Vol. 52, Issue 1, 63-90, March 2000

Role of High-Affinity Receptors and Membrane Transporters in Nonsynaptic Communication and Drug Action in the Central Nervous System

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

	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.

	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).

View larger version (35K): [in this window] [in a new window]   Fig. 1.   Synaptic and nonsynaptic interaction between neurons. The transmitter release from varicosity without synaptic contact diffuses far away from the release site and activates remote receptors of high affinity. The transmitter concentration in the extracellular space is low and drops in a function of 3. In the synapse, the transmitter concentration is very high, and there is a possibility of spillover. Transmitter released is taken up by plasma membrane transporters located in the synapse or extrasynaptically.

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.

	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).

View this table: [in this window] [in a new window]   TABLE 1 Characteristics of different types of transmitter release

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; Paton and Vizi, 1969; Vizi and Knoll, 1971). Although NE or epinephrine inhibited the release of ACh in a concentration-dependent manner, phenylephrine did not affect it. The release in response to axonal stimulation was increased when the -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; Löffelholz and Muscholl, 1969a). These two observations provided the first evidence for presynaptic interactions between neurons by means of their transmitters, via heteroreceptors. The main difference between these two effects is that in the Auerbach plexus, there is no synaptic contact between noradrenergic and cholinergic axon terminals (Gordon-Weeks, 1982), but still there is a functional connection; stimulation of a noradrenergic axon results in an inhibition of ACh release (Vizi and Knoll, 1971; Manber and Gershon, 1979), whereas in the heart, vagal nerve endings make synaptic contacts with the noradrenergic axon terminals (Ehinger et al., 1970).

Interaction via heteroreceptors (_2A, _2B, M2, µ , and so on) located on varicosities has been shown (cf. Vizi, 1979; Starke, 1981; Starke et al., 1989; Göthert and Schlicker, 1991) between different axon terminals in different neurons (Table 2). Because the amount of transmitters released depends on the magnitude and duration of terminal depolarization and on Ca²⁺ influx, ionotropic heteroreceptors that depolarize and/or increase Ca²⁺ influx increase the release. In contrast, metabotropic heteroreceptors that enhance K⁺ or Cl 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.

View this table: [in this window] [in a new window]   TABLE 2 References for the effect of stimulation of presynaptic receptor (ionotropic and metabotropic) activation by major transmitters and ATP (adenosine) on [Ca2+]o-dependent transmitter release in the CNS [neurochemical and electrophysiological (EP) evidence]

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).

The notion that the release of NE (Starke, 1971; Langer, 1974; Stjärne, 1981, 1989), and other transmitters (Langer, 1974; Starke, 1977; Westfall, 1977; Vizi, 1979, 1984a; Starke et al., 1989; Kalsner and Westfall, 1990; Vizi and Lábos, 1991; Kilbinger et al., 1993; Göthert and Schlicker, 1997; Vizi and Kiss, 1998) can be modulated via stimulation of presynaptic autoreceptors (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.

a. Nicotinic Acetylcholine Receptors. Several lines of neurochemical, pharmacological, morphological, and electrophysiological evidence indicate that in the CNS, nAChRs are mainly involved in presynaptic modulation of transmitter release and are not receptors of postsynaptic localization transmitting cholinergic messages (Wonnacott et al., 1989, 1995; cf. McGehee et al., 1995; Vizi et al., 1995; McGehee and Role, 1996; Sershen et al., 1997; Wonnacott, 1997; Vizi and Kiss, 1998). Activation of nAChRs in brain regions either results in a transmitter release or facilitates the release due to axonal stimulation (cf. MacDermott et al., 1999; Vizi and Lendvai, 1999). ACh increases ACh via nACh autoreceptors (Marchi et al., 1999) and Glu, NE, 5-HT, -aminobutyric acid (GABA), and DA release via nACh heteroreceptors (cf. Wonnacott, 1997; Vizi and Lendvai, 1999). Lena et al. (1993) suggested that presynaptic nAChRs, depending on their apparent localization, may differentially influence the release of transmitter that is associated with nerve conduction and that is not resulted from axonal conduction. The release of NE from the hippocampal slices (Vizi et al., 1995; Sershen et al., 1997) and DA from striatal slices (Marshall et al., 1996) evoked by nAChR activation is tetrodotoxin- and mecamylamine-sensitive and [Ca²⁺]_o-dependent (Sershen et al., 1997; cf. Vizi and Lendvai, 1999). In contrast, the release from synaptosomal preparation (defined as presynaptic elements) in nAChR stimulation was tetrodotoxin(TTX)-insensitive (Clarke and Reuben, 1996). The TTX sensitivity of nAChRs-evoked transmitter release has been interpreted as "preterminal" rather than presynaptic location of nAChRs (Wonnacott, 1997). This would indicate that the nAChRs are expressed on the preterminal axon and that their activation elicits an action potential that consequently opens voltage-dependent Ca²⁺ channels in the terminal to release transmitter. A more convincing explanation is that nAChRs are expressed on the boutons and their activation results in depolarization and Ca²⁺ influx (for review, see MacDermott et al., 1999; Vizi and Lendvai, 1999). Presynaptic nAChRs are likely to be as diverse in subunit composition as their somatodendritic counterparts (cf. Vizi and Lendvai, 1999).

An important question arises as to whether presynaptic nAChRs could be targeted by endogenously released ACh, which is limited by fast enzymatic hydrolysis, or whether they are silent receptors that are activated only during smoking or cholinesterase inhibition. Taking into account the diffuse cholinergic projections and the relatively low proportion of cholinergic boutons making synaptic contact (7-14%) in the CNS (Descarries et al., 1997), it seems likely that ACh released from varicose axon terminals plays both synaptic and nonsynaptic presynaptic modulator roles. Kása et al. (1995) showed in the cortex that ACh could be released even from nonsynaptic varicosities.

Regardless of the interaction between cholinergic terminals and noradrenergic, dopaminergic, and serotonergic varicosities equipped with nAChRs, the stimulation of these receptors by nicotine inhaled during smoking may result in a release of excitatory amino acids (Toth et al., 1993) and NE, DA, or 5-HT, transmitters that are able to diffuse far away from the release site as demonstrated by microdialysis studies (Schneider et al., 1994) and affect tonically the release of other transmitters or the firing rate of other circuitry.

b. Glutamate Receptors (N-Methyl-D-aspartic Acid, -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). Glu is a fast excitatory transmitter in the CNS and has been shown, with GABA, to interact primarily with receptors in the synaptic cleft (Tong and Jahr, 1994; Geiger et al., 1997; Jensen et al., 1998; Dingledine et al., 1999; MacDermott et al., 1999).

There are several reports of presynaptic localization of GluRs and their involvement in transmitter release (Table 2). The fact that NMDA releases Glu (Pittaluga et al., 1996), DA (Kuo et al., 1998), and NE (Pittaluga and Raiteri, 1996) from axon terminals indicates that Glu released is able to facilitate transmitter release via NMDA receptors. In addition, presynaptic AMPA receptor activation results in an increase of Glu release, provided that the receptor's fast desensitization was prevented by cyclothiazide (Barnes et al., 1994; Desai et al., 1994). However, Montague et al. (1994) hinted that there is some doubt regarding this conclusion. They showed that Glu and NE release from cortical synaptosomes was in correlation with NMDA-induced production of nitric oxide (NO), an endogenous chemical that is able to inhibit basal membrane transporters, thereby increasing the concentration and life-span of transmitters (e.g., Glu and NE) released into the extracellular space. The inhibition of neuronal NO synthase by 7-nitroindazole protects against NMDA-mediated excitotoxic lesions but not against those evoked by AMPA or KA (Schulz et al., 1995).

It has also been shown that KA and Glu can reduce Glu release via a presynaptic receptor that controls chloride channels (Sarantis et al., 1988). In the presence of uptake inhibitors, even Glu (Asztely et al., 1997; Kullman and Asztely, 1998) and GABA (Isaacson et al., 1993) may have extrasynaptic actions. Until now, there has been no convincing evidence for the nonsynaptic release of Glu. In the synapse, an active transport mechanism limits the intrasynaptic concentration of Glu (cf. Gelagashvili and Schousboe, 1998).

In addition, it has been shown that presynaptic AMPA receptors (cf. Tarnawa and Vizi, 1998) play a role in the regulation of the release of neurotransmitters in several brain areas. Activation of AMPA receptors releases NE from nerve terminals. GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepine], a non-NMDA receptor antagonist (cf. Vizi et al., 1996, 1997), blocked aspartate release from forebrain slices, Glu release from cerebellar cultures and hippocampal synaptosomes, and DA release from rat mesencephalic cultures evoked by AMPA receptor stimulation. The release of DA from nigrostriatal axon terminals in the striatum is also increased by stimulation of NMDA and non-NMDA receptors (Kuo et al., 1998; for a review, see Morari et al., 1998). These data provide increasing support for the conclusion that NMDA and non-NMDA receptors (AMPA and KA) are located on presynaptic nerve terminals and are able to influence transmitter release (MacDermott et al., 1999).

c. -Aminobutyric Acid_A Receptors. Frank and Fuortes (1951) were the first to show that the inhibition of excitatory postsynaptic potentials in motoneurons is a presynaptic event. Several reports (Kardos, 1999) have shown that most of the physiological actions of GABA are mediated via GABA_A (Seabrook et al., 1997; Sieghart et al., 1999; Vizi and Sperlágh, 1999; Whiting, 1999), and these receptors (Barnard et al., 1998) are involved in the presynaptic inhibition of signal transmission in, for example, the hippocampus (Vautrin et al., 1994) and feline spinal motoneurons (Stuart and Redman, 1992). These effects are mediated via a rapid increase of chloride-dependent conductance (cf. Mody et al., 1994; Vautrin et al., 1994). Phasic and tonic types of GABA_A receptor-mediated inhibition have been described in cerebellar granule cells (Brickley et al., 1996; cf. Nusser et al., 1998). These cells, however, receive GABAergic input only from a single cell type (Golgi cells). Nevertheless, Nusser et al. (1998) showed that exclusive extrasynaptic presence of the -subunit-expressing GABA_A receptors suggests that tonic inhibition could be mediated mainly by nonsynaptic 62/3 receptors, whereas phasic inhibition is due to the stimulation of intrasynaptic GABA_A receptors. It has been shown (Herrero et al., 1999) that GABA_A receptor activation by GABA reduces and increases Glu release from cortical neurons in culture, depending on the membrane potential.

d. 5-Hydroxytryptamine₃ Receptors. 5-HT₃ receptors have a much lower affinity than 5-HT₁ receptors (Hoyer, 1990) and have a high density in the area postrema, the entorhinal cortex, and the amygdala (Kilpatrick et al., 1990), indicating their role in transmission. The activation of 5-HT₃ receptors makes the membrane permeable to Na⁺ and K⁺ and mostly impermeable to divalent cations. 5-HT₃ receptor antagonists possess medical applications as antiemetics, anxiolytics, and antipsychotics (cf. Göthert and Schlicker, 1997).

Electrophysiological evidence was obtained that the stimulation of 5-HT₃ receptors leads to the increased release of GABA (cf. Peters et al., 1992; Piguet and Galvan, 1994), DA (Zazpe et al., 1994), 5-HT (Martin et al., 1992; Bagdy et al., 1998), and NE (Allgaier et al.,1995).

e. P2X Receptors. Extracellular ATP acts as a signal transmitter through P2X receptors, which are ligand-gated ion channels, with a significant permeability to Ca²⁺, Na⁺, and K⁺ (cf. Bean, 1992; Ralevic and Burnstock, 1998). These receptors are distributed throughout the body, including synapses where ATP is able to transmit signals (cf. Sperlágh and Vizi, 1996; Sperlágh et al., 1997, 1998; Khakh and Kennedy, 1998). Their locations could be presynaptic and postsynaptic. P2X receptors are also known for their high Ca²⁺ permeability (Rogers et al., 1997) and capacity to increase transmitter release from nerve terminals (ACh: Sperlágh and Vizi, 1991; Sun and Stanley, 1996; Glu: Gu and MacDermott, 1997; Khakh and Henderson, 1998; DA: Zhang et al., 1996; NE: Boehm, 1999).

4. 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.

a. 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 G_i. 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). Therefore, it has been suggested that ₂-adrenoceptors may inhibit transmitter release (e.g., NE) by inhibiting adenylyl cyclase (Schoffelmeer et al., 1986).

Pharmacologically, four subtypes of the ₂-adrenoceptor have been identified: _2A, _2B, _2C, and _2D (Bylund et al., 1988a,b; Bylund et al., 1991, 1992, 1994; Deupree et al., 1996). Genetically, _2A and _2D subtypes were shown as orthologs, with the _2A being present in humans (Bylund et al., 1988a, 1991), pig, and rabbit. Table 3 shows the presynaptic localization of different subtypes of 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).

View this table: [in this window] [in a new window]   TABLE 3 Subtypes of presynaptic auto- and hetero-2-adrenoceptors expressed on axon terminals and on locus ceruleus For expression of mRNA of 2-adrenoceptor subtypes, see Winzer-Sershan et al. (1997a,b).

Presynaptic inhibitory ₂-adrenoceptors are present on serotonergic nerve endings of the human neocortex (Raiteri et al., 1990a; Grijalba et al., 1996), and endogenous NE is able to control the release of 5-HT from human and rat neocortex (Feuerstein et al., 1993).

b. Dopamine Receptors (D₁, D₂). DA receptors are divided into two families designated D₁ and D₂. D₁ receptors activate G_s proteins, and D₂ receptors activate G_i proteins (cf. Missale et al., 1998). Stimulation of D₂ receptors results in the inhibition of the release of DA from dopaminergic nerves (Hársing and Zigmond, 1997). Activation of these presynaptic receptors inhibits the release from their respective nerve terminals of other neurotransmitters, such as NE, ACh, and GABA (Hársing and Zigmond, 1997), from the striatum. Although D₂ receptors are coupled to inhibition of adenylyl cyclase in some cell types (Onali et al., 1985), this pathway is unlikely to be involved in the autoinhibition of DA release (cf. Starke et al., 1989), because forskolin failed to affect D₂ receptor-mediated inhibition (Bowyer and Weiner, 1989). Evidence was obtained that DA receptors and transporters are located at more remote sites (Smiley et al., 1994; Nirenberg et al., 1996, 1997). The stimulation of D₁ receptors increases Ca²⁺ influx (cf. Missale et al., 1998) and increases GABA release from the striatum (Floran et al., 1990; Hársing and Zigmond, 1997).

c. Muscarinic Receptors (M1, M2). There are at least three muscarinic receptor subtypes (M1, M2, and M3) involved in the modulation of transmitter release (Starke et al., 1989; Raiteri et al., 1990c; Caulfield, 1993; Caulfield and Birdsall, 1998). This receptor diversity may to some extent explain the diverse range of signal transduction mechanisms; these include inhibition of Ca²⁺ influx (Allen and Brown, 1993; 1996) and adenylyl cyclase, stimulation of guanylyl cyclase, activation of phospholipase C, and direct inhibition of Ca²⁺ channels and activation of K⁺ channels (cf. Felder, 1995). There is reasonably good evidence that the M2 (M4) receptors expressed on cholinergic (Lapshak et al., 1989; Quirion et al., 1995; Allen and Brown, 1996) and noradrenergic varicosities play a physiologically important role in the modulation of transmitter release.

The muscarinic receptors that inhibit NE release appear to be of the M2 subtype in the periphery and CNS (cf. Raiteri et al., 1990), but there is no such a modulation in the hippocampus (Milusheva et al., 1994; Jackisch et al., 1999b). The stimulation-evoked release of NE from hippocampal slices is not modulated by muscarinic receptors, because noradrenergic boutons are not equipped with muscarinic receptors (Milusheva et al., 1994; Jackisch et al., 1999b). In contrast, there are muscarinic receptors, apparently of the M1 subtype, that increase the release of NE (North et al., 1985; Raiteri et al., 1990c) expressed on noradrenergic axon terminals in the periphery. The M₁ receptor is generally coupled to PTX-insensitive G protein. Its activation results in formation of inositol trisphosphate and diacylglycerol. In contrast, the M2 receptor is coupled via PTX-sensitive G protein to the N-type Ca²⁺ channel (Hille, 1992). The role of M4 in "negative feedback" modulation (McKinney et al., 1993) has been questioned by the finding that after a selective lesion of the fimbria fornix there was a loss in M2 but an increase in M4 receptors (Wall et al., 1994). The relative importance of these inhibitory and stimulatory muscarinic receptors may vary in noradrenergic neurons from different locations.

d. 5-Hydroxytryptamine Receptors. The pharmacology of 5-HT receptors has made tremendous progress in the past decade. Although more than 14 identified receptors have been discovered (cf. Hoyer et al., 1994; Murphy et al., 1999), only a few selective receptor agonists or antagonists are available. It is generally accepted that [Ca²⁺]_o-dependent release of 5-HT from neurons originated from brainstem raphe nuclei (Törk, 1990) can be modulated by presynaptic autoreceptors (cf. Göthert and Schlicker, 1997) and heteroreceptors (cf. Göthert and Schlicker, 1991). Evidence for inhibitory presynaptic 5-HT autoreceptor was shown first by Farnebo and Hamberger (1971b). The serotonin autoreceptors have been classified as 5-HT_1B/D (Engel et al., 1986; Maura and Raiteri, 1986). In guinea pig hippocampal slice, the release of 5-HT is modulated via 5-HT_1D autoreceptors, as in humans (Maura et al., 1993; Galzin et al., 1995), whereas they are of the 5-HT_1B subtype in rats. Activation of these receptors results in a decrease of 5-HT release evoked by axonal stimulation (Maura and Raiteri, 1986; Limberger et al., 1991).

5-HT_1A receptors, which are also called autoreceptors, are expressed on the soma and dendrites of the neurons of the raphe nucleus. Their activation inhibits the firing rate of the serotonergic fibers and their desensitization after long-term treatment with 5-HT uptake blocker restores action potential firing. Therefore, the 5-HT_1A receptor plays an important role in the effect of antidepressants (Mongeau et al., 1997). 5-HT_1A knockout mice had elevated anxiety as a consequence of increased 5-HT release (cf. Murphy et al., 1999).

e. Metabotropic Glutamate Receptors. The presence of G protein-coupled glutamate receptors (metabotropic Glu receptors) has been described, and since 1991 (cf. Conn and Pin, 1997), eight receptors have been discovered and classified into three groups based on their linkage to second messenger systems and their pharmacology: group I acts via the phosphoinositol system, and groups II and III inhibit adenylyl cyclase. In addition, the stimulation of receptors of these three groups directly influences voltage-gated Ca²⁺ and K⁺ channels through their G proteins, but their physiological correlate has not yet defined.

In a calyx-type nerve terminal in the brain stem (Takahashi et al., 1996), the activation of metabotropic Glu receptors has been observed to inhibit Ca²⁺ currents, rather than activation of presynaptic K⁺ currents, and is responsible for presynaptic inhibition of transmitter release. Glu and quisqualate inhibit neuronal Ca²⁺ currents via a G protein-linked mechanism (Lester and Jahr, 1990), and this action may provide negative feedback control of Glu release (Terrian et al., 1991; Barnes et al., 1994; Malva et al., 1996).

f. -Aminobutyric Acid_B Receptors. The metabotropic GABA_B receptors are widely distributed in the CNS, where they are located (Bowery, 1993; Billinton et al., 1999) at both presynaptic and postsynaptic locales (Billinton et al., 1999), inhibiting the presynaptic release of neurotransmitters (see Table 2) and the postsynaptic activity of certain K⁺ channels (cf. Misgeld et al., 1995). The activation of presynaptic GABA_B receptors is long-lasting, being mediated through G protein-coupled processes (cf. Mody et al., 1994), and results in an inhibition of Ca²⁺ and activation of K⁺ conductances (Bowery, 1993; Billinton et al., 1999). GABA_B receptors may influence K⁺ channels through a physical coupling to the channel, but this effect is not mediated via a G protein intermediate (cf. Schousboe, 1999). The two isoforms (GBR1a and GBR1b) of GABA_B receptors seem to be associated with presynaptic and postsynaptic elements in rat and human cerebellum (Billinton et al., 1999).

g. Adenosine A₁ Receptors. Adenosine inhibits the evoked release of many neurotransmitters, both from peripheral nerves and in the CNS (see Table 2). The inhibitory effect of adenosine on NE (Fredholm, 1976; Fredholm and Dunwiddie, 1988) and ACh (Vizi and Knoll, 1976; Sperlágh et al., 1997) release has been particularly well described and proved to be mediated by adenosine A₁ receptors. Adenosine A₁ receptors have the general structure expected of G protein-linked receptors, and there is evidence that G_i proteins are involved in the inhibitory effects of adenosine on neurotransmitter release, inhibiting cAMP production and N-type Ca²⁺ channels and activating K⁺ permeability. In addition, there is some evidence that the activation of high-affinity adenosine A_2A receptors increases the release of different transmitters (Glu: Gu and MacDermott, 1997; ACh: Cunha et al., 1994; DA and NE: Sebastiao and Ribeiro, 1992) and has an effect on G_s protein and subsequently increases cAMP level. In contrast, its stimulation reduces the release of GABA from the recurrent collaterals of striatopallidal neurons (Kirk and Richardson, 1994).

The basal level of adenosine (20-300 nM) in the extracellular space is able to influence the activity of the neurons that are equipped with abundant adenosine A₁ and A_2A receptors.

The key question is: What is the role of extracellular adenosine either released from cells (cf. Mitchell et al., 1993; Thompson et al., 1993) or decomposed from ATP (ADP and AMP: Sperlágh and Vizi, 1996), especially during ischemia? It seems that adenosine, via activation of A₁ heteroreceptors being able to inhibit the release of different transmitters in the CNS (e.g., ACh: Cunha et al., 1994), plays an important role in dampening neuronal firing in epilepsy and ischemia, and it is neuroprotective (Thompson et al., 1993).

h. P2Y Receptors. Metabotropic P2Y receptors are coupled with G_q/11, G_s, and G_i proteins (cf. Ralevic and Burnstock, 1998). The stimulation of P2Y receptors activates phospholipase C, releases intracellular Ca²⁺, and is coupled to adenylyl cyclase (cf. Khakh and Kennedy, 1998). It has been shown that P2Y receptors are involved in the reduction of NE release from rat cortical (von Kügelgen et al., 1994) and hippocampal (Koch et al., 1997) slices.

B. 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).

It has been suggested (cf. Majewski and Iannazzo, 1998) that PKC, activated by diacylglycerol and/or arachidonic acid, through presynaptic receptors (M1, angiotensin, bradykinin) or nerve depolarization is involved in the facilitation of transmitter release from neurons. Majewski and Ianazzo (1998) suggested that this facilitation is mediated by the phosphorylation of proteins involved in vesicle dynamics, although a role for ion channels cannot be ruled out. Nevertheless, taking into account recent studies (cf. Shinomura et al., 1999), it seems most likely that PKC does not directly affect the release process; more likely it blocks the uptake, thereby more transmitter remains extracellular, once transmitter has been released.

b. Voltage Dependence and Modulation by Receptors. It has been shown (Lester et al., 1994; Sonders et al., 1997; Zahniser et al., 1998) that the transporter velocity is increased by hyperpolarization of the membrane and is decreased by depolarization (Sonders et al., 1997). A possible interaction between transporter and auto- or heteroreceptors is that function of the uptake system is a voltage-dependent process and membrane potential can be influenced through receptor activation. For example, stimulation of D₂ receptors opens inwardly rectifying potassium channels, resulting in transient hyperpolarization (Lacey et al., 1987). Thus, hyperpolarization produced by stimulation of receptors expressed on varicosities may result in an increase in the velocity of the uptake process, reducing the amount of transmitter in the extracellular space. This is supported by the findings of Dickinson et al. (1998) that in genetically engineered mice (D₂^/), 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., 1993). In addition, it has been shown (Barbour et al., 1988) that at high extracellular K⁺ concentrations (i.e., under conditions in which the cell is depolarized), Glu uptake is abolished (Szatkowski et al., 1990) and a marked release of Glu occurs.

Because a discrepancy was observed between transport rates and substrate-gated ion fluxes (e.g., Na⁺) determined for different substrates, it was suggested (Sitte et al., 1998) that plasma membrane amine transporters operate in a channel mode. The releasing action would depend on current induced by the substrate rather than on their uptake rate. Na⁺ would be the potential charge carrier, which could trigger carrier-mediated release of DA by enhancing [Na⁺]_i at the cytoplasmic site of the DAT (Levi and Raiteri, 1976; Liang and Rutledge, 1982; Bönisch, 1986; Yamazaki et al., 1996).

c. Temperature Dependence. The capacity of inward transport of transmitters depends on the temperature; at low temperatures, transporters fail to operate (Lindmar and Löffelholz, 1972; Asztely et al., 1997; Vizi, 1998). When the temperature is reduced from 37°C to 25°C, the DA uptake by striatal preparations results in a mild reduction in K_m and a dramatic decrease in V_max (Liang and Rutledge, 1982; Bonnet et al., 1990). Indeed, desipramine, an uptake blocker, fails to increase NE release in response to axonal stimulation when the temperature was reduced to 17°C (Vizi, 1998). A 10°C increase in temperature doubled the turnover rate of GAT (Schwartz and Tachibana, 1990). At a low temperature (17°C), the exocytotic release of NE, DA (Vizi, 1998), and GABA (Vizi and Sperlágh, 1999) is not affected or increased; the carrier-mediated release of different transmitters (NE, DA, GABA) evoked by ischemia or ouabain administration was completely blocked (Vizi, 1998; Toner and Stamford, 1999; Vizi and Sperlágh, 1999). This fact indicates that the carrier-mediated release of transmitters is of cytoplasmic origin.

2. 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.

b. Dopamine Transporter. DAT is a plasma membrane glycoprotein that reaccumulates DA released into the synaptic and extraneuronal space by varicose axon terminals and thereby regulates the lifetime of DA in the extracellular space (Amara and Kuhar, 1993; Page et al., 1998). The uptake process depends on Na⁺ and Cl. In line with these observations using electron microscopy, it has been shown (Hoffmann et al., 1998) that DATs are not located at the synaptic density but are confined to perisynaptic areas, implying that DA diffuses away from the synapse. Besides its physiological role, DAT is a pharmacological target of cocaine and amphetamine in rat (Heikkila et al., 1975a,b) and in mammalian cells transfected with human DAT (Sitte et al., 1998). In an elegant experiment, it was shown in homozygote mice (DA^/) 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). Amphetamine failed to release DA from homozygote mice striatum (Giros et al., 1996). In addition, it has been shown (Giros et al., 1996) that DAT is an obligatory target of cocaine and amphetamine, because these drugs have no effect on locomotor activity or DA release and uptake in DAT knockout homozygote mice. These findings indicate that blockade of uptake allows DA released from nonsynaptic varicosities to reach a much higher concentration and to remain increased in the extracellular space for a much longer time than under conditions in which the inactivation by transporter is not inhibited.

c. Glutamate Transporter. The excitatory amino acid Glu is the most prevalent transmitter in the brain; its effect on postsynaptic receptors is limited by uptake process (Erecinska, 1987) and by diffusion of Glu from the cleft. The removal of Glu from the extracellular fluid, limitation of its action occurs by uptake and by diffusion (Tong and Jahr, 1994). This is accomplished by a transporter in the plasma membrane of both neurons and astrocytes (Brooks-Kayal et al., 1998; Gelagashvili and Schousboe, 1998). Electrophysiological evidence was obtained that the block of Glu transporters potentiates postsynaptic excitation of Glu receptors (Tong and Jahr, 1994). The cellular uptake of Glu is driven by the electrochemical gradients of Na⁺ and K⁺ and is accompanied by voltage and pH changes. The Glu transporter limits Glu concentration in the synapse and spillover from one synapse to another.

d. -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 GABA_B receptor-mediated transmission (Dingledine and Korn, 1985; Isaacson et al., 1993). A high-affinity transporter for GABA (K_m = 0.01-1 µM) has been shown in the CNS (Iversen and Kelly, 1975). Blockade of GABA uptake, which reduces the amount available for diffusion and thereby limits the remote effect of GABA, significantly enhanced the slow IPSC (Isaacson et al., 1993) that represents an extrasynaptic effect. According to Schwartz (1987), the reverse operation of the carrier can raise the GABA sufficiently high to provide extracellular concentration of transmitter to a level that would affect receptors.

e. Serotonin Transporter. The serotonin transporter is also a member of a superfamily of Na⁺- and Cl-dependent neurotransmitter transporters, which are important targets for both drugs of abuse and antidepressant compounds (Amara and Kuhar, 1993; Blakeley et al., 1994).

5-HT transporter / 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). In these transporter-deficient mice, no change in response to (+)-amphetamine was found when the locomotor stimulation was studied. In contrast, the effect of cocaine on behavior was increased (Sora et al., 1998), and the locomotor-stimulatory effect of 3,4-methylenedioxymethamphetamine (Ecstasy) was reduced.

	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 specializations of cholinergic varicosities using cholineacetyltransferase immunostaining (Descarries et al., 1997). A similar observation was made by Kása et al. (1995, 1997) in the main olfactory bulb.

Although anatomical studies reveal the presence of nonsynaptic varicosities, functional studies are required to establish the precise mode of chemical transmission.

Indeed, strong neurochemical evidence is available that nonsynaptic varicosities release transmitters. Descarries et al. (1977, 1980, 1987) demonstrated that nonsynaptic varicosities in the CNS appear to have all the apparatus normally associated with synaptic release. Subsequently, ultrastructural examination of noradrenergic varicosities in several tissues confirmed that both large and small vesicles could undergo exocytosis in the absence of structurally specialized active zones (Thureson-Klein and Stjärne, 1981; Thureson-Klein, 1983, 1984; Zhu et al., 1986). In addition, morphological evidence was provided (Buma, 1989) for exocytosis release sites that do not make synaptic contact in rat median eminence and mesencephalic central gray substance.

The hippocampus is very rich in noradrenergic innervation originating from the locus ceruleus (Loy et al., 1980). Fine varicose axons are present in every layer of the hippocampus, but the overwhelming majority of varicosities (2.1 million/mm³) do not make synaptic contact (Table 4). This means that each varicosity, provided they are evenly distributed, may control a volume of ~500 µm³. The distance between varicosities plays an important role in setting the concentration of transmitters in the extracellular space, because the concentration of transmitter drops in a function of 3. This means that ~10 µm is the average distance between each varicosity (Fig. 2), but they are not evenly distributed, indicating that there are regions in which the local concentration of transmitters could be much higher.

View this table: [in this window] [in a new window]   TABLE 4 Density of varicosities in the CNS

View larger version (63K): [in this window] [in a new window]   Fig. 2.   Scheme of varicose axon terminals. The average distance between varicosities in the hippocampus is 10 µm (for details and calculations, see the text), and in the cortex, the average distance is 66 µm, provided the varicosities are evenly distributed, but this is not the case. According to Schneider et al. (1994), DA released in response to axonal activity is able to diffuse ~50 µm. This means the transmitter is released from only one varicosity; it diffuses cylindrically and the concentration drops in a function of 3. However, when the neurons fire in concert, the concentration can be much higher depending on the spatial distribution of varicosities.

Descarries et al. (1977) presented evidence that like the hippocampus, the cerebral cortex has rather dense noradrenergic innervation with remarkably uniform distribution. The latter is different from that of hippocampus. The cerebral cortex contains 346 noradrenergic varicosities/mm² and >6000/mm³; therefore, each varicosity may control a volume of 150.000 µm³.

This arrangement suggests that every varicose arborization equipped with heteroreceptors may lie within 66 µm of a noradrenergic varicosity devoid of synaptic specialization (Fig. 1).

With this calculation, we anticipated that noradrenergic varicosities in the hippocampus and cortex are evenly distributed, but this is certainly not the case. Of course, the extracellular concentration of transmitters may vary from site to site and from time to time, because there is a possibility of spatial and temporal summation of transmitters released from different varicosities.

The density of serotonergic varicosities varies between 0.24 and 2 million/mm³ (Beaudet and Sotelo, 1981; Table 4) in the cerebellar cortex.

	IV. Extracellular Space as a Communication Channel of Nonsynaptic Interaction

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Microdialysis studies show that virtually all the transmitters in the CNS are present in the extracellular space. A very important factor that determines the peak concentration of transmitter in this space is its volume accessible for the transmitter. It has been shown (Nicholson, 1985; cf. Nicholson and Rice, 1991) that this space is ~12 to 25% of the brain volume. Activity-induced changes of extracellular space in excitable tissues are a well known phenomenon. In response to neuronal activity and in parallel with an increase in extracellular K⁺ concentration, shrinkage of the extracellular space can be observed in vivo (Svoboda and Sykova, 1991; cf. Holthoff and Witte, 1998). This, in fact, can influence the concentration of transmitters released into the extracellular space.

Another important factor is the amount of transmitter released from axon terminals. A critical aspect of nonsynaptic interaction theory is that a given neuron with its numerous nonsynaptically ending varicosities (which could be a few hundred thousand!) need not, by itself, be of sufficient strength to significantly change the extraneuronal concentration of the transmitter. If that neuron is fired at the same time as a number of other neurons, their combined action may be able to increase transmitter concentration in the extracellular space to such a level that a large field will be influenced; of course, only those neurons whose terminals or dendrites are equipped with receptor sensitive to the transmitter are affected. If, in contrast, a given neuron fires asynchronously with most of the other neurons, there will be no effect on the target cell. Table 5 shows the extracellular concentration of different transmitters in the extracellular space determined by microdialysis.

View this table: [in this window] [in a new window]   TABLE 5 Concentrations of transmitters in the vesicle, synaptic cleft, and extracellular space

Diffusion of transmitters through the extracellular space in brain slices (McBain et al., 1990) is anisotropic in both hippocampus and cortex (Nicholson and Syková, 1998), indicating some specificity. The half-life of extracellular 5-HT is 0.21 s in the substantia nigra and 0.09 s in the dorsal raphe nucleus (Bunin et al., 1998), suggesting that in the dorsal raphe nucleus, the nonsynaptic transmission is a more likely mode of communication than in the substantia nigra.

Richfield et al. (1989) succeeded in showing that there are differences in anatomical distributions and affinity states of D₁ and D₂ receptors in the rat brain. The proportion of high-affinity sites is quite different between the two subtypes. The high affinities for DA binding to receptors in striatal slices were near 40 nM (range, 9-74 nM), and the low affinities for DA were near 2 to 4 µM.

One question regarding the cellular location of D₁ and D₂ receptors is whether they are both located on the same neuron and/or they are expressed presynaptically or postsynaptically, synaptically or nonsynaptically. For the time being, no method is available to answer these questions. It is therefore a plausible assumption that the affinity of DA for the DA receptors and the DAT and nonsynaptic DA concentration should be related to each other.

It has been speculated that the synaptic DA concentration is in the range of 10 µM and that DA is accordingly able to act on the low-affinity states of the receptors (Gonon and Buda, 1985).

The release of GABA, reaching a peak concentration of ~1 mM (Clements et al., 1992), would correspond to 3.000 to 7.500 molecules of transmitter released (Destexhe and Sejnowski, 1995). A spillover of GABA may account for differences between inhibitory responses in the hippocampus and thalamus (Destexhe and Sejnowski, 1995). It is highly probable that diffusion of transmitter between two neighboring synapses (i.e., cross-talk; Barbour and Häusser, 1997) plays an important role in long-term potentiation and long-term depression phenomena (Kullmann et al., 1996) in which associativity and cooperativity of synapses are important. This may be also involved in the activation of nearby synapses (cf. Barbour and Häusser, 1997), affecting presynaptic and postsynaptic ionotropic receptors and producing electrophysiologically detectable changes in synaptic current waveform and metabotropic receptors that may not produce a direct electrical action. However, the fact that low-affinity receptors are expressed in the synapse makes it seems likely that the cross-talk will only occasionally affect them, with the concentration of the transmitter outside the synaptic gap being much lower than that in the gap (~100 µM).

A similar observation was made with DA in the striatum (Wightman et al., 1988; Van Horne et al., 1992). DA released from the varicose axon terminals of the nigrostriatal pathway may be able to diffuse far away from release sites (Schneider et al., 1994) and inhibit the release of ACh from cholinergic interneurons. However, all of the observations made with microdialysis suggest that transmitters (NE, DA, 5-HT, and ACh) released mainly from nonsynaptic terminals are present in the extracellular space.

	V. Nonsynaptically Expressed Receptors and Membrane Transporters of High Affinity as Therapeutic Targets

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Many instances have been found in which the distribution of the receptors does not match the distribution of transmitter (Herkenham, 1987, 1991). Several lines of data (Table 6) indicate there are extrasynaptic receptors and transporters in different brain regions (Somogyi et al., 1989; Baude et al., 1995; Yung et al., 1995; Venkatesan et al., 1996; Descarries et al., 1997; Nusser et al., 1998) that are accessible for endogenous ligands. These, being located nonsynaptically, however, possess a high-affinity property and may play a physiological role in accepting chemical messages from distant neurons. Even when the synaptic and nonsynaptic receptors do not differ in affinity, however, they may be used with a different level of neuronal activity. Somogyi et al. (1989) showed in cerebellum that at a low frequency of neuronal firing, GABA released into the synaptic cleft acts at the synaptic junctions. The small amount of GABA can be removed by the transporter without reaching the extrasynaptic receptors. However, at increased excitatory input, GABA released in a much higher amount may reach remote receptors of nonsynaptic location.

View this table: [in this window] [in a new window]   TABLE 6 Immunocytochemical localization of nonsynaptic receptors

In contrast, there are heteroreceptors or transporters expressed on some neurons that are not accessible by transmitters. These receptors and transporters, in addition to those previously mentioned, are of pharmacological importance because they may never reach effective concentrations of the appropriate endogenous ligands in vivo but they could be the target for drugs or they could be occupied by endogenous ligands in toxic conditions.

A. Nonsynaptic Receptors

To act effectively at a distance and at a low concentration, transmitters require high-affinity receptors (Isaacson et al., 1993). The affinity of receptors expressed in the synapse cannot be determined, because there is no method available to separate intrasynaptic and extrasynaptic receptors. Katz and Miledi (1977) showed that a low concentration of ACh has a minimal effect on the postsynaptic nAChRs, which are known to possess a low affinity for ACh (Colguhoun and Odgen, 1988). Because the intrasynaptic concentration of transmitters (see Table 5) is in the range of 0.01 to 6 mM (Kuffler and Yoshikami, 1975; Clements et al., 1992; Bunin and Wightman, 1998, 1999), the postsynaptic receptors are relatively insensitive and are of low affinity. It is therefore suggested that these receptors cannot be affected by drugs being distributed in the body in low concentrations; drugs may be able to affect these intrasynaptic receptors only at extremely high and toxic concentrations. These receptors are not targets for remote (i.e., nonsynaptic) modulation or remote signal transmission. However, there are receptors and transporters expressed on varicosities without synaptic contact that are easily reached by endogenous substances (i.e., transmitters, modulators, and so on) and drugs (antidepressants, nicotine), and they might be affected by relatively low (0.01-1 µM) concentrations of drugs (Table 7) with a selective effect on receptors (Vizi, 1984a; Vizi and Lábos, 1991). Dense nonsynaptic localization of 5-HT₁ receptors was shown (Kia et al., 1996) in substantia nigra pars reticulata, where the extracellular concentration of 5-HT is 55 nM (Bunin and Wightman, 1999). Therefore, it is suggested that receptors located on varicosities without making synaptic contact seem likely to be the target for exogenous compounds (medications) acting as agonists, partial agonists, or antagonists (Vizi and Lábos, 1991). Indeed, several drugs used in clinical practice have been developed on the concept of presynaptic modulation of chemical transmission (cf. Langer, 1997; Langer et al., 1998).

View this table: [in this window] [in a new window]   TABLE 7 Extracellular concentration of drugs in the plasma and cerebrospinal fluid

B. Nonsynaptic Transporters

There are only few reports of transporter density or localization in the CNS. These data will help us to better understand the nonsynaptic interactions between neurons. It is possible that there are regions in which the density of a transporter is much lower than that in other regions; therefore, remote interaction in this region is more likely. It has been shown (Descarries et al.,1977, 1995) that labeled 5-HT and NE can be taken up from the extracellular space by varicosities without making synaptic contact. Since then, much evidence has been provided (Lester et al., 1996) that transmitter-selective transporters are expressed on nonsynaptic varicosities and are able to take up transmitters from the extracellular space, limiting the concentration of transmitter released from varicosities. Transporters regulate the lifetime of the transmitter in the extracellular space and thus the distance it can diffuse away from its release site. Therefore, the area over which a transmitter released into the extracellular space can act and the concentration of transmitter may vary from region to region, depending on the local density of transporter. It has been shown that Glu is removed from the synapse into the nerve terminal and into the glia by a low-affinity transporter (Gelagashvili and Schousboe, 1998). Similarly, the nonsynaptic and synaptic GABA transporters restrict fast GABA_A receptor-mediated transmission, preventing its spillover, and spread to reach remote presynaptic GABA_B receptors.

The importance of noradrenergic, serotonergic, and dopaminergic transporters has long been appreciated (e.g., the therapeutic effect of antidepressants is based on their blocking action on these transporters; cf. Barker and Blakely, 1995). Antidepressants (e.g., imipramine, fluoxetine), acting at low concentrations on nonsynaptically located membrane transporters of high affinity, are able to inhibit the uptake of NE and/or 5-HT, thereby increasing the concentration, life span, and transmission distance of the transmitter released into the microenvironment.

The diffusion of DA over long distances (a few millimeters) through a large volume of striatal tissue was observed (Doucet et al., 1986; Schneider et al., 1994) when either the nigrostriatal dopaminergic pathway was destroyed or the reuptake was inhibited. In these experiments in intact animals, DA released in response to neuronal activity diffused ~50 µm in the striatum (Schneider et al., 1994).

C. Nonsynaptic Interaction between Neurons without Receptors

Within the past few years, evidence has accumulated that NO and carbon monoxide are present in the CNS (cf. Szabó, 1996; Moncada et al., 1997) and are able to operate as signal transmitters. Nevertheless, they have not yet met all criteria necessary to be classified as transmitters. They are not synthesized in synaptic vesicles, but they are liberated as gases and then they are simply diffusing far away from their synthesis site, able to activate G proteins of remote cells and influence transporters. It has been shown that the free radical NO might play a role as an intercellular messenger in the brain (Garthwaite et al., 1988). One of the physiological functions of NO may be to prevent the uptake of different neurotransmitters. Several studies provided evidence that NO inhibits the plasma membrane transporters of different neurotransmitters. NO inhibited [³H]DA (Lonart and Johnson, 1994; Pogun et al., 1994a; Cutillas et al., 1998) and [³H]Glu uptake (Lonart and Johnson, 1994; Pogun et al., 1994b) but increased 5-HT uptake (Miller and Hoffman, 1994). In regard to NE uptake, according to Pogun et al. (1994a) NO had no effect, whereas Lonart and Johnson (1995a,b) reported an inhibitory effect. In all of these studies, the authors directly measured the transmitter uptake (usually in synaptosomes) in the presence of exogenously applied NO produced from different NO generators. In our study, in hippocampal slice preparation (Kiss et al., 1996), we inhibited the neuronal NO synthase, which reduced the endogenous NO production. This manipulation increased the ability of dimethylphenyl-piperazinium, an nAChR agonist, to evoke carrier-mediated release. These data suggest that endogenously produced NO is able to inhibit the operation of NE uptake carrier (at least if the direction of NE transport is reversed due to certain conditions). In addition, with the use of microdialysis, it has been shown (Kiss et al., 1999) that the systemic administration of N-nitro-L-arginine methyl ester, an NO synthase inhibitor, significantly reduced the release of DA from the striatum (Kiss et al., 1999). It was also seen that NO synthesized in neurons by inducible NO synthase in several regions of the brain can release ACh (Ikarashi et al., 1998) and that the NO generator sodium nitroprusside (500 µM) increases extracellular DA levels in the striatum (West and Galloway, 1999) in a [Ca²⁺]_o-dependent manner.

The synthesis of NO in the CNS is mainly linked to the activation of NMDA receptors by Glu. Montague et al. (1994) have shown that the activation of NMDA receptors in synaptosomal preparations from guinea pig cerebral cortex released both Glu and NE and that the release is blocked by drugs that inhibit NO production or remove NO from the extracellular space. In addition, the activation of AMPA/KA receptors also increases NO production. It is also known that the stimulation of NO production is a [Ca²⁺]_o-dependent process (Garthwaite and Boulton, 1995). These findings suggest that Glu released from axon terminals increases NO production via NMDA receptor activation and is able to potentiate the release of Glu and other transmitters from the neighboring synapses. Therefore, it seems likely that NO is involved in the modulation of NMDA-induced release of neurotransmitters (Montague et al., 1994; Sandor et al., 1995; Segovia and Mora, 1998; cf. West and Galloway, 1999).

With a half-life of a few seconds, NO generated at a single point source should be able to influence function within a sphere with a diameter of ~300 to 350 µm (Garthwaite and Boulton, 1995), which is very large compared with the dimensions of a synapse. According to Gally et al. (1990), NO may diffuse up to 100 µm in 5 s. Therefore, it is suggested that NO is an ideal endogenous substance for nonsynaptic interaction and may transmit long-distance messages from transmitters (e.g., Glu) exclusively released into the synaptic gap.

	VI. Clinical Implications

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High-affinity transmitter receptors and transporters located nonsynaptically are the targets of many drugs of therapy and abuse. Are the receptors and transporters located outside the postsynaptic density of the synapse functionally part of a single synapse? Taking into account the morphology of arborization of noradrenergic, dopaminergic, serotonergic, and cholinergic systems, the answer is certainly no. These receptors and transporters, having no synaptic arrangements, are promiscuous and accessible to chemicals released from numerous synapses and/or nonsynaptic boutons. They are certainly accessible to drugs taken by the patients with agonist/antagonist activity on these receptors. It is well established, for example, that the uptake of NE by noradrenergic varicosities is largely mediated by high-affinity NETs (cf. Trendelenburg, 1991). The monoamine transporters are the therapeutic targets for tricyclic antidepressants, psychostimulants (amphetamine), and cocaine. Serotonin uptake blockers, such as fluoxetine (Prozac), have been used for the treatment of depression, obsessive-compulsive disorder, and sleep and eating disorders.

It has been observed that the activity of GABA transporter is reduced in human epileptic hippocampus (During et al., 1995). Therefore, it was suggested that GABA uptake blockers may be used as anticonvulsive drugs. Although a loss of benzodiazepine binding sites is characteristic of temporal lobe epilepsy, recent data show that an up-regulation of GABA_A receptors (Nusser et al., 1998) in hippocampal dentate gyrus granule cells represents a compensatory mechanism (cf. Fritschy et al., 1999). There is an interaction between serotonergic and GABAergic neurons in the hippocampus (cf. Gulyás et al., 1999); the evoked GABA_B receptor-mediated slow inhibitory postsynaptic potentials (IPSPs) measured in pyramidal cells and mediated via nonsynaptic 5-HT_1A receptors (Segal, 1990) are reduced, and the GABA_A receptor-mediated IPSPs are increased (via 5-HT₃ and 5-HT₂ receptors; Shen and Andrade, 1998), thereby shifting the GABAergic inhibition into the perisomatic region. The possible involvement of GABAergic interneurons (cf. Freund and Buzsáki, 1996) in schizophrenia and other psychoses has been recently reviewed (Keverne, 1999). Inhibitory GABAergic interneurons with their serotonergic, dopaminergic, and cholinergic inputs play an important role in maintaining network oscillations (Buzsáki and Chrobak, 1995).

Cocaine inhibits monoamine (NE, DA, and 5-HT) transporters (Ritz et al., 1987; cf. Lester et al., 1994). As far as its reinforcing action is concerned, the inhibition of the DAT is the most important (Ritz et al.,1987). Cocaine blockade of DAT results in an increased level of extracellular DA (Rocha et al., 1998) in the limbic system, an effect widely accepted to be the primary cause of the reinforcing and additive effects of cocaine (Kuhar et al., 1991).

It seems likely that the mode of effect of 3,4-methylenedioxymethamphetamine (Ecstasy) is mediated via serotonin transporter, producing a heterologous exchange (Rudnick and Wall, 1992). Amphetamine is taken up by NETs and DATs in expense of transporting NE and DA out from the cytoplasm.

It seems plausible that the effects on the manic-depressive state that are due to influences on noradrenergic transmission may be mediated through changes in the release of other transmitters at the cortical level. Several reports have suggested that long- but not short-term treatment with certain tricyclic antidepressants decreases the functional sensitivity of ₂-adrenoceptors in brain (McMillen et al., 1980; Spyraki and Fibiger, 1980). It has been shown that clonidine inhibition of the acoustic startle reflex in the rat, a behavioral measure of ₂-adrenoceptor sensitivity after desipramine administration, was also attenuated (McMillen et al., 1980; Davis and Menkes, 1982). The presynaptic link between the noradrenergic and serotonergic (Feuerstein et al., 1993) axon terminals, NE, reduces the release of 5-HT and could explain how by increasing the biophase concentration of endogenous NE in the vicinity of ₂ heteroreceptors, a selective NE uptake blocker may inhibit or reduce the release of 5-HT. As a consequence, both ₂- and 5-HT receptors are up-regulated. Under this condition, any increase in 5-HT release might induce suicidal behavior. Thus, the density or sensitivity of the presynaptic ₂-autoreceptor expressed on the noradrenergic varicosities and of the heteroreceptor expressed on the serotonergic varicosities could result in inhibition of neuronal release of NE/5-HT and lead to depression. Increased density (Callado et al., 1998) and sensitivity of _2A-adrenoceptors in prefrontal cortex could represent a common feature of the reduced monoaminergic (noradrenergic and/or serotonergic) function postulated in depression (Garcia-Sevilla et al., 1999).

On the basis of the hypothesis that an increased 5-HT release relieves certain symptoms of depression, blockade of the negative feedback modulation of 5-HT release has become an attractive concept for antidepressant drug development (cf. Göthert and Schlicker, 1997), in particular when combined with selective uptake blocker. ₂-Adrenoceptors other than autoreceptors are also down-regulated by chronic inhibition of NE uptake by tricyclic antidepressant treatment (Bill et al., 1989). Although many studies indicate that a down-regulation of central -adrenoceptor sensitivity accompanies chronic antidepressant administration, the consequences of such treatment on ₂-adrenoceptor function are more equivocal (Charney et al., 1981; Sugrue, 1988). Accordingly, biochemical and functional studies have demonstrated that depressed patients have an increased density and sensitivity of platelet ₂-adrenoceptors (Piletz et al., 1986) and that these receptor abnormalities are confined to the high-affinity state (_2H) of the receptor that preferentially recognizes agonists (Garcia-Sevilla et al., 1981, 1986, 1987). In addition, a correlation between ₂-adrenoceptors and suicide was established (De Permentier et al., 1997). There is some evidence that suggests that mania is related to disturbances in catecholaminergic neurotransmission (Silverstone, 1985). In contrast to depression, mania may be characterized by increased noradrenergic and/or dopaminergic transmission. An increase in noradrenergic metabolism is supported by the higher excretion of urinary 3-methoxy-4-hydroxyphenylglycol in manic compared with depressive episodes and the notable increase in cerebrospinal fluid NE itself. Moreover, there are some indirect pharmacological data suggesting that drugs able to decrease noradrenergic transmission, such as reserpine, might be associated with an increased incidence of depression and therapeutic effects in mania. Conversely, most tricyclic and monoamine oxidase inhibitor antidepressants potentiate the noradrenergic system and may potentiate manic shifts (cf. Mongeau et al., 1997). Moreover, the -adrenoceptor agonist clonidine, which decreases firing of the noradrenergic cells of the locus ceruleus by acting preferentially at presynaptic autoreceptors (Svensson et al., 1975) and reduces the NE release, has antimanic properties. Many antipsychotic drugs inhibit MK-801 (dizocilpine) binding to NMDA receptors with IC₅₀ values in the micromolar range (Shim et al., 1999), but their clinical effect may not be mediated via these receptors.

There is increasing interest in developing therapeutic agents that will prevent Glu neurotoxicity, an effect mediated via postsynaptic receptors. Therefore, most of the efforts are involved in a search for Glu receptor antagonists. However, presynaptic receptors able to inhibit Glu release offer another target at which the drug would be able to reduce Glu release. This type of drug would be effective in convulsion and in ischemic insult (cf. Tapia et al., 1999). The NMDA receptor may also be involved in a variety of psychiatric illnesses, including schizophrenia (cf. Shim et al., 1999).

It is generally accepted that the activity of cholinergic innervation of the cerebral cortex plays a crucial role in cortical arousal and attention and is critically involved in memory and learning (Dunnett et al., 1991; Harder et al., 1998). The specific lesions of basal nucleus of Meynert produce cognitive impairment, whereas lesions of the medial septum result in large and permanent impairments of certain types of conditional learning. In addition, the discovery that in Alzheimer's disease there is a very substantial loss of this cholinergic input (Whitehouse et al., 1982; cf. Kása et al., 1997) and its involvement in cognitive deficits observed in patients (Dunnett et al., 1991) just further increased the interest in this topic (Giacobini, 1998). Cholinesterase inhibitors are the current drugs of choice in the treatment of Alzheimer's disease (cf. Giacobini, 1998). A direct correlation was found between the level of acetylcholinesterase inhibition, increase in extracellular concentration of ACh in cortex and hippocampus, and cognitive improvement (cf. Kiss et al., 1999). In addition, it has been shown (Kiss et al., 1999) that cholinesterase inhibition enhanced both ACh (Moor et al., 1995) and NE release in the hippocampus. These findings may help to understand the beneficial effect of cholinesterase inhibition in Alzheimer's disease. Similarly, a selective M2 subtype antagonist with an exclusive effect on cholinergic varicosities and able to cross the blood-brain barrier and to increase ACh release by preventing the negative-feedback inhibition of ACh release would be a potential therapy.

Activation of presynaptic inhibitory muscarinic receptors inhibits the excitatory intrinsic fiber synaptic glutamatergic transmission and prevents recall of previously learned memories from interfering with the learning of new memories (Hasselmo and Bower, 1992, 1993; Hasselmo and Schnell, 1994; Hasselmo and Barkai, 1995).

If the cholinergic high-affinity M2 receptor-mediated suppression of intrinsic glutamatergic input to pyramidal cells is in operation, the advantage of increased ACh release can be used in learning, provided the effect of ACh on dendrites to increase excitability of pyramidal cells is not inhibited (cf. Hasselmo and Bower, 1993).

The effect of nicotine to increase NE release (cf. Wonnacott, 1997) and synaptic transmission (cf. Chiodini et al., 1999) from the hippocampal noradrenergic varicosities is in correlation with its beneficial action on learning and memory. Because this effect is mediated via high-affinity nAChRs of presynaptic location (cf. Wonnacott, 1997; cf. Vizi and Kiss, 1998), attempts have been made to find an nAChR agonist for treatment of Alzheimer's patients. It is also a very well established concept that activation of dopaminergic transmission (increase of DA release) via activation of nAChRs is beneficial in Parkinson's disease (cf. Reader and Dewar, 1999).

	VII. Summary

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The synaptic information flow has been the most frequently studied field of neuroscience for the past ~50 years, but recent developments that point to different types of release of transmitter (Table 1) from varicosities without synaptic contact and receptors and transporters of nonsynaptic location is based on nonsynaptic communication (Vizi and Knoll, 1971; Vizi, 1974, 1979, 1980b, 1984, 1990, 1991; Fuxe and Agnati, 1991; Vizi et al., 1991; Vizi and Lábos, 1991; Bach-y-Rita, 1993; Zoli and Agnati, 1996; Vizi and Kiss, 1998; Zoli et al., 1999) not requiring impulse frequency coding. The findings of Herkenham (1987, 1991) that there are mismatches between release sites and receptors, represented important support for the nonsynaptic interaction hypothesis. The formerly more restricted view of chemical signal transmission within the synapse has to be extended, because considerable evidence has accumulated to show that although the brain is a wired instrument, its neurons, besides cabled information signaling (through synapses), are able to talk to each other without synaptic contact (i.e., "wireless"). These apparently nonsynaptic arrangements furnish an efficient way to influence neuronal activity continuously in a large field, involving vast neuronal ensembles, without directly contacting every single cell. They are comparable with radiowave transmission instead of the telephone system; the message is sent in a long-distance manner, and only a properly tuned receiver can accept it. Thus, only cells that are equipped with proper receptors sensitive to the ligand can accept the chemical message. Because recent studies (Nicholson and Rice, 1991; Routtenberg, 1991) showed that the size of extracellular space is ~20% of brain volume, it is suggested that this is the space in which transmitter released from varicosities can diffuse away from the release site. Because the extracellular concentrations of transmitters in this space are in the nanomolar to micromolar ranges, the receptors of nonsynaptic location are of high affinity. The high-affinity uptake system located nonsynaptically plays a critical role in terminating the effect of transmitters released from nonsynaptic varicosities on receptors expressed nonsynaptically.

The nonsynaptic communication system has a similar degree of selectivity as that of synaptic circuitry but possesses, in addition, a domain of versatility and plasticity in "hardwared" circuitry.

Gone is our understanding of hard-wired neuronal circuitry created for the amplification of digital information in the synapse, with the use of very fast transmitters able to produce "on" and "off" signals within us; we have to change our mentality and accept there is a nonsynaptic communication system that in the brain, an analog information transfer, whose time constant may be seconds or even minutes. The digital information traffic is affected from time to time by chemical messages sent from neurons located far away. Thus, if a transmitter is released from neurons in concert, resulting in a long-lasting high concentration of the transmitter, it will be able to modulate tonically the release of another transmitter.

The original observations made in 1968 and 1969 (Lindmar et al., 1968; Vizi, 1968; Löffelholz and Muscholl, 1969a,b; Paton and Vizi, 1969) that the release of transmitter can be influenced (inhibited or increased) through the activation of presynaptic receptors by chemicals released from another neuron led to a novel mechanism of interaction of neurons equipped with different transmitters and opened a new strategy of drug therapy. Therefore, it seems likely that compounds with a selective effect on high-affinity receptors and transporters expressed on varicosities of nonsynaptic location may represent the beginning of a new generation of innovative drugs.

	Acknowledgments

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This work was supported by the Hungarian Research Fund (OTKA), the Medical Research Council (ETT), and a Philip Morris research grant.

	Footnotes

¹ Address for correspondence: Dr. E. Sylvester Vizi, Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, POB 67, H-1450 Budapest, Hungary. E-mail: ESVIZI@KOKI.HU

	Abbreviations

ACh, acetylcholine; AMPA, -amino-3-hydroxy-5-methylisoxazole-4-propionic acid; [Ca²⁺]_o, extracellular Ca²⁺ concentration; [Na⁺]_i, intracellular Na⁺ concentration; CNS, central nervous system; DA, dopamine; DAT, dopamine transporter; GABA, -aminobutyric acid; Glu, glutamate; IPSP, inhibitory postsynaptic potential; KA, kainate; nAChR, nicotinic acetylcholine receptor; NE, norepinephrine; NET, norepinephrine transporter; NMDA, N-methyl-D-aspartic acid; NO, nitric oxide; PKC, protein kinase C; 5-HT, serotonin; TTX, tetrodotoxin.

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