuronal conduction and not of
vesicular origin. It has been reported that transmitters can be
released by drugs (e.g., ouabain, indirectly acting sympathomimetic
amines) or conditions (e.g., ischemia) in the absence of
[Ca2+]o (cf.
Ádam-Vizi, 1992
; Bernáth, 1992
), which has been attributed to an increase in intracellular Na+
concentration ([Na+]i;
Vizi, 1972
; Baker and Crawford, 1975
; Erulkar and Rahamimoff, 1978
;
Schoffelmeer and Mulder, 1983
). This type of release is not subject to
presynaptic modulation (Vizi, 1984
) and is carried out by reversed
operation of the plasma membrane transporter mediated via an increase
in [Na+]i (Table 1). The
carrier-mediated release (Vizi, 1972
, 1978
; Vizi et al., 1985
;
Kauppinenen et al., 1988
; Pin and Bockaert, 1989
; Attwell et al., 1993
;
Levi and Raiteri, 1993
; Milusheva et al., 1994
, 1996
; Malva et al.,
1998a
,b
; cf. Vizi and Kiss, 1998
) does not require energy and is
consistent with a drop in intracellular ATP levels and the consequent
inhibition of
Na+,K+-activated ATPase
activity, which leads to a decline in the Na+
electrochemical gradient across the plasma membrane and accumulation of
[Na+]i (Nicholls and
Attwell, 1990
). The excessive transmitter release of nonvesicular
origin (Attwell et al., 1993
) cannot be modulated via presynaptic
receptors (Table 1). A similar mechanism is responsible for
[Ca2+]o-independent
release of different transmitters during ischemia simulated by oxygen
and glucose withdrawal (Kauppinenen et al., 1988
; Budd, 1998
).
K+ excess has been used for a long time to study transmitter release. It is [Ca2+]o-dependent and is likely to be of vesicular origin (Table 1), at least at low concentrations.
The overwhelming majority of the evidence for presynaptic receptor-mediated modulation of transmitter release derives from assays of agonist- and antagonist-induced changes in the release rate from in vitro (slice, synaptosomes) and in vivo (microdialysis, amperometry) preparations. Although assay of the amount of transmitters in the superfusate or in the dialysate is limited in spatial and temporal resolution, electrophysiological methods (e.g., whole-cell recording) in brain slices or in cell culture help us to overcome these problems and to study the effects of ligands on presynaptic terminals recording the postsynaptic responses. However, even the electrophysiological recordings of the frequency of spontaneous postsynaptic currents or the amplitude of the evoked postsynaptic current, without a change in postsynaptic sensitivity to the synaptic transmitter, provide convincing evidence that the receptor in the study is expressed on the terminal. This technique fails to exclude the possibility that a chemical is released from the postsynaptic site that may act retrogradely, affecting the release of transmitter from the presynaptic site. Therefore, to circumvent these difficulties, the final conclusion should be drawn from data obtained from different techniques.
1. Heteroreceptor-Mediated Control of Transmitter Release. An important consequence of the expression of receptors on axon terminals is the capability of modulation (increase or decrease) of transmitter release triggered by the action potentials when they invade presynaptic terminals. Heteroreceptors are located presynaptically; they bind transmitters other than those released by the axon terminal on which they reside. Heteroreceptors can be ionotropic or metabotropic.
The first neurochemical and pharmacological evidence of heteroreceptors was obtained when it was shown in guinea pig ileal longitudinal muscle strip preparation that the stimulation-evoked release of ACh from the Auerbach plexus is tonically controlled by NE released from the neighboring noradrenergic neurons via
-adrenoceptors (Vizi, 1968
-adrenoceptor antagonist
phentolamine was present, indicating that the release was tonically
controlled by endogenous NE. This was the first indication of
inhomogeneity of
-adrenoceptors; NE and phenylephrine, two
-adrenoceptor agonists, have different effects on ACh release.
Today, they are designated
2- and
1-adrenoceptors. Also, the stimulation-evoked
release of NE from sympathetic nerve in the heart is inhibited by ACh
released from the vagal nerve (Lindmar et al., 1968
2A,
2B, M2, µ , and so on) located on
varicosities has been shown (cf. Vizi, 1979
conductance and
are coupled to G proteins reduce the release. This type of presynaptic
modulation is graded. Only axodendritic axosomatic and dendrodendritic
synaptic or nonsynaptic interactions regulate the generation of an
action potential.
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2. Autoreceptor-Mediated Control of Transmitter Release.
The
first evidence was provided in the 1970s when Starke (1971)
and others
(De Potter and Chubb, 1971
; Farnebo and Hamberger, 1971a
; Kirpekar and
Puig, 1971
) showed that NE inhibits its own release via
-adrenoceptors. Later, it turned out that these receptors are
different from those located on the postsynaptic site. Therefore, presynaptic
-adrenoceptors have been named
2-adrenoceptors (Langer, 1977
, 1981a
,b
).
2, M2, µ, and so on) sensitive to
transmitter released from axon terminal on which the receptor is
expressed is now widely accepted (Table 2). This can be envisaged as an
attempt to limit the release of excessive amounts of transmitter to
keep postsynaptic responses within the physiological range.
3. Presynaptic Ionotropic Receptors.
Recent convergence of
data from morphological and functional (pharmacological, neurochemical,
and electrophysiological) studies provided new insights into the role
of presynaptic ligand-gated ion channels (cf. McGehee and Role, 1996
;
MacDermott et al., 1999
) in modulation of transmitter release, thereby
in the efficacy of synaptic and nonsynaptic communication. Activation
of ionotropic receptors results in very rapid changes of ion channels.
-aminobutyric acid (GABA), and DA release via
nACh heteroreceptors (cf. Wonnacott, 1997
-Amino-3-hydroxy-5-methysoxazole-4-propionic Acid, and Kainate
Receptors).
The vast majority of excitatory synapses are
glutamatergic, in which Glu transmits the signal through postsynaptic
ionotropic [N-methyl-D-aspartic acid
(NMDA),
-amino-3-hydroxy-5-methysoxazole-4-propionic acid (AMPA),
and kainate (KA)] and metabotropic receptors (Bettler and Mulle,
1995
-Aminobutyric AcidA Receptors.
Frank and
Fuortes (1951)
-subunit-expressing GABAA receptors suggests
that tonic inhibition could be mediated mainly by nonsynaptic
6
2/3
receptors, whereas phasic inhibition is due to the
stimulation of intrasynaptic GABAA receptors. It
has been shown (Herrero et al., 19994. Presynaptic Metabotropic Receptors.
The activation of
membrane receptors expressed in the membrane is a common mechanism
through which cellular functions, including neurotransmitter release,
can be modulated (Table 2). Metabotropic receptors are coupled to G
proteins. The latter are proteins (containing
-,
-, and
-subunits) that are present in membranes of the cell and transduce
the receptor activation event to changes in enzyme or ion-channel activity.
2-Adrenoceptors.
It is clear from their
structure and pharmacology that
2-adrenoceptors belong to the G protein-linked
family and, in most cell types, are coupled to PTX-sensitive G
proteins. It is well established that some receptors inhibit adenylyl
cyclase through the G protein Gi. The activation
of
2-adrenoceptor subtype has been shown to
inhibit adenylyl cyclase activity, decrease cAMP levels, and inhibit
Ca2+ channels in many cell types, including
neurons. cAMP has a facilitatory effect on many transmitter systems,
including the noradrenergic system (Majewski et al., 1990
2-adrenoceptors may
inhibit transmitter release (e.g., NE) by inhibiting adenylyl cyclase
(Schoffelmeer et al., 1986
2-adrenoceptor have been identified:
2A,
2B,
2C, and
2D (Bylund et
al., 1988a
2A and
2D subtypes were shown as orthologs, with the
2A being present in humans (Bylund et al.,
1988a
2-adrenoceptors. It is interesting to note
that the
2B subtype of autoreceptors is mainly
located in varicosities of noradrenergic terminals in the periphery and
that
2A is mainly located in the CNS.
Both subtypes are involved in autoregulation of NE release. The
heteroreceptors expressed on varicosities synthesizing ACh and 5-HT are
of the
2A subtype (Table 3).
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2-adrenoceptors are
present on serotonergic nerve endings of the human neocortex (Raiteri
et al., 1990a
-Aminobutyric AcidB Receptors.
The
metabotropic GABAB receptors are widely
distributed in the CNS, where they are located (Bowery, 1993B. Plasma Membrane Transporters.
Na+/Cl
-dependent
transporters, such as DA, 5-HT, NE, GABA, glycine, taurine, proline,
and betaine, are members of a large family of
Na+/Cl
-containing
putative transmembrane domains (Kanner and Schuldiner, 1987
; Amara and
Kuhar, 1993
; Lester et al., 1994
; Nelson, 1998
). These ion-coupled
transporters are "electrogenic" and lead to conductive properties
(cf. Lester et al., 1996
). These transporters are different from that
expressed in the membrane of vesicles (Henry et al., 1998
). It is
generally accepted that these high-affinity transporters located on the
nerve terminals and surrounding glial cells (cf. Nelson, 1998
) control
the temporal and spatial concentration of transmitters released into
the intrasynaptic and extrasynaptic spaces via rapid uptake into nerve
terminals. For example, in tissue with dense noradrenergic and
GABAergic innervation, as much as 70 to 80% of released NE
(Bönisch and Brüss, 1994
) and GABA (Iversen and Kelly,
1975
) may be recaptured, indicating that the transporter plays an
important role in setting the concentration of transmitter in the
extracellular space. Thus, plasma membrane transporters maintain low
intrasynaptic and extrasynaptic neurotransmitter concentrations,
thereby regulating synaptic and nonsynaptic efficacy; many of the
transporters have been implicated as important sites for drug actions.
1. Characteristics of Transporters.
a. Protein Kinase C Dependence.
It has been suggested that
protein kinase C (PKC) plays a role in acute modulation of
Na+/Cl
-coupled
transporters, including GABA, DA, and 5-HT (Corey et al., 1994
; Osawa
et al., 1994
; Zhang et al., 1997
; Ramamoorthy et al., 1998
). Activation
of PKC by phorbol ester inhibits the uptake of GABA (Osawa et al.,
1994
), DA (Zhu et al., 1997
), 5-HT (Qian et al., 1997
; Ramamoorthy et
al., 1998
), and NE (Apparsundaram et al., 1998
).
/
), the DA transporter
(DAT) function was lacking, compared with D2+/+ mice, and that raclopride
(D2 receptor antagonist) decreased the activity
of the transporter in D2+/+
mice. That DAT can be modulated by D2
autoreceptors has already been suggested (Meiergerd et al., 19932. Substrate Selectivity.
a. Norepinephrine Transporter.
NE transporters (NETs) located
in the neuronal plasma membrane mediate the removal of NE from the
extracellular space (cf. Graefe and Bönisch, 1988
; cf.
Trendelenburg, 1991
; Nelson, 1998
), limiting the activation of auto-
and hetero-adrenoceptors expressed on different neurons by reducing the
extracellular concentration of NE and thereby the amount of NE
available for diffusion. NETs also transport structurally similar
molecules, including DA, tyramine, and amphetamine (Bönisch,
1986
; Bönisch and Brüss, 1994
). Similar to other
transporters, NETs use the energy of the transmembrane Na+ gradient to take up NE inside the neuron from
the intrasynaptic and/or extrasynaptic space. The direction of
transport can be reversed by inward transport of any substrate (cf.
Chen and Justice, 1998
). At a high frequency of stimulation, so much
transmitter is being released that the transporter capacity (which has
been used up) becomes fully exploited and unable to continue to clear the extracellular space.
. In line with
these observations using electron microscopy, it has been shown
(Hoffmann et al., 1998
/
) that DA released from
nigrostriatal varicose axon terminals into the extrasynaptic space
persists at least 100 times longer than in wild-type animals and that
diffusion is the only mechanism for clearance (Gainetdinov et al.,
1998
-Aminobutyric Acid Transporter.
The role of GABA
transporter is to terminate synaptic events evoked by GABA released
from GABAergic terminals. GABA uptake inhibitors increase and prolong
GABAB receptor-mediated transmission (Dingledine
and Korn, 1985
-dependent neurotransmitter transporters,
which are important targets for both drugs of abuse and antidepressant
compounds (Amara and Kuhar, 1993
/
mice demonstrated a complete lack of
high-affinity 5-HT uptake and have increased extracellular 5-HT levels
and an increased anxiety-related behavior (cf. Murphy et al., 1999| |
III. Nonsynaptic Varicosities |
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It is well known that axons both in the CNS and in the autonomic
nervous system form varicose (boutons-en-passant) branches. The varicose axon terminals, which in the overwhelming majority do not
make synaptic contacts, are the main target of presynaptic modulation.
A substance released in or diffusing to the vicinity of the axon
terminal can modulate the release of the principal transmitter or that
of another modulator provided the axon is equipped with sensitive
receptors. Many authors (cf. Langer, 1977
; cf. Starke, 1977
) support
the idea that presynaptic modulation is a question of secretion
coupling. However, others (Alberts et al., 1981
; Stjärne, 1981
)
suggest that mechanisms related to the failure of varicosity invasion
are responsible for presynaptic inhibition. It was suggested that
presynaptic inhibition is the reduction in the safety factor for
terminal varicosity invasion by the axonal nerve impulse
(Stjärne, 1981
, 1989
). The release of NE from sympathetic nerve
terminals by the invading nerve impulse is a very uncertain process,
with a high proportion of failures at any individual varicosity
(Blakeley and Cunnane, 1979
), so that any procedure marginally reducing
the chance of invasion may have profound effects. Alberts et al. (1981)
suggested that varicosity hillocks could control the excitability of
the varicosity and the invasion of the more distal parts of the branch.
The wave of depolarization arriving at the varicosity hillock reaches
the firing level and generates a propagating impulse in the next
intervaricose section. However, this site of action seems very unlikely
because it is based on acceptance that the method of action potential conduction in a varicose terminal is similar to that in a neuron, and
this is not the case. The action potential attempts to invade the whole
branch without alternating depolarization with action potential
generation and intervaricosital axonal conduction. The bouton is small;
therefore, the action potential arriving at the first and consecutive
boutons tries simply to depolarize and pass them. Although methods for
analysis of the mode of impulse conduction in
boutons-en-passage terminals are not available, it is
tempting to speculate that the difference in size between the cross
section of the intervaricosital axonal part and the bouton makes it
difficult for impulses to invade the whole branch. The sudden change in size of the varicose branch at the bouton might produce changes in, for
example, the length constant (Vizi, 1984
) and thereby influence the
length of invasion of the rather lengthy arborization.
There is convincing neurochemical evidence, mainly based on studies
with synaptosomal preparations and potassium-induced release, that the
site of action is on the axon terminals. Therefore, there is general
agreement that secretion coupling is affected by the modulators (cf.
Langer, 1977
; cf. Starke, 1977
).
Although the axo-axonic synapse is the anatomical correlate of
presynaptic modulation, convincing anatomical evidence is available that noradrenergic (cf. Oleskevich et al., 1989
), serotonergic (Descarries et al., 1975
; Seguela et al., 1989
; Oleskevich et al.,
1991
), dopaminergic (Descarries et al., 1991
), and cholinergic (Descarries et al., 1997
) varicosities in the CNS in a rather high
percentage do not make synaptic contact. A very low synaptic incidence
of monoaminergic innervation has already been documented in the adult
rat cortex (Descarries et al., 1975
, 1977
; Beaudet and Descarries,
1978
; Seguela et al., 1990
, 1989
), hippocampus (Oleskevich et al.,
1989
; Daszuta et al., 1991
; Umbriaco et al., 1995
), dorsal horn of the
spinal cord (Ridet et al., 1993
), and cerebellum (Beaudet and Sotelo,
1981
).
Although the incidence of nonsynaptic nerve terminals amounted to 64%
for 5-HT and 57% for NE in the dorsal horn of the spinal cord (Ridet
et al., 1993
), in the ventral horn (Privat et al., 1988
) the synaptic
contacts were the predominant, indicating that nonsynaptic
communication is characteristic of the dorsal horn, and
low-affinity 5-HT2 receptors are numerous in the
ventral horn but scarce in the dorsal horn (Pazos et al., 1985
, Pazos
and Palacios, 1985
).
Recent immunoelectromicroscopic studies have revealed a low incidence (14% in the cerebral cortex, 7% in the hippocampus, and 9% in the neostriatum) of synaptic