Neurochemistry International 38 (2001) 83±106
www.elsevier.com/locate/neuint
Review
The reverse transport of DA, what physiological signi®cance?
Vincent Leviel*
Centre d'Etude et de Recherche MeÂdicale par Emission de Positons (CERMEP), 59 Bd Pinel, 69008 Lyon, France
Received 29 February 2000; accepted 18 May 2000
Abstract
It is well established that midbrain dopamine neurons innervating the striatum, release their neurotransmitter through an
exocytotic process triggered by the neural ®ring and involving a transient calcium entry in the terminals. Long ago, it had been
proposed, however, that another mechanism of release could co-exist with classical exocytosis, involving the reverse-transport of
the cytosolic amine by the carrier, ordinarily responsible for uptake function. This atypical mode of release could be evoked
directly at the preterminal level by multiple environmental endogenous factors involving transient alterations of the sodium
gradient. It cannot be excluded that this mode of release participates in the ®ring-induced release. In contrast with the classical
exocytosis of a preformed DA pool, the reverse-transport of DA requires simultaneous alterations of intraterminal amine
metabolism including synthesis and displacement from storage compartment. The concept of a reverse-transport of dopamine is
coming from the observations that releasing substances, such as amphetamine-related molecules, actually induce this type of
transport. A large set of arguments advocates that reverse-transport plays a role in the maintenance of basal extracellular DA
concentration in striatum. It was also often evoked in physiopathological situations including ischemia, neurodegenerative
processes, etc. The most recent studies suggest that this release could occur mainly outside the synapses, and thus could constitute
a major feature in the paracrine transmission, sometimes evoked for DA. 7 2001 Elsevier Science Ltd. All rights reserved.
Keywords: Dopamine; Striatum; Release; Synthesis; Uptake; Neurotransmission
Contents
1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
2.
Taking an object lesson from amphetamine action . . . . .
2.1. The ®rst step (accumulation) . . . . . . . . . . . . . . .
2.2. Second step (increasing cytosolic DA) . . . . . . . . .
2.2.1. Reducing DA catabolism . . . . . . . . . . . .
2.2.2. Displacing DA from intraterminal stores.
2.2.3. Increasing DA synthesis. . . . . . . . . . . . .
2.3. The mechanism of release . . . . . . . . . . . . . . . . .
3.
From an amphetamine-induced mechanism to a physiological mechanism of release . . . . . . . . . . . . . . . . . . . . . . . . 87
4.
Biology of intraterminal DA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
5.
Reverse transport regulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
5.1. The DA synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
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* Tel.: +33-4-72-68-86-08; fax: +33-4-72-68-86-10.
E-mail address: [email protected] (V. Leviel).
0197-0186/01/$ - see front matter 7 2001 Elsevier Science Ltd. All rights reserved.
PII: S 0 1 9 7 - 0 1 8 6 ( 0 0 ) 0 0 0 7 6 - 0
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V. Leviel / Neurochemistry International 38 (2001) 83±106
5.2.
5.1.1. Intraterminal DA . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.2. Extraterminal DA . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.3. The calcium ions . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.4. Can an increased synthesis induce an activated DA-RT?
The DA transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.1. DA and DA receptors . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.2. Serotonin (5HT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.3. Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.4. Ascorbic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.5. Oestradiol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.6. Ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.7. Voltage dependency. . . . . . . . . . . . . . . . . . . . . . . . . . .
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90
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6.
Reverse transport and other atypical releasing mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
6.1. Dendritic release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
6.2. Paracrine and/or nonsynaptic DA neurotransmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
7.
Physiopathological incidences of DA-RT.
7.1. Ischemia . . . . . . . . . . . . . . . . . . .
7.2. Weaver mutant mice . . . . . . . . . .
7.3. Partial lesions . . . . . . . . . . . . . . .
8.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
8.1. Physiological signi®cance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
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95
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96
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
1. Introduction
A long time ago, it was proposed that neurons communicate using chemical messengers, called neurotransmitters, which are released by emitting neurons, and
recognized by receiving neurons through speci®c receptors. Neurotransmitter emission thus constitutes a key
step in interneuronal communications and the nature
of the released substances as well as the regulatory
mechanisms of this release have been extensively studied during the last decades. Several possible mechanisms were evoked for the release of neurotransmitters
in the central nervous system. The manner in which
neurons extrude neurotransmitters remains the subject
of controversial debate and it is likely that various
molecular processes act simultaneously. The most commonly admitted process to date, in the central nervous
system, is based on the exocytosis of vesicles containing stored neurotransmittory molecules. This phenomenon occurs in the active zone of a morphologically
well-described apparatus called the synapse. It is a
consequence of a massive Ca2+ inward ¯ux into the
end-terminal in response to a transient inversion of the
membrane potential. Several released neurotransmittory molecules have been identi®ed and numerous studies have been devoted to their metabolism inside and
outside the terminals. This has led to the observation
that neural cells are not only able to release signaling
molecules but also possess the ability to re-uptake
them from extracellular space. Several models have
been proposed for this transport, with most of them
based on an exchange-di€usion between extra- and
intra-terminal space (Stein, 1967; Bogdanski and Brodie, 1969; Paton, 1973a).
For the neurons using catecholamines as neurotransmitters, in both the central and peripheral nervous systems, an active-transport uptaking dopamine (DA) or
norepinephrine (NE) was identi®ed a long time ago.
The kinetic parameters of this active transport were
extensively studied using various methods and several
potentially inhibiting substances were characterized
(Glowinski et al., 1966; Fuxe and Ungerstedt, 1968). A
protein, embedded in the cytoplasmic membrane and
responsible for this transport, was later isolated and
referred to DAT for DA and NET for NE. Only
recently has the messenger RNA responsible for its
synthesis been cloned and the amino acid sequence of
the protein determined (Shimada et al., 1991; Amara
and Kuhar, 1993; Giros and Caron, 1993).
2. Taking an object lesson from amphetamine action
Using pharmacological tools releasing DA or NE,
the concept emerged progressively that the active
transport could be bidirectional and able to release
molecules by the same exchange-di€usion process as
that involved in the uptaking function. Thus, the concept of reverse transport (RT) was ®rst evoked in the
molecular mechanisms of releasing agents such as am-
V. Leviel / Neurochemistry International 38 (2001) 83±106
phetamine, tyramine, etc. Only later was it considered
as a possible mode of release responsible for DA or
NE over¯ow, even in the absence of any exogenous
releasing substances. The function of RT in basal
neural activity remains todate unclear, but its mechanism of action and its regulatory process have been
extensively studied.
The mechanism by which amphetamine and other
DA/NE-releasing agents involve RT follows several
steps (Fig. 1), identi®ed during the last 20 years. First,
the releasing molecules enter the terminal buttons,
uptaken or not by the carrier itself. Second, the concentration of neurotransmitters rises in the terminal
cytosol. As discussed below, this rise results from multiple origins. Third, transmitter molecules are transported outside the cell most likely through an
exchange-di€usion process. The exchange-di€usion
processes have been extensively studied and various
mathematical models were proposed over the course of
the last three decades (Thoenen et al., 1969; Chubb et
al., 1972; Ziance et al., 1972; Ziance and Rutledge,
1972; Stein, 1990 for a review; Wheeler et al., 1993).
2.1. The ®rst step (accumulation)
Several DA releasing substances such as amphetamine, have been shown to accumulate in the DAterminals. Amphetamine accumulation was observed,
on synaptosomal preparations, to be inhibited by
agents which also inhibit the uptake of DA (Azzaro et
al., 1974; Arnold et al., 1977). Various sympathomimetic amines (tyramine, amphetamine, parahydroxyamphetamine, etc.) are substrates for uptake into
neuron terminals and are able to competitively inhibit
DA transport (Ross and Renyi, 1964; Horn, 1973). It
Fig. 1. The reverse transport of dopamine (DA-RT), when evoked
by a releasing substance (Rs), is based on three successive steps.
First, the Rs enters the terminal by the DA-uptake carrier or not.
When using the DA-carrier, ions are co-transported. Second, Rs
induces a rise in cytosolic DA acting on the DA synthesis, the DA
catabolism and/or the DA stores. Third, the cytosolic accumulated
DA is co-transported with ions outside the terminal.
85
was also observed that when this occurs, transport of
tyramine and amphetamine is Na+-dependent
(BoÈnisch, 1986) and that the potentials of amphetamine-like drugs to release cytoplasmic [3H]DA is well
correlated with the IC50 values of these agents in inhibiting DA uptake (Parker and Cubeddu, 1988).
A large set of substances can compete with DA for
uptake, but only a few of them possess the releasing
activity. Thus, benztropine, nomifensine, methyl phenidate seem to be uptake blockers only (Hunt et al.,
1974; Bauman and Maitre, 1976; Hunt et al., 1979;
Miller and Shore, 1982; Bonnet et al., 1984). Many of
these uptake blocker substances are blocking agents of
the amphetamine e€ect as visualized in vivo with
microdialysis techniques (Butcher et al., 1988; Hurd
and Ungerstedt, 1989a; Arbuthnott et al., 1990). It was
shown that synaptosomal sequestration of [3H]methylenedioxyamphetamine and [3H]amphetamine is inhibited by permeant cations (Na+, K+), is saturable and
temperature sensitive (Zaczek et al., 1990). High and
low anity sites have been characterized, with Kd of
295 nM and 45 mM, respectively. This con®rmed the
presence of an active transport for these substances.
Ross and Renyi (1966) had also found that [3H]amphetamine is incorporated into mouse brain cortical
slices. However, they had failed to inhibit this incorporation with cocaine or reserpine known to block
cytoplasmic and vesicular DA uptake, respectively.
Thus, it was also believed that amphetamine could
enter terminals by free di€usion (Fischer and Cho,
1976, 1979) and did not need DA carrier protein. For
Zaczek et al. (1990), the rapid in¯ux of amphetamine
observed ®t badly with a carrier mediated process. In
addition, they proposed that intraterminal sequestration involves an acetylated acidic aminoacid or a peptide. A major problem in studying the transport and
sequestration of amphetamine-related substances is
due to the double gate constituted by the plasma membrane and the vesicle membrane. The plasma membrane does not determine a pH gradient, while the
vesicular matrix does not exceed pH 5. Thus, internalization could involve two di€erent mechanisms, one
for cytosolic accumulation and the other for vesicular
sequestration (Zaczek et al., 1991). Our understanding
of the mechanism by which these drugs enter the terminals remains incomplete, but at least part of them or
even the whole, enter the cell terminals using the DA
speci®c carrier, following the experimental conditions.
2.2. Second step (increasing cytosolic DA)
The origin of the amine released by amphetamines
and other releasing agents is now better understood.
Indeed, if the mechanism by which amphetamines
released DA involves DAT, which is located on the
cytoplasmic membrane, DA e‚ux elicited by amphet-
86
V. Leviel / Neurochemistry International 38 (2001) 83±106
amine should derive from a presumably cytoplasmic
compartment. Firstly, one must consider the nature of
the terminal compartment involved in the amphetamine action. Amphetamine likely releases DA from a
single cytoplasmic pool since the amphetamine e€ect is
insensitive to reserpine (Liang and Rutledge, 1982;
Niddam et al., 1985; Parker and Cubeddu, 1988). The
cytoplasmic compartment is maintained by a continuous DA synthesis and replenished by the displacement
from the vesicular stores constituting the endogenous
DA. It is now well established that the main catabolic
enzyme in DA metabolism, the mono-amino-oxydase
(MAO), is located intraterminally, associated with
mitochondrial crests and gives origin to the dihydroxyphenyl-acetic acid (DOPAC). Until now, there was no
evidence of an active mechanism for DOPAC e‚ux.
Finally, the natural uptake of DA through DAT also
participates in replenishing the cytosolic DA compartment. Endogenous DA, located mainly in a vesicular
compartment, appears to be less sensitive to amphetamine than cytosolic DA. It can thus be concluded
that DA is present in the terminal, separated in two
di€erent compartments (see below), and that amphetamine acts preferentially on the cytoplasmic pool (Parker and Cubeddu, 1986b; Arbuthnott et al., 1990). We
directly observed this phenomenon in vivo (Leviel and
Guibert, 1987). During continuous superfusion of the
cat caudate nucleus with [3H]tyrosine, the neosynthesized [3H]DA was ®rst released by amphetamine, the
unlabeled stored amine being only secondarily
released. As we will see below, the amount of cytosolic
DA is likely very small and a central point of the amphetamine-like drug e€ect is the process by which the
substances are able to induce the intraterminal rise in
cytoplasmic DA.
DA half-life and thus increases the extracellular DA
concentration. In contrast, amphetamine reduced the
amplitude of DA over¯ow induced by K+ or electrical
stimulation (Kuhr et al., 1985). That led Kamal et al.
(1983) to propose the hypothesis of an intraterminal
transfer of DA by amphetamine from an electrically
releasable pool (likely the vesicular one) to a compartment only releasable by amphetamine and related substances (likely the cytoplasmic one).
Displacement from vesicular stores may involve the
vesicular transport mechanism and Fairbrother et al.
(1990) reported a reduction of the tyramine e€ect by
reserpine, a substance inhibiting the vesicular DA
transport. However, amphetamine action was weak or
not a€ected at all by reserpine or tetrabenazine (an
other inhibitor of the vesicular DA transport). The
mechanism of e‚ux and the role of the transporter are
thus still unclear. Erecinska et al. (1987) reported a
strong homology between the amphetamine and
NH4Cl actions on the DA release. They proposed that
NH4Cl collapsed the transvesicular pH gradient responsible for the amine leakage into the cytosol. Later,
it was proposed that a weak base model could explain
the amphetamine action (Sulzer and Rayport, 1990;
Rudnick and Wall, 1992; Sulzer et al., 1993, 1995).
Indeed, it was already known that a vesicular pH gradient is required for monoamine accumulation (Johnson, 1988; Henry et al., 1998). Weak bases and
amphetamine could abolish the intracellular pH gradient, causing a huge increase of cytosolic DA and giving rise to the DA over¯ow (Schuldiner et al., 1993).
The same mechanism was also evoked to explain the
releasing action of 3,4-methylendioxy-methamphetamine (``ectasy''), and fen¯uramine on serotonin (5HT,
Rudnick and Wall, 1992).
2.2.1. Reducing DA catabolism
The work of Miller and Shore (1982) revealed that
amphetamine could enhance the cytoplasmic amine
compartment by reducing the MAO action on neosynthesized DA. The inhibitory action on MAO
(IMAO) of the amphetamine was long time reported
(Rutledge, 1970; Miller et al., 1980). However, it was
also observed that the dose reducing the DOPAC
e‚ux was higher than that producing DA release
(Leviel and Guibert, 1987; Butcher et al., 1988). Thus,
the IMAO e€ect of amphetamine is likely only complementary of its releasing action.
2.2.3. Increasing DA synthesis
Increased DA synthesis after amphetamine treatment was often reported (Uretsky and Snodgrass,
1977; Uretsky et al., 1979; Niddam et al., 1985). For
Kuczenski (1975), however, this e€ect was dose-dependent and more complex, in that low doses induced an
increased synthesis and, in contrast, high doses
decreased tyrosine hydroxylase (TH) activity. As it will
be discussed below, DA could act as an end-product
TH inhibitor, thus explaining this dual e€ect.
2.2.2. Displacing DA from intraterminal stores
The idea that amphetamine displaces DA from
intraterminal stores arises from the observation that
amphetamine did not act in synergy with a K+ application or an electrical stimulation (Kamal et al., 1981;
Langer and Arbilla, 1984). The consequence of an
uptake blockade is that it prolongs the extracellular
Fischer and Cho (1979) proposed that amphetamine-like substances produced a chemical release of
DA by an exchange-di€usion taking place at the binding site of the uptake carrier. They observed that this
exchange is temperature-dependent, saturable, Na+dependent, stereoselective, and cocaine-sensitive. Raiteri et al. (1979) tested amphetamine, octopamine and
2.3. The mechanism of release
V. Leviel / Neurochemistry International 38 (2001) 83±106
b-phenylethylamine as DA-releasing substances and
observed the same blockade with another uptake inhibitor, nomifensine. Using in vivo or in vitro experiments as well, many studies conducted during the last
15 years have con®rmed the role played by DAT in
the releasing mechanism (Butcher et al., 1988). Thus,
Nash and Brodkin (1991) reported that methylenedioxymethamphetamine released DA through a carrier
mediated process blocked by mazindol and GBR12909
(two uptake blockers) and also activated by 5HT but
insensitive to ketanserin (5HT2 antagonist). The ®nding by Giros et al. (1996) that mice lacking the DA
carrier protein due to disruption of the transporter
gene are insensitive to amphetamine, thus unable to
increase extracellular DA, is the most recent and direct
demonstration of the involvement of DAT in the amphetamine releasing e€ect.
Thus, it may be said that a general agreement exists
about the fact that amphetamine-like substances
release DA, at least partly, by inducing DA-RT from
a cytosolic DA compartment, even if the molecular
mechanisms involved are not completely understood.
3. From an amphetamine-induced mechanism to a
physiological mechanism of release
A monoamine e‚ux via a carrier mediated process
was proposed in the early seventies by Paton (1973a,
1973b) in studies involving the rabbit atria. In line
with observations reported in the preceding paragraph,
Paton observed ®rst that the ability of NE, metaraminol and tyramine to increase pre-loaded [3H]NE e‚ux
was consistent with an exchange-di€usion model previously described (Stein, 1967). Secondly, it was
observed that ouabain and K+ omission in the superfusing medium increased [3H]e‚ux likely by inhibiting
the coupled Na+±K+ pump. This phenomenon was
inhibited by cocaine and desipramine (inhibitors of NE
uptake carrier) and sensitive to temperature. Thus the
mechanism of the evoked NE e‚ux appeared to be
compatible with the Na+ gradient model, an hypothesis proposed by Bogdanski and Brodie (1969).
Using the same strategy but conducted on synaptosomal preparations, the mechanisms responsible for
NE and g-aminobutyric acid (GABA) release were
analysed by Levi et al. (1976) and Raiteri et al. (1977)
with similar conclusions concerning the two neurotransmitters, which were reviewed later (Raiteri and
Levi, 1978). Raiteri et al. (1979) also observed, as
others, that nomifensine had no e€ect on the spontaneous release of [3H]DA from synaptosomes prepared from rat striatum (Hunt et al., 1974; Schacht et
al., 1977). However, the increased release of [3H]DA
produced by superfusion with a Na+-free medium,
was almost completely prevented by nomifensine. As
87
in the earlier work of Paton (1973a), inhibition of
Na+±K+ ATPase with ouabain and superfusion with
free K+ also produced and increased [3H]DA release,
blocked by nomifensine. A major point of these works
was the inability of carrier inhibition to reduce the
spontaneous release of [3H]DA from synaptosomes.
This suggests that this mode of release is involved in a
transient process and not in a simple continuous leakage. It was initially proposed that depolarizationinduced DA release could be independent of the DA
transport (Raiteri et al., 1979), however the recent
model described by Wheeler et al. (1993) is consistent
with the participation of the transporter in depolarization induced release (see below).
It was from these original works that numerous investigators developed studies giving evidence of a carrier-mediated e‚ux of DA from the striatum DA
terminals (Levi and Raiteri, 1993). These works used
various techniques, including experimental Na+±K+±
ATPase inhibition with ouabain and experimentallyinduced alterations of intracellular Na+. Saturability,
temperature dependence, and uptake inhibition were
also tested. Synaptosomal preparations were the most
commonly used as experimental models but striatal
slices and in vivo experiments were also used.
From striatal slices treated with pargyline (IMAO)
and reserpine, Liang and Rutledge (1982) observed an
increased release of preloaded [3H]DA after ouabain.
This e€ect was dose-dependent. Reducing ATP production with cytochrome-oxydase inhibitor (sodium
cyanide), oxidative-phophorylation inhibitor (2,4-dinitrophenol) and glycolysis inhibitor (iodoacetic acid)
also increased [3H]DA e‚ux, and these e€ects were
signi®cantly reduced by 10ÿ5 M benztropine (inhibitor
of DA uptake). The antagonistic e€ect of nomifensine
on ouabain-evoked DA e‚ux was also observed in the
cerebro-spinal ¯uid of anesthetized rat by Elghozi et
al. (1983). In addition, Sweadner (1985) reported that
the releasing e€ect of ouabain is independent of extracellular Ca2+ and is blocked by tetrodotoxin (Na+channel blocker) con®rming the importance of a rise in
the concentration of intracellular Na+. This was
further investigated by BoÈnisch (1986) for norepinephrine on the rat vas deferens. He proposed that an
intraterminal Na+ inward ¯ux could lead to an
increased availability of the carrier sites on the inner
axonal membrane. An increase in the Na+ concentration could also increase the anity of NE for the
carrier and thus amplify the outward movement of
amine. Using in vivo microdialysis on anesthetized
rats, Hurd and Ungerstedt (1989c) did the inverse experiment, lowering the extracellular Na+ concentration. This also led to the inversion of sodium
gradient and resulted in an increased DA over¯ow.
The excessive e‚ux of DA, induced by the low extracellular sodium was markedly reduced by pretreatment
88
V. Leviel / Neurochemistry International 38 (2001) 83±106
with Lu 19-005 and nomifensine, potent inhibitors of
DA transport (Hurd and Ungerstedt, 1989c).
The e€ect of ouabain was also observed in microdialysis studies (on conscious rats) but with more complex conclusions (Sirinathsinghji et al., 1988; Westerink
et al., 1989). First, at low concentrations (1±100 mM),
the ouabain-evoked DA release appeared to be sensitive to TTX and Mg2+ (blockers of Na+ and Ca2+
channels, respectively). Secondly, in contrast, higher
ouabain concentrations lead to calcium-independent
e‚ux. This could be due to the involvement of a carrier mediated e‚ux by high doses of ouabain, but in
this study the authors did not mention any e€ect of
the uptake inhibitors.
Observation of nonexocytotic release of NE was
also reported from studies on the in vitro superfused
guinea pig or rat hearts (BoÈnisch et al., 1983; SchoÈmig
et al., 1987, 1988). These researchers proposed that an
increase of the intraneuronal sodium concentration by
veratridine (blocked by TTX) could result in a nonexocytotic release of NE, which is insensitive to extracellular calcium but inhibited by uptake carrier blockers
(Haass et al., 1989).
Low extracellular chloride produced an increase of
the spontaneous DA e‚ux on incubated rabbit striatal
slices (Diliberto et al., 1987, 1989). The question was
to determine whether this e€ect involved the exocytotic
process or not. On striatal slices depleted of DA stores
with reserpine, low Clÿ still produced a DA e‚ux,
which was insensitive to TTX. This suggested that a
depolarization-evoked-release was not involved (Diliberto et al., 1989). In contrast with what was observed
during alterations of the Na+ extracellular concentration, the uptake inhibitors enhanced the low-Clÿinduced DA e‚ux. It was thus concluded that in the
absence of Clÿ the DA natural uptake is substantially
reduced and increased the carrier-mediated release. It
will be seen below that factors regulating uptake often
in¯uence in opposite ways the carrier-mediated release.
Still working on striatal synaptosomes, it was
observed that the outward movement of DA and NE
induced by veratridine (a Na+ ionophore) was independent of the extracellular Ca2+ concentration
(Okada et al., 1990). Increased by the presence of
EGTA (a calcium chelator) during the superfusion
with a Ca2+±Mg2+-free medium, the release of both
DA and NE was considered to result from the in¯ux
of Na+ through the Ca2+ channels in the absence of
divalent cation. The relation between the extracellular
Ca2+ concentration and the carrier-mediated DA
release appears to be rather complex, since we
observed in our laboratory an increased release of DA
in vivo in the presence of the Ca2+ channel blocker
cadmium (Leviel et al., 1994). This was later con®rmed
to be sensitive to the uptake blocker GBR12909 (Olivier et al., 1995). It is unlikely that this e€ect is the
consequence of a Na+ inwarding ¯ux through Ca2+
channels. A more likely explanation is that the Cd2+
ions would have produced a Na+±K+±ATPase inhibition (Rajanna et al., 1990; Chetty et al., 1992)
increasing the intracellular Na+ concentration. In the
experiments reported by Olivier et al. (1995), both the
electrically-evoked DA release and the carrier-mediated
DA release were observed simultaneously in vivo. As
discussed below, the complexity of the Ca2+ action on
DA ¯ow comes from the involvement of this ion in
multiple terminal metabolisms.
A common point to all of these studies is the fact
that increased intraterminal concentration of Na+
results in an outward ¯ux of DA and NE from catecholaminergic terminals. This outward movement,
being highly sensitive to uptake inhibitors and presenting characteristics of an active transport (saturability,
temperature dependence, etc.), likely involves the carrier protein also responsible for the uptake mechanism.
The temperature depence was used recently by Vizi
(1998) to propose a simple model on superfused slices
preparations to separate the two types of releases. Several points will need to be considered about the carrier-mediated catecholamine release in the following
paragraphs. First, amine can only be released from a
cytoplasmic pool, thus the mechanisms contributing to
state the cytoplasmic DA concentration are potentially
modulators of this mode of release as was the case for
the amphetamine action.
4. Biology of intraterminal DA
Whatever the trigger involved in amphetamines or
Na+ action, the presence of a cytosolic DA compartment is dependent on the DA-RT concept. Several studies were devoted to understand the biology of this
DA compartment, since in contrast with vesicularisation of the amine, it does not constitute an actual way
of storage but only a step in the catecholamine metabolic pathway.
A major point to consider in intraterminal monoamine metabolism is that molecules synthesized ®rst
are also the ®rst to be released. Originally, it was proposed that catecholamines could be stored in more
than one storage pool (Glowinski et al., 1965; Sedvall
et al., 1968). It has been con®rmed that newly synthesized DA is preferentially released from DA neurons (Besson et al., 1969, 1973, 1974; Kapatos and
Zigmond, 1977) as occuring in peripheral noradrenergic neurons (Kopin et al., 1968). This came from in
vitro and in vivo experiments as well. As proposed by
Glowinski (1975), a majority of DA molecules could
be stored in vesicles constituting two di€erent pools:
one with the newly synthesized amine, available for an
immediate release and another one constituted of older
V. Leviel / Neurochemistry International 38 (2001) 83±106
synthesized amine, not immediately available for
release. The newly synthesized amine does not seems
to exceed about 20% of the total intraterminal amine.
The replenishement of the newly synthesized amine
compartment after release is questionable. Vesicles
containing older synthesized DA could be used for an
ulterior release. However, this implies a transfer of vesicles from a storage region in the terminal to an active
zone of synapses; this is dicult to imagine when considering the relationship between vesicles and cytosqueleton (Walker and Agoston, 1987; Maley et al., 1990;
Gotow et al., 1991). More likely, old synthesized DA
could be released into the cytoplasm and integrated in
the neosynthesized pool (Michael et al., 1987; Leviel et
al., 1989).
The preferential release of newly synthesized molecules is not in contradiction with the DA-RT theory.
Indeed, as already mentioned, the amphetamine e€ect
(Chiueh and Moore, 1975) and generally the consequences of Na+ gradient alterations both mainly a€ect
cytosolic neosynthesized DA. However, the presence of
di€erent mechanisms of release requiring di€erent
intraterminal pools of neurotransmitter raises the level
of complexity because exocytosis necessitates the presence of granular DA, when DA-RT should involve
cytoplasmic molecules. Thus, the so called releasable
compartement likely have to be further subdivided into
both a cytoplasmic and a vesicular part. Two main
enzymes are responsible for DA synthesis in DA terminals, TH (the rate limiting enzyme) and the DOPA
decarboxylase. They are both soluble enzymes, thus
they lead to a primary cytosolic DA pool. This cytosolic DA is likely secondary vesicularized. Primary cytosolic DA and vesicles containing neosynthesized DA
are likely constituting the releasable amine. The
amount of each of those and their respective turn-over
rates (probably very di€erent) remain, however,
unclear and it can be expected that cytosolic DA be
submitted to very rapid variations as will be discussed
below.
Several studies con®rm the presence of two releasable DA compartments. We already mentioned the
absence of synergy between amphetamine action and a
local K+ application (Kamal et al., 1981; Langer and
Arbilla, 1984). In addition, low doses of amphetamine
seem able to activate TH, the enzyme responsible for
DA synthesis, while high doses, in contrast, produced
an inhibition of the DA synthesis (Kuczenski, 1975;
Roberts and Patrick, 1979). This observation is in line
with the presence of two DA pools, one of these interacting with TH thus having a cytosolic location. It is
known that DA can act as an end product inhibitor
on TH inside the DA terminal. Thus, drugs blocking
vesicular DA uptake (reserpine or tetrabenazine)
should induce an increase of the DA concentration of
a cytoplasmic pool, in turn inhibiting TH. This was
89
indeed observed in vivo (Leviel et al., 1989) and likely
constitutes a regulatory process of the synthesis but
not the only one exclusively. Similar conclusions were
reached by McMillen et al. (1980) considering that damphetamine e€ects are inhibited by pretreatment with
a-mpt but not by reserpine. This suggested the existence of a cytosolic amphetamine-sensitive DA pool.
The cytosolic DA compartment was later studied in
the vas-deferens noradrenergic innervation, by Stute
and Trendelenburg (1984) who proposed that sodium
entrance could be responsible for the increase in a net
leakage of NE from the storage vesicles. Properties of
the cytoplasmic DA pool were further studied in the
following years (Schoemaker and Nickolson, 1983;
Herdon et al., 1985; Michael et al., 1987; Arbuthnott
et al., 1990).
From these studies and after the model proposed by
Glowinski (1975), some models later subdivided the
releasable DA pool. Basically, the DA synthesis could
lead to a cytoplasmic DA submitted to the RT following particular and transient conditions. This compartment is where DA metabolite, DOPAC, is formed by
the action of intraterminal MAO and where DA can
be vesicularized. There is general agreement that two
di€erent granular compartments exist, one with a fast
turn over and being preferentially released by depolarization and the other with a slow turn over rate, often
considered as an inactive form of stored DA (Groppetti et al., 1977; McMillen et al., 1980; Nicolaysen
and Justice, 1988; Leviel et al., 1989). Some discrepancies between the models proposed in the literature are
mainly concerned with the functionnal relationships of
the de®ned compartments but all of the models place
the cytosolic DA compartment in a pivotal role distributing neosynthesized DA into vesicular storage, DART or enzymatic catabolism (Fig. 2).
The concentration of cytosolic DA is likely very
Fig. 2. The di€erent steps in the intraterminal DA metabolism are
organized around the cytoplasmic DA with a very fast turn over rate
and a very low basal amount. Three functions produce cytoplasmic
DA, the synthesis, the uptake and the displacement of intraterminal
stores. Cytosolic DA can be catabolized by MAO in DOPAC,
released by DAT or by exocytosis after vesicularization. DA can also
be stored in a compartment with a slow turn-over rate.
90
V. Leviel / Neurochemistry International 38 (2001) 83±106
small as evidenced by attempts to directly measure it.
Using a voltammetric electrode with a tip diameter of
2±12 mm, or capillary electrophoresis, on the large DA
neurons of the left pedal ganglion of Planorbis corneus,
the cytoplasmic DA has been found to be in the
micromolar range (Chien et al., 1990; Ole®rowicz and
Ewing, 1990). This value is higher than the Km found
in general for the uptake carrier (about 0.2 mM) but
lower than the inhibitory constant (30 mM) of DA for
TH reported by Pasqualini et al. (1994). Cytosolic DA
pool appears to be submitted to a rapid turn over, and
not in equilibrium with other compartments of intraterminal DA. Cytosolic DA cannot be considered as a
storage compartment but only a step in the DA metabolism. Thus, substantial release of DA by RT necessitates a simultaneous activation of an exchangedi€usion process and a sudden rise in the cytosolic
DA. Blockade of catabolism, increased synthesis and
displacement of DA from stores are likely obligatory
companion-processes to the exchange-di€usion.
5. Reverse transport regulation
Some steps may be targets for regulatory processes
of DA-RT: the DA concentration inside the terminal,
the translocating activity and the number of sites. The
displacement from DA from the intraterminal stores
has already been evoked. We would ®rst evoke the
possible role of an activated synthesis. After that, various factors altering uptake process will be reviewed
and their possible involvement in DA-RT. Particular
attention will be given to regulatory function of glutamate (GLU).
5.1. The DA synthesis
We have already taken a lesson from the mechanism
of the action of amphetamine and amphetamine-like
drugs. In 1975, Chiueh and Moore (1975) considered
that the sustained release of DA by amphetamine
appears to be dependent on an activated synthesis. In
the same year, Kuczenski (1975) observed an increased
rate of DA synthesis after amphetamine treatment.
For these authors, this increase was mainly a consequence of the release induced by the drug. However,
for Uretsky and Snodgrass (1977), the synthesis
induced by amphetamine was not only considered to
be compensatory of the release. In the following years,
more and more arguments supported the concept that
amphetamine is able to increase DA synthesis not as a
consequence of the increased release. This came about
mainly from the observation that Ca2+ is necessary
for the amphetamine action on DA synthesis in contrast with that observed with the amphetamine action
on the DA release (Schwartz et al., 1980; Fung and
Uretsky, 1982; Philips and Robson, 1983). In more
recent years, some reports have been concerned with
the dissociation between the mechanisms controlling
synthesis and those controlling release. An increased
synthesis could thus be observed in the absence of an
increased release (Commissiong et al., 1990; Leviel et
al., 1990, 1991; Desce et al., 1993; Pasqualini et al.,
1994). Since the amphetamine-evoked DA release
appears to be more sensitive to the synthesis than to
the presence of intraterminal stores (Parker and
Cubeddu, 1986a, 1986b), it could be that the synthesis
activity constitutes a regulatory mechanism of the DART. That could explain the Ca2+ dependence of the
amphetamine releasing action reported by Hurd and
Ungerstedt (1989b). Various factors a€ect DA synthesis and thus constitute indirect regulatory agents of
the DA-RT, these include the GLU, the calcium ions
and intra and extraterminal DA.
5.1.1. Intraterminal DA
As mentioned previously, DA constitutes an end
product inhibitor of TH in the DA terminals (Nagatsu
et al., 1964; Udenfriend et al., 1965; Ikeda et al.,
1966). The constant of inhibition (Ki) of DA for TH
was calculated to be 30 mM. In a series of reports it
was shown that a consequence of TH activation (by
PKc, PKa and calcium calmodulin-dependent phosphorylations), was an increase of the KiDA (Pasqualini
et al., 1993, 1994, 1995). The increase in KiDA means
that the cytosolic concentration necessary to inhibit
the enzymatic TH activity increases and that the basal
intraterminal DA concentration can be tonically
enhanced. A tonically increased DA concentration
should lead to an increased amount of DA released by
RT when and only when, it is transiently activated.
5.1.2. Extraterminal DA
TH is under tight autoinhibition by extracellular
DA. In the neostriatum, autoreceptors are known to
have pronounced in¯uences on DA synthesis (Nowycky and Roth, 1978; see for a review Wolf and Roth,
1987).
5.1.3. The calcium ions
A particular mention must be given to the role of
calcium. The DA-RT is clearly independent of Ca2+
¯uxes, in contrast with the DA synthesis, clearly
dependent on Ca2+ ions. A large number of studies
have pointed out the role of Ca2+ in the TH activity
in vitro. In a recent study realized in vivo, a set of
arguments were raised, in line with a Ca2+ dependence
of the synthesis with indirect consequences on the carrier mediated release (Leviel et al., 1994; Olivier et al.,
1999). On one side, it was evidenced that increased
Ca2+ in¯ux (by the presence of a calcium ionophore)
activates the TH enzyme activity, which can be visual-
V. Leviel / Neurochemistry International 38 (2001) 83±106
ized by increased neosynthesized DA in terminals. On
the other side, it was proposed that this increase in the
intraterminal DA pool could favour DA-RT rather
than exocytosis. This led to the conclusion that DART is well dependent on Ca2+ entry (even if indirectly)
or of an intraterminal mobilization of the Ca2+ pools.
The case of GLU is of particular interest, since the
releasing action of GLU is likely to involve DA-RT
(see below). Moghadam et al. (1990) proposed that the
stimulatory e€ect of GLU on DA release may be due
to an activation of DA synthesis rather than release.
This was also proposed by Leviel et al. (1990, 1991)
and later con®rmed by others (Desce et al., 1992; Fillenz, 1993; Castro et al., 1996).
5.1.4. Can an increased synthesis induce an activated
DA-RT?
Alterations in DA synthesis were generally expected
to occur after treatments which lead to DA release.
Our laboratory has simultaneously monitored the
release of both neosynthesized and endogenous DA
during in vivo push±pull superfusion experiments.
Neosynthesized amine was evaluated by measuring the
neoformed [3H]DA during a continuous labeling of the
tissues with [3H]TYR. The total DA released was also
measured using electrochemical detection after HPLC
analysis. The ratio between these two parameters (the
speci®c activity of the released amine, DAsa) could
give a continuous index of the activity of the DA synthesis in vivo. For the ®rst time with this method, it
was con®rmed directly that electrically-evoked neuronal ®ring evoked the release of previously stored
amine as evidenced by a lowered DAsa (Leviel et al.,
1991). In contrast, a local application of GLU
increased DA release but simultaneously increased
DAsa, giving evidence that a preferential release of
neosynthesized amine existed. Amphetamine, like
GLU, initially acts on the neosynthesized amine,
increasing DAas (Leviel and Guibert, 1987). Some
other treatments previously considered to be able to
increase the DA release were clearly more ecient on
the DA synthesis than on the release (Leviel et al.,
1989; Gobert et al., 1992; Pasqualini et al., 1995).
These observations led us to propose that intraterminal DA concentration may be the target of presynaptic regulations in the caudate nucleus leading in ®ne
to a modulation of the amount of DA releasable by
DA-RT (Olivier et al., 1999).
To conclude about the possible role of DA synthesis
in regulating DA-RT, it is ascertained now that pharmacological treatments or any factor enhancing DART also produces increase of the DA synthesis. That
does not mean that an increased synthesis is an
unequivocal index of DA-RT. Indeed, K+ depolarization (Soares da Silva and Garret, 1990) as well as ®ring interruption (Roth et al., 1976) were described as
91
able to increase DA synthesis. However, in the case of
DA-RT, in contrast with exocytotic release, it can be
hypothesized that increased DA synthesis is a necessary step for DA-RT. Two arguments can be proposed.
First, the amount of cytosolic DA, as already mentioned, is likely to be very reduced and second, as was
observed recently, the carrier protein exists mainly in
extrasynaptic locations (Nirenberg et al., 1996; Hersch
et al., 1997). Thus, DA-RT likely represents a nonsynaptic DA release (see below). If this is true, this hypothesis implies that amounts of amine that have been
released to alter extracellular DA concentration (an
open medium) are much more important than in
synapses (a con®ned medium), making the synthesis of
new molecules necessary.
5.2. The DA transport
Since DA-RT uses the same translocating system as
for uptake, virtually every factor in¯uencing uptake is
also potentially a regulator of the DA-RT. The large
di€erence between extracellular and intracellular
media, however, indicates that an increased uptake is
not necessarily linked to an increased DA-RT. As we
shall see, the two functions appear to be regulated in
opposite directions.
Side by side with classical in vitro methods, in vivo
regulation of DA uptake was often investigated by
measuring the clearance of DA in the extracellular
space. Some authors introduced a pulse of DA
through an implanted micropipette and monitored the
disappearance of this extrinsic substance (Stamford et
al., 1984; Luthman et al., 1993; David et al., 1998).
Others used an electric stimulation of the DA ®bers
(Wightman et al., 1988; Wightman and Zimmerman,
1990; Suaud-Chagny et al., 1995) and monitored the
time needed to return to the basal level. These voltammetric methods allowed a detailed analysis of the consequences of alterations in DA uptake. However, they
are sometimes hard to interpret, due to the multiple
factors which can interact with extracellular DA clearance including nonsynaptic uptake, glial uptake, tissue
di€usion, etc. We have already mentioned the sensitivity of exchange-di€usion to temperature and Na+
gradient. In addition, certain endogenous factors and
hormones were also involved in the regulation of DA
transport.
5.2.1. DA and DA receptors
Substrate concentration can a€ect the potency of a
carrier. Recently, Zahniser et al. (1999) reported that
the transport velocity of DA carrier and thus DA
clearance is regulated by the extracellular DA concentration. This phenomenon was described long ago by
Stein (1990) and called the facilitated transfer. This
may explain the non-linearity of the transport when
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V. Leviel / Neurochemistry International 38 (2001) 83±106
the amount of the substrate increases. From biochemical studies after chronic treatments with uptake blockers, it seems that the DA carrier is not regulated in the
same way as receptors, and not subjected to upregulation and supersensitization by treatments with antagonists (Kula and Baldessarini, 1991). Some authors
have shown that the DA receptor of D2 type (DA-D2)
mediates a decrease in the rate of DA uptake (Cass
and Gerhardt, 1994; Meiergerd et al., 1993; Parsons et
al., 1993). For others, the uptake kinetics parameters
remained unchanged by the presence of metoclopramide and sulpiride (May and Wightman, 1989) or
were increased after chronic deprenyl (Wiener et al.,
1989). Using genetically engineered mice devoid of
DA-D2, Dickinson et al. (1999) observed a reduction
in DA clearance not related with a reduction in DAT
expression. This is consistent with the idea that DAD2 could modulate the activity of the DA carrier.
The case of DA-RT is more complex. Some authors
reported that the releasing action of amphetamine is
modi®ed by the presence of DA-D2 agonists or antagonists (Wieczorek and Kruk, 1994), while other have
reported the opposite (Kamal et al., 1981; Kuczenski
et al., 1990). Vizi reported that idazoxan, a pure a2
blocking agent, failed to enhance DA release evoked
by 1-phenylephrine which was proved to be Ca2+
independent (Vizi et al., 1986). The question of a DAD2 regulated DA-RT and uptake has not been completely resolved yet.
5.2.2. Serotonin (5HT)
5HT and DA are closely related neurotransmitters
in the central nervous system. Clearly, an increased
extracellular level of 5HT in the striatum leads to an
increased DA. The 5HT re-uptake blockers, including
alaproclate (Yadid et al., 1994), ¯uoxetine (Sill et al.,
1999) and fen¯uramine (de Deurwaerdere et al., 1995),
all enhance extracellular DA. There is no clear consensus about the mechanism by which 5HT releases DA.
Nearly all the 5HT receptor types were evoked in mediating the action of 5HT on the DA release (Benloucif
et al., 1993; Bonhomme et al., 1995; di Giovanni et al.,
1999; Matsumoto et al., 1999; Ng et al., 1999; Lucas et
al., 2000). The e€ect of 5HT on basal DA over¯ow
was not altered by the serotonin antagonist, methysergide, or the serotonin re-uptake blocker, chlorimipramine, but was reversed by the DA re-uptake carrier
inhibitors, nomifensine and benztropine. In addition,
5HT does not modulate K+-induced release of DA in
the nucleus accumbens or striatum (Nurse et al., 1988).
Using phenylbiguanide (PBG), a 5HT type 3 receptor
agonist, it was observed that the PBG-evoked DA out¯ow from striatal slices can be inhibited by nomifensine, is insensitive to reserpine and does not require
the presence of Ca2+ ions in the superfusing medium
(Nurse et al., 1988; Schmidt and Black, 1989; Benuck
and Reith, 1992). It was thus concluded by these
authors that PBG could promote the e‚ux of DA by
a carrier dependent mechanism. The possibility that
5HT enhances DA e‚ux by a process of exchange-diffusion was also proposed by Yi et al. (1991) but they
considered that 5HT could act as amphetamine or tyramine by entering the DA terminals. This was con®rmed latter by Jacocks and Cox (1992) and Crespi et
al. (1997).
5.2.3. Glutamate
DA uptake velocity was found to be increased by
the agonist NMDA (Welch and Justice, 1996) and this
e€ect was antagonized by AP5 (NMDA antagonist).
The same activation was obtained with kainic acid.
These e€ects were proposed to be receptor-mediated,
direct and independent of action potentials. NMDA,
however, also causes arachidonic and nitric oxide
release which inhibit DA uptake in striatal synaptosomes (Lonart and Johnson, 1994; Pogun et al., 1994;
L'hirondel et al., 1995). This could explain the reduction of DA uptake by NMDA, also reported by
Lin and Chai (1998). Finally, NMDA facilitates an
inward calcium movement that in turn could activate
the PKc enzyme and it was observed that PKc activators decrease the DA transport in the COS cells
(Kitayama et al., 1994).
Considering that the corticostriatal pathway is likely
to be glutamatergic in nature (at least in part), the relationship between a€erent GLU path to the striatum
and the local DA release is of primary interest and has
been extensively studied. DA release can be elicited in
the striatum by GLU or GLU agonist and this e€ect
is clearly independent of DA neuron ®ring. The role of
GLU in DA release was reviewed by Grace (1991). It
is likely that GLU could interfere with DA mainly
through NMDA receptors located on the DA terminals, even if kainate and/or quisqualate receptors were
also evoked. The way in which GLU increases extracellular DA could be a reduction of the DA uptake.
Recently, some observations showed that simultaneously GLU may promote DA-RT. Extensive studies were devoted to the regulation of DA release by
excitatory amino acids and particularly GLU (Giorguie€ et al., 1977; Roberts and Shari€, 1978; Roberts
and Anderson, 1979; Clow and Jhamandas, 1989).
Early observations revealed that this e€ect of GLU
was insensitive to TTX and thus unrelated to the depolarization-induced ®ring. This was recently con®rmed by Keefe et al. (1993) who observed that
NMDA applied directly in the striatum of unanesthesized rats produced a signi®cant elevation in extracellular DA during the blockade of impulse activity in DA
neurons with TTX. For these authors, the GLU does
not tonically regulate the extracellular concentration of
DA in resting conditions (Keefe et al., 1992). This con-
V. Leviel / Neurochemistry International 38 (2001) 83±106
trasted with our proposal of a tonic inhibition of the
DA synthesis in the striatum through the glutamatergic cortico striatal pathway (Leviel et al., 1990) coming
from the observation of an increased e‚ux of [3H]DA
during cortical xylocaine application. It should be
noted, however, that this treatment did not signi®cantly a€ect the basal DA release leading us to propose a dual potency of GLU, a tonic inhibition on the
DA synthesis (direct or indirect) associated with a phasic ability to induce release (direct). Indeed, it has been
proposed that the primary in¯uence of GLU is not on
the DA release but on the DA synthesis (Leviel et al.,
1990) and an activation of the TH, independent of the
mechanism of release, was also observed after GLU
applications (Desce et al., 1993; Castro et al., 1996).
Lonart and Zigmond (1991) suggested that one component of the action of GLU on DA release could
involve its uptake into DA terminals as proposed for
GABA by Bonanno and Raiteri (1987). It seems likely
that Na+ co-transported with GLU acts to depolarize
the terminal (McMahon et al., 1989) promoting the
DA-RT. The DA release under these conditions is
both Ca2+ independent and blocked by nomifensine
(Lonart and Zigmond, 1990). The dual e€ect of GLU
through NMDA and Kainate receptors was studied by
Olivier et al. (1995). It appeared from these experiments that NMDA and kainate induce a blockade of
the ability of DA terminal to release DA by a ®ringdependent process. In contrast, extracellular DA was
enhanced by the presence of these two substances, an
e€ect blocked by systemic injection of GBR12909.
These results were substantially con®rmed one year
later with a di€erent method by Iravani and Kruk
(1996).
5.2.4. Ascorbic acid
This endogenous substance was often considered a
modulator of the DA uptake (Sershen et al., 1987;
Debler et al., 1988; Berman et al., 1996). In a study of
the DA-RT on mouse striatal synaptosomes, it was
revealed that external ascorbic acid enhanced the e‚ux
of preloaded [3H]DA (Debler et al., 1991). Since
ascorbic acid does not appear to be a substrate for the
carrier, it may be more likely a modulator of the carrier translocation, promoting the conformation of the
binding site oriented toward the side with the lowest
ascorbic acid concentration (Debler et al., 1991).
5.2.5. Oestradiol
It has been known for a long time that steroid hormones a€ect the DA system (Barber et al., 1976;
Ramirez et al., 1985). Oestradiol was reported to a€ect
receptors coupled to adenylate cyclase (Maus et al.,
1990) and the DA synthesis (Pasqualini et al., 1995).
Recently, an inhibition of the DA transport was also
reported (Disshon et al., 1998). The action of estradiol
93
on DA-RT remains thus questionable but this substance is a good candidate as DA-RT modulator.
5.2.6. Ethanol
From the various pharmacological situations interfering with DAT, the case of ethanol is interesting
enough. The e€ects of ethanol on the DA transmission
remains controversial (Lynch and Littleton, 1983;
Snape and Engel, 1988; Blanchard et al., 1993; Lin
and Chai, 1995). Using in vivo voltammetry, Lin and
Chai (1995) observed that local pressure ejection of
ethanol in the rat striatum did not elicit signi®cant
changes in spontaneous DA release. However, this
treatment augmented the time course of NMDA
evoked DA release as did nomifensine. These results
have been con®rmed by others (Woodward and Gonzales, 1990; Brown et al., 1992) as the fact that the
rate of DA clearance was reduced after ethanol treatment (Daoust et al., 1986; Smolen et al., 1984). These
data demonstrate that ethanol simultaneously inhibits
NMDA evoked DA uptake, suggesting a role for ethanol on the translocation of the carrier. Recently, using
in vivo voltammetry on urethane anesthetized rats, it
was observed that local ethanol application in the
striatum reduced the potassium evoked DA over¯ow,
when, in contrast, the same treatment remained ineffective on the tyramine induced DA over¯ow (Wang et
al., 1997). The reduction in the e€ect of potassium for
these authors is relevant to an activated DA clearance
through a facilitated DA uptake by ethanol. These
controversial observations show, however, that the
uptake function of the DA transport may be regulated
di€erently from the releasing function.
5.2.7. Voltage dependency
A voltage dependence of the DA uptake was directly
observed by Zahniser et al. (1998), using a patch
clamp technique on xenopus oocytes expressing the
cloned human DAT. Several substances responsible for
membrane depolarization (KCl, veratridine, ouabain)
also induced a reduction of the DA uptake, but the
method used by Zahniser and coworkers allowed a
direct correlation of membrane potential and DA
uptake velocity. Clearly, hyperpolarization increased
the uptake velocity and depolarization reduced it.
The DAT exists in various forms including a low
and an a high anity state for DA and cocaine-like
substances (Calligaro and Eldefrawi, 1988; Boja et al.,
1992a). It has been demonstrated that the anity of
the DAT is consistent with its charge-states (Gracz
and Madras, 1995). Furthermore, clear indications
reveal that DA distinguishes high and low anity
components for at least two charge states. Thus, it was
proposed that the process involved in altering the
charges of the carrier may induce conformational
changes. One cannot actually ascertain whether the
94
V. Leviel / Neurochemistry International 38 (2001) 83±106
high and low anity states represent separate sites on
di€erent protein populations or independent sites on a
single molecule (Gracz and Madras, 1995; Boja et al.,
1992b). The voltage dependence of DAT means that
DA-RT cannot be di€erentiated from exocytosis by
any ®ring dependence. The model validated by
Wheeler et al. (1993) showed a possible reversal of the
direction of operation consistent with the participation
of the transporter in depolarization induced release.
DA-RT can likely participate in a ®ring independent
mode of release, as it will be reported in the e€ect of
GLU for instance, but it can also participate in the depolarization induced release.
These recent results, based on the direct observation
of the coupling between polarity/translocation, are
consistent with the numerous proposals which already
show that DA-RT could be triggered by an inversion
of the membrane polarity and coming from pharmacological studies.
6. Reverse transport and other atypical releasing
mechanisms
Various types of neuronal communications have
been proposed to occur in the central nervous system.
Particularly, authors have suggested the existence of
nonsynaptic relations between neurons. For some of
them, this involved a particular mechanism of release
but others have only considered the ability of the
released DA to di€use in the extracellular space until
reaching distant targets. The former could be relevant
to the DA-RT, while the others can also be based on a
leakage of DA from more classical synapses.
6.1. Dendritic release
The way by which DA can be released from dendrites of DA neurons remains a puzzling problem.
The dendrites of nigro striatal DA neurons are
located in both the pars compacta (short dendrites)
and pars reticulata (long radiating dendrites) of the
substantia nigra (SN). DA molecules are present in
the whole dendritic arborescence of DA neurons
(BjoÈrklund and Lindvall, 1975). Evidence of DA
release from these dendrites is abundant and come
from numerous in vitro and in vivo experiments.
The presence of DA sensitive adenylate cyclase was
observed (Premont et al., 1976; Phillipson and
Horn, 1976; Kebabian and Saavedra, 1976) and the
existence of an auto-inhibition of DA neurons was
reported (Bunney et al., 1973; Groves et al., 1975).
A DA sensitivity of nonDA neurons was also
found (Rueux and Schultz, 1980). An extensive
series of experiments were conducted, assessing a
spontaneous and evoked DA release in this region
(Nieoullon et al., 1977; Leviel et al., 1979; CheÂramy
et al., 1981). The dendritic DA release was further
investigated in vivo and in vitro during the following two decades (Elverfors and Nissbrandt, 1991;
Santiago and Westerink, 1991; Kalivas and Du€y,
1991; Heeringa and Abercrombie, 1995; Cragg et
al., 1997, 1998) using di€erent techniques including
microdialysis and voltammetry.
The localization of DA storage in the dendrites
of DA was investigated because dendrites lack
characterized synaptic junctions with vesicular accumulation as terminals. The absence of a DA vesicular compartment in the nigral dendrites was ®rst
emphasized by Sotelo (1971). This was later con®rmed by many authors (Pickel et al., 1977; Cuello
and Iversen, 1978; Wassef et al., 1981). It appeared
thus that DA was more likely stored in smooth
endoplasmic reticulum (Groves and Linder, 1983;
Elverfors and Nissbrandt, 1991; Chan et al., 1995).
The size of the releasable compartment of DA was
also questioned since the number of vesicles available for an exocytotic release is clearly limited (Nirenberg et al., 1996) and indeed a pharmacological
approach using amphetamine led to the same conclusion (Heeringa and Abercrombie, 1995). This was
consistent with the observation that dendritic DA
release is particularly sensitive to any blockade of
the synthesis (Nissbrandt et al., 1985).
Midbrain DA neurons present a rich DAT-immunoreactivity (Giros and Caron, 1993; Shimada et al.,
1991; Ciliax et al., 1995) and numerous DAT binding
sites (Donnan et al., 1991; Mennicken et al., 1992). In
the SN, DAT appears to be located into dendrites of
DA neurons. and found in smooth endoplasmic reticulum (Ciliax et al., 1994; Hersch et al., 1997; Nirenberg
et al., 1996).
The relation between DA release and spike-evoked
depolarization was dicult to establish (Green®eld,
1985). The mechanism by which DA is released from
dendrites has long been a subject of debate arising
from the observation that dendritic release of DA was
K+ and Ca2+ dependent (Ge€en et al., 1976; Santiago
and Westerink, 1991) but enhanced by TTX (CheÂramy
et al., 1981). This last observation was however counteracted by the observation of Santiago and Westerink
(1991), using microdialysis on conscious rat. They
found that the spontaneous nigral DA release was
completely interrupted during local superfusion with
TTX. Numerous hypotheses about particular conductance properties of dendrites were advanced (Llinas et
al., 1984; Llinas, 1988; Stuart and Sakmann, 1994)
that proposed that DA release from nigral dendrites
could be spike-dependent (HaÈusser et al., 1995; Rice et
al., 1997). Due to the particular biophysical properties
of neural dendrites and the atypical DA storage, it is
dicult to ascertain that DA-RT is involved in the
V. Leviel / Neurochemistry International 38 (2001) 83±106
dendritic release, however, more than one mechanism
of release are likely involved (Groves and Linder,
1983; Nirenberg et al., 1996) and DA-RT was also
proposed to occur in this region (Kalivas and Du€y,
1991; Atwell et al., 1993; Nirenberg et al., 1996).
6.2. Paracrine and/or nonsynaptic DA neurotransmission
The communication between neurons is a subject of
old debate in the neurobiological literature (Del Castillo and Katz, 1956; Hubbard, 1970) and the concept
that there exists another mode of interneuronal communication besides the neuron-to-neuron synaptic transmission has been amply commented on and reviewed
(Cuello, 1983; Vizi, 1980, 1984; Agnati et al., 1986;
Vizi and Labos, 1991; Fuxe and Agnati, 1991; BachY-Rita, 1993; Descarries et al., 1996; Barbour and
HaÈusser, 1997; Vizi and Kiss, 1998). The general term
of Paracrine neurotransmission can be used to describe
this mode of communication in which one neuron, or
a group of neurons, sends a chemical signal to another
group of neurons, by di€usion through extracellular
space. The notion of a nonexocytotic release is more
restricted to the mechanism by which given neurons
extrude the neurotransmitter without regard to destination (Tauc, 1982; Uvnas and Aborg, 1984; Cooper
and Meyer, 1984; Vizi, 1984; Grace, 1991; Adam-Vizi,
1992; Bernath, 1992; Atwell et al., 1993). Theoretically
a nonexocytotic release (as DA-RT for instance) could
occur inside or outside the synapses as well and paracrine transmission may or may not have its origin in a
synaptic release. Thus, it was recently proposed that
the so called Volume Transmission could be of synaptic
origin (Zoli et al., 1998).
The concept of a nonsynaptic DA release in the neostriatum is based on observations at an electron microscopic level of the nigrostriatal DA terminals. From
initial studies, neostriatal DA buttons seemed to make
asymmetrical synaptic contacts with dendritic spines,
suggesting the presence of excitatory synapses with
spiny type I neurons of the striatum (see Groves
(1983) for a review). Other electron microscopic studies
on the other hand reported the presence of symmetrical synapses (Descarries et al., 1980; Pickel et al.,
1981). Using polyclonal antibodies, however, it was
later observed that the frequency of characterized
synapses on identi®ed DA terminals was only in the
range of 30±40%. This was in line with previous observations about the rather sparse synaptic contacts
between DA terminals and striatal neurons (Tennyson
et al., 1974; Arluison et al., 1978a, 1978b) and enlarged
the idea that monoaminergic neurons could release
biogenic amines from nonsynaptic varicosities (Descarries et al., 1975; Dismukes, 1977; Beaudet and Descarries, 1978). These data suggested a dual mode of
95
operation for the nigrostriatal DA system, synaptic as
well as nonsynaptic. (Descarries et al., 1996).
It is likely that DA transporter plays a major role in
nonsynaptic release of DA (Vizi, 2000), however it
cannot be ascertained whether nonsynaptic DA release
in striatum strikingly involves DA-RT or not. Indeed,
DA-RT involves DAT protein and recent works using
electron microscopy clearly localized DAT outside the
DA synapses and all along the DA ®bers (Nirenberg
et al., 1996; Hersch et al., 1997). The absence of carrier
proteins in active synaptic zones observed by using
anatomical methods con®rmed the remark of Garris et
al. (1994) that ``dopamine e‚ux from the synaptic cleft
is not restricted by binding to intrasynaptic proteins on
the time scale of the measurements (50±100 ms)''. Thus
it is likely that DA-RT regulates the extracellular and
nonsynaptic DA concentration. The presence of di€erent mechanisms in regulating extracellular and intrasynaptic DA concentration have been already analyzed
in details (Grace, 1991).
7. Physiopathological incidences of DA-RT
Since DA-RT functions in normal animals is dicult
to de®ne, its role in physiopathological situations has
often been evoked. Of note, alterations in carrier
potency during ischemia, and neurodegenerative situations were studied.
7.1. Ischemia
The striatum is one of the most sensitive areas to
ischemia (Pulsinelli, 1985). The intrinsic medium-sized
spiny neurons are seriously damaged after forebrain
ischemia (Benfenati et al., 1989; Nemeth et al., 1991).
There is a general agreement in the literature about
the role of the massive release of GLU and DA in the
pathogenesis of ischemia. It is of particular interest
that nigrostriatal DA lesions, DA synthesis inhibition
or DA protection with antioxydants attenuated the
ischemic cell damage (Globus et al., 1988; Marie et al.,
1992; Hoyt et al., 1997; Stamford et al., 1999) which
suggests that DA could contribute to the striatal
injury. The possible pathological role of DA in striatum was already evoked in other physiopathological
situations such as Parkinson's disease for example
(Maker et al., 1986; Zigmond and Stricker, 1988; Filloux and Townsend, 1993; Hastings et al., 1996). On
perfused isolated rat hearts, the noradrenergic neurons
release the neurotransmitter in response to a global
ischemia (SchoÈmig et al., 1984; Carlsson et al., 1987;
Du et al., 1998). A maximal e‚ux was further
observed during the ®rst minutes of reperfusion. These
e€ects were not sensitive to the absence of calcium
ions or verapamil (calcium channel blocker). In con-
96
V. Leviel / Neurochemistry International 38 (2001) 83±106
trast, various NE uptake blockers markedly reduced
the ischemia induced release of [3H]NE. Most of these
authors concluded that the release was partly mediated
via a carrier mediated process.
An increased extracellular DA in striatum was long
ago observed after experimental ischemia (Kogure et
al., 1975; Lavyne et al., 1975). As observed in rat
heart, excess DA release induced during ischemia
appears as biphasic (Ahn et al., 1991) with a rapid
release during early ischemia and a massive secondary
DA release during reperfusion.
It must be noted that the mechanism by which ischemia induces DA release is still unclear. Indeed, ischemia leads to both hypoxia and hypoglycemia and if
hypoxia increases the stimulation evoked DA release
without e€ect on the resting DA release, hypoglycemia
is more concerned with the DA resting release (Pastuszko et al., 1982; Milusheva et al., 1992). The role of
nitric oxide (NO) was investigated and some authors
concluded a NO-modulated DA release (Kahn et al.,
1995) when others suggested that the basal level of NO
is not involved in DA release during ischemia (Spatz et
al., 1995). Studies using lactate, malonate and NMDA
receptor blockers led to the conclusion that oxygen
free radicals play a role in the extracellular release of
DA but also glutamatergic mechanisms (Remblier et
al., 1998, 1999a; Ferger et al., 1999). More in line with
the present review are the attempts to characterize the
mecanism of release per se during experimental ischemia. On rat striatal slices, it was observed that the DA
release, induced by combination of hypoxia and hypoglycemia was impaired by Ca2+ withdrawal and tetrodotoxin, arguing for an exocytotic process (Milusheva
et al., 1992). The voltage-dependent calcium channels
were also involved in the mechanism of DA release
induced by ischemia (Ooboshi et al., 1992; Werling et
al., 1994). In contrast, the enhancement of DA release
by high frequency stimulation and high K+ application was observed to be impaired in rats exposed to
short time ischemia (Inoue et al., 1995). In addition
the process involved during ischemia appears as temperature-dependent (Vizi, 1998; Toner and Stamford,
1999). It was observed on rats synaptosomes by Santos
et al. (1996), that anoxia and ischemia induced release
of DA correlated well with ATP depletion. They concluded that the decrease in Na+ and K+ gradients
resulting from this loss in energetic disposibility could
promote an already evoked process, the reversal of the
DAT. These conclusions recall those of Liang and
Rutledge (1982), already mentioned and were also
reached by other authors (Milusheva et al., 1996;
Buyukuysal and Mete, 1999). These controversial
results could be reconciled by the studies of Kim et al.
(1995) and Remblier et al. (1999b). These authors proposed that ischemia induced DA release results from a
dual mechanism dependent or not on the Ca2+ ions.
The ®rst observed simultaneously on superfused striatal slices that during an ischaemic period, the induced
release of DA could be attenuated by TTX, verapamil,
omega-conotoxin (in line with an exocytotic release)
but also nomifensin (more in line with DA-RT). It was
observed by the second that striatal lactic acid perfusion produces a biphasic increase in extracellular DA
(Remblier et al., 1998) and more recently that the ®rst
increase could be attributed to DA-RT while the second could more likely be due to the release of vesicular
DA by exocytosis.
Studies are needed to clarify the mechanisms leading
hypoxia and hypoglycemia to increase extracellular
DA but it appears today that both exocytosis and DART are likely involved.
7.2. Weaver mutant mice
This type of mouse has a genetically determined
defect in the nigrostriatal dopaminergic system. The
resting DA release of these mice was increased and the
striatal tissue content enhanced by >75% when compared to the control (Simon et al., 1991). The fractional release of DA (i.e. the ratio between the released
DA and the tissue amine) was increased. Comparing
mice that exhibited either or no mutated genotype, it
was observed on superfused striatal slices that a potassium pulse resulted in a DA over¯ow of the same
amplitude on the two types of animals. In contrast,
amphetamine e€ects were enhanced on the mutated
mice in spite of the fact that the uptake process
appeared strongly reduced (Ro‚er-Tarlov et al., 1990).
The DA release attributable to the DA-RT has been
studied on weaver mutant mice (Richter et al., 1995),
and reported to be increased (Simon et al., 1991).
7.3. Partial lesions
For a long time, it has been well known that DA
turn over is increased after nigrostriatal lesions (Agid
et al., 1973; Hefti et al., 1980; Zigmond and Stricker,
1988 for a review) and that even if as little as about
10±20% of DA neurons are preserved in the SN pars
compacta, the DA function remains almost unmodi®ed
(Robinson and Whishaw, 1988; Zhang et al., 1988;
Altar and Marien, 1989). The ®rst question was therefore to determine if the remaining neurons are activated or if the pattern of their activity is profoundly
changed. Electrophysiological studies, have established
that changes in DA neurons activity only occurs after
a drastic lesion exceeding 80% (Hollerman and Grace,
1990). However, many authors reported that extracellular DA was maintained or increased in the striatum of rat with partial nigral lesions (Robinson and
Whishaw, 1988; Zhang et al., 1988; Altar and Marien,
1989; Zigmond et al., 1990; Sarre et al., 1992; Espino
V. Leviel / Neurochemistry International 38 (2001) 83±106
et al., 1995). It then became apparent that extracellular
DA concentration was unrelated to a sustained activation of the spared DA nigral neurons.
Several authors have proposed that the amount of
DA released per pulse could be increased (Stachowiak
et al., 1987; Snyder et al., 1990) while others have spoken about a reduction of the amount of DA released
per pulse (Wang et al., 1994; Garris et al., 1997). This
question remains unsolved.
The extracellular DA concentration maintained in
spite of the reduced number of DA terminals could
involve a reduced uptake. A general agreement was
found for a reduction of the uptake sites density after
partial lesions (Earl et al., 1998; Cass et al., 1995; Gerhart et al., 1996). However, the density of DA uptake
sites (evidenced by immunoautoradiography with
radioactive inhibitors) is considered as an index of the
DA denervation and the number of uptake sites per
terminal has never been shown to be reduced. The anity of DAT has been also questioned and Maloteaux
et al. (1988) reported that it remained unchanged on
parkinsonian patients.
As previously mentioned, GLU is likely able to
reduce the DA uptake through NMDA receptors (Lin
and Chai, 1998). In addition, we have also reported in
the present review that GLU could induce DA release
most likely through DA-RT. Thus, the role of corticostriatal glutamatergic pathway has to be questioned
in the situations of partial lesions of the subtantia
nigra or parkinsonian degenerescence. It can ®rst be
noted that an increased level of GLU in CSF of parkinsonian patients was reported (Iwasaki et al., 1992).
In addition, an increased density of the NMDA receptors was observed in the striatum of parkinsonian
patients and of lesioned rats (Weihmuller et al., 1992;
Samuel et al., 1990; Wullner et al., 1994). Increased
expression of NMDA receptors subunit of the NR2A
type has also been reported after partial nigral lesions
on the rat (Ulas and Cotman, 1996) which lead to
modi®ed activity of the NMDA receptors (Richard
and Bennett, 1995; Standaert et al., 1996). In addition, Oh et al. (1998) proposed that the nigrostriatal
DA lesion was responsible for an increased phosphorylation of the NR2A and NR2B subunits which
could lead to an increased anity of NMDA receptors. Finally, Meshul et al. (1999), observed morphological modi®cations of striatal synapses after partial
lesions of DA tractus. An increased number of asymmetric synapses was associated with an increased
extracellular concentration of GLU. All these observations are consistent with a possible involvement of
the cortico striatal glutamatergic path in a reduction
of DA uptake and an increased DA release in the
striatum.
From these physiopathological observations, it
appears that DA-RT can be submitted to long term
97
alterations. This could lead to a sustained extracellular
DA even with a reduced or unchanged ®ring dependent DA release.
8. Conclusions
From the present, and unfortunately non-exhaustive,
review of the literature, it can be said that DA neurotransmission and possibly also NE neurotransmission
are not simply carried out through an exocytotic process occuring in synaptic junctions. To summarize
these studies, a concept is arising, which advocates the
ability of nigro-striatal DA neurons to simultaneously
perform both a neuron-to-neuron transfer of information, and a paracrine environmental modulation of
the striatal medium. The physiological signi®cance of
DA-RT, however, needs to be questioned.
8.1. Physiological signi®cance
This question should likely be considered in the light
of the diversity of the functions attributed to nigrostriatal DA innervation. DA, like other monoamines,
is often considered a neuromodulator more than a
neurotransmitter. Its most often evoked function in
striatum is a ®ltering of the a€erent cortico-striatal
(glutamatergic) path on the GABAergic neurons constituting the e€erent system of striatum. The large
extension of the DA terminals ®eld when compared to
the restricted number of originating cells in midbrain,
also supports this concept of a rather di€use and general regulatory process. Finally, the late survey of clinical symptoms in Parkinson's disease when at least 40±
50% of DA neurons have degenerated in the SN,
could lead to minimize the role of the neuronal connections in the motor control realized by dopaminergic
innervation of the striatum.
The anatomical and electrophysiological approaches
of the midbrain dopaminergic pathways innervating
the striatum argues against this simplistic view. Indeed,
the nigro-striatal pathway appears to be rather strictly
organized and a precise somatotopy of the neurons
making this pathway is now established (Maurin et al.,
1999). In addition, this anatomical organization seems
to correspond well to the various functionalities recognized for the extrapyramidal system (Alexander and
Crutcher, 1990). Electrophysiological analysis of the
activity of DA neurons during behavioral test have
also demonstrated that these neurons are activated by
very speci®c situations (Schultz, 1986; Mirenowicz and
Schultz, 1996). Finally, the importance of neuronal
connections in the occurrence of motor symptoms in
Parkinson's disease could have been underestimated in
humans since motor dysfunctions were reported to
occur on MPTP chronically treated monkeys as early
98
V. Leviel / Neurochemistry International 38 (2001) 83±106
as in the ®rsts weeks of the treatment (Hantraye et al.,
1990). It could be that in humans non-extrapyramidal
compensation could occur.
From these considerations DA modulation could
operate in the following two ways in the striatum: a
di€use and long lasting action on the terminal environment, likely realized in part by the DA-RT regulated
by preterminal a€erences and a more targeted in¯uence involving synaptic contacts.
References
Adam-Vizi, V., 1992. External Ca2+-independent release of neurotransmitters. J. Neurochem. 58, 395±405.
Agid, Y., Javoy, F., Glowinski, J., 1973. Hyperactivity of remaining
dopaminergic neurons after partial destruction of the nigrostriatal
dopaminergic system in the rat. Nature 245, 150±151.
Agnati, L.F., Fuxe, K., Zoli, M., Zini, I., To€ano, G., Ferraguti, F.,
1986. A correlation analysis of the regional distribution of central
enkephalin and beta endorphin immunoreactive terminals and of
opiate receptors in adult and old male rats. Evidence for the
existence of two main types of communication in the central nervous system: the volume transmission and the wiring transmission. Acta Physiol. Scand. 128, 201±207.
Ahn, S.S., Blaha, C.D., Alkire, M.T., Wood, E., Gray-Allan, P.,
Marroco, R.T., Moore, W.S., 1991. Biphasic striatal dopamine
release during transcient ischemia and reperfusion in gerbils.
Stroke 22, 674±679.
Alexander, G.E., Crutcher, M.D., 1990. Functional architecture of
basal ganglia circuits: neural substrates of parallel processing.
Trends in Neurosci. 13, 266±271.
Altar, C.A., Marien, M.R., 1989. Preservation of dopamine release
in the denervated striatum. Neurosci. Lett. 96, 329±334.
Amara, S.G., Kuhar, M.J., 1993. Neurotransmitter transporters:
recent progress. Annu. Rev. Neurosci. 16, 73±93.
Arbuthnott, G.W., Fairbrother, I.S., Butcher, S.P., 1990. Dopamine
release and metabolism in the rat striatum: an analysis by `in
vivo' brain microdyalisis. Pharmac. Ther. 48, 281±293.
Arluison, M., Agid, Y., Javoy, F., 1978a. Dopaminergic nerve endings in the neostriatum of the rat. Part 1. Identi®cation by intracerebral injections of 5-hydroxydopamine. Neuroscience 3, 657±
673.
Arluison, M., Agid, Y., Javoy, F., 1978b. Dopaminergic nerve endings in the neostriatum of the rat. Part 2. Radioautographic
study following local microinjections of tritiated dopamine.
Neuroscience 3, 675±683.
Arnold, E.B., Molino€, P.B., Rutledge, C.O., 1977. The release of
endogenous norepinephrine and dopamine from cerebral cortex
by amphetamine. J. Pharm. Exp. Therap. 202, 544±557.
Atwell, D., Barbour, B., Szatkowski, M., 1993. Nonvesicular release
of neurotransmitter. Neuron 11, 401±407.
Azzaro, A.J., Ziance, R.J., Rutledge, C.O., 1974. The importance of
neuronal uptake of amines for amphetamine-induced release of
3
H-norepinephrine from isolated brain tissue. J. Pharm. Exp.
Therap. 189, 110±118.
Bach-Y-Rita, P., 1993. Neurotransmission in the brain by di€usion
through the extracellular ¯uid: a review. NeuroReport 4, 343±
350.
Barber, P.V., Arnold, A.G., Evans, G., 1976. Recurrent hormonedependent chorea: e€ects of oestrogens and progesterone. Clin.
Endocrinol. 5, 291±293.
Barbour, B., Hausser, M., 1997. Intersynaptic di€usion of neurotransmitter. Trends Neurosci. 20, 377±384.
Bauman, P.A., Maitre, L., 1976. Is drug inhibition of dopamine
uptake a misinterpretation of in vitro experiments? Nature 264,
789±790.
Beaudet, A., Descarries, L., 1978. The monoamine innervation of rat
cerebral cortex: synaptic and non synaptic axon terminals.
Neuroscience 3, 851±860.
Benfenati, F., Merlo Pich, E., Grimaldi, R., Zoli, M., Fuxe, K.,
To€ano, G., Agnati, L., 1989. Transcient forebrain ischemia produces multiple de®citsin dopamine D1 transmission in the lateral
neostriatum of the rat. Brain Res. 498, 376±380.
Benloucif, S., Keegan, M.J., Galloway, M.P., 1993. Serotonin-facilitated dopamine release in vivo: pharmacological characterization.
J. Pharm. Exp. Therap. 265, 373±377.
Benuck, M., Reith, M.E.A., 1992. Dopamine releasing e€ect of phenylbiguanide in rat striatal slices. Naunyn Schmiedeberg's Arch.
Pharmac. 345, 666±672.
Berman, S.B., Zigmond, M.J., Hastings, T., 1996. Modi®cation of
dopamine transporter function: e€ect of reactive oxygen species
and dopamine. J. Neurochem. 67, 593±600.
Bernath, S., 1992. Calcium-independent release of amino acid neurotransmitters: fact or artifact. Prog. Neurobiol. 38, 57±91.
Besson, M.J., CheÂramy, A., Feltz, P., Glowinski, J., 1969. Release of
newly synthesized dopamine from dopamine containing terminals
in the striatum of the rat. Proc. Natl. Acad. Sci. 62, 741±748.
Besson, M.J., CheÂramy, A., Gauchy, C., Glowinski, J., 1973. In vivo
continuous estimation of 3H-dopamine synthesis and release in
the cat caudate nucleus. Naunyn Schmiedeberg's Arch.
Pharmacol. 278, 101±105.
Besson, M.J., CheÂramy, A., Gauchy, C., Glowinski, J., 1974. In vivo
spontaneous and evoked release of newly synthesized dopamine
in the cat caudate nucleus. Adv. Neurology 5, 69±78.
BjoÈrklund, A., Lindvall, O., 1975. Dopamine in dendrites of substantia nigra neurons: suggestions for a role in dendritic terminals.
Brain Res. 83, 531±537.
Blanchard, B.A., Steindorf, A., Wang, S., Glick, S.D., 1993. Sex
di€erences in ethanol-induced dopamine release in nucleus accumbens and in ethanol consumption in rats. Alcohol 17, 968±973.
Bogdanski, D.F., Brodie, B.B., 1969. The e€ects of inorganic ions on
the storage and uptake of [3H]norepinephrine by rat heart slices.
J. Pharm. Exp. Ther. 165, 181±189.
Boja, J.W., Markham, L., Patel, A., Uhl, G., Kuhar, M.J., 1992a.
Expression of a single dopamine transporter cDNA can confer
two cocaine binding sites. NeuroReport 3, 247±248.
Boja, J.W., Mitchell, W.M., Patel, A., Kopajtic, T.A., Carroll, F.I.,
Lewin, A.H., Abraham, P., Kuhar, M.J., 1992b. High-anity
binding of [125I]RTI-55 to dopamine and serotonin transporters
in rat brain. Synapse 12, 27±36.
Bonanno, G., Raiteri, M., 1987. Coexistence of carriers for dopamine and GABA uptake on a same nerve terminal in the rat
brain. Br. J. Pharmacol. 91, 237±243.
Bonhomme, N., de Deurwaerdere, P., Le Moal, M., Spampinato, U.,
1995. Evidence for 5HT4 receptor subtype involvement in the
enhancement of striatal dopamine release induced by serotonin: a
microdialysis study in the halothane-anesthetized rat.
Neuropharmacology 34, 269±279.
Bonnet, J.J., Lemasson, M.H., Costentin, J., 1984. Simultaneous
evaluation by a double labelling method of drug-induced uptake
inhibition and release of dopamine in synaptosomal preparation
of rat striatum. Biochem. Pharmacol. 33, 2129±2135.
BoÈnisch, H., Graefe, K.H., Keller, B., 1983. Tetrodotoxin-sensitive
and resistant e€ects of veratridine on the noradrenergic neurone
of the rat vas deferens. Naumyn Schmiedeberg's Arch.
Pharmacol. 324, 264±270.
BoÈnisch, H., 1986. The role of co-transported sodium in the
e€ect of indirectly acting sympathomimetic amines. Naumyn
Schmiedeberg's Arch. Pharmacol. 332, 135±141.
Brown, L.M., Trent, R.D., Jones, T.W., Gonzales, R.A., Leslie,
V. Leviel / Neurochemistry International 38 (2001) 83±106
S.W., 1992. Alcohol inhibition of NMDA-stimulated catecholamine e‚ux in aging brain. Alcohol 9, 555±558.
Bunney, B.S., Aghajanian, G.K., Roth, R.H., 1973. Comparison of
e€ects of l-dopa, amphetamine and apomorphine on ®ring rate of
rat dopaminergic neurones. Nature 245, 123±125.
Butcher, S.P., Fairbrother, I.S., Kelly, J.S., Abuthnott, G.W., 1988.
Amphetamine induced dopamine release in the rat striatum: an in
vivo microdialysis study. J. Neurochem. 50, 346±355.
Buyukuysal, R.L., Mete, B., 1999. Anoxia-induced dopamine release
from rat striatal slices: involvement of reverse transport mechanism. J. Neurochem. 72, 1507±1515.
Calligaro, D.O., Eldefrawi, M.E., 1988. High anity stereospeci®c
binding of [3H] cocaine in striatum and its relationship to the
dopamine transporter. Membr. Biochem. 7, 87±106.
Carlsson, L., Graefe, K.H., Tredelenburg, U., 1987. Early intraneuronal mobilization and deamination of noradrenaline during global ischemia in the isolated perfused rat heart. Naunyn
Schmiedeberg's Arch. Pharmacol. 336, 508±518.
Castro, S.L., Sved, A.F., Zigmond, M.J., 1996. Increased neostriatal
tyrosine hydroxylation during stress: role of extracellular dopamine and excitatory amino acids. J. Neurochem. 66, 824±833.
Cass, W.A., Gerhardt, G.A., 1994. Direct in vivo evidence that D2
dopamine receptors can modulate dopamine uptake. Neurosci.
Lett. 176, 259±263.
Cass, W.A., Gerhart, G.A., Zhang, Z., Ovadia, A., Gash, D.M.,
1995. Increased dopamine clearence in the non lesioned striatum
of rhesus monkeys with unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) striatal lesions. Neurosci. Lett. 185, 52±
55.
Chan, J., Nirenberg, M.J., Peter, D., Liu, Y., Edwards, R.H., Pickel,
V.M., 1995. Localisation of the vesicular monoamine transporter2 in the dendrites of dopaminergic neurons: comparison of rat
substantia nigra and ventral tegmental area. Soc. Neurosci.
Abstr. 21, 373.
CheÂramy, A., Leviel, V., Glowinski, J., 1981. Dendritic release of
dopamine in the substantia nigra. Nature 289, 537±542.
Chetty, C.S., Cooper, A., McNeil, C., Rajanna, B., 1992. The e€ects
of cadmium in vitro on adenosine triphosphatase system and protection by thiol reagents in rat brain microsomes. Arch. Environ.
Contam. Toxicol. 22, 456±458.
Chien, J.B., Wallingford, R.A., Ewing, A.G., 1990. Estimation of
free dopamine in the cytoplasm of the giant dopamine cell of planorbis corneus by voltametry and capillary electrophoresis. J.
Neurochem. 54, 633±638.
Chiueh, C.C., Moore, K.E., 1975. d-amphetamine induced release of
newly synthesized and stored dopamine from the caudate nucleus
in vivo. J. Pharm. Exp. Therap. 192, 642.
Chubb, I.W., De Porter, W.P., De Schaepdryver, A.F., 1972.
Tyramine does not release noradrenaline from splenic nerves by
exocytosis. Naunyn Schmiedeberg's Arch. Pharmacol. 274, 281±
286.
Ciliax, B.J., Hersch, S.M., Levey, A.I., 1994. Immunocytochemical
localization of D1 and D2 receptors in rat brain. In: Niznik, H.B.
(Ed.), Dopamine Receptors and Transporters: Pharmacology,
Structure, and Function. Dekker, New York, pp. 383±399.
Ciliax, B.J., Heilman, C., Demchyshyn, L.L., Pristupa, Z.B., Ince,
E., Hersch, S.M., Niznik, H.B., Levey, A.I., 1995. The dopamine
transporter: immunochemical characterization and localization in
brain. J. Neurosci. 15, 1714±1723.
Clow, D.W., Jhamandas, K., 1989. Characterization of L-glutamate
action on the release of endogenous dopamine from the rat caudate putamen. J. Pharm. Exp. Therap. 248, 722±728.
Commissiong, J.W., Slimovitch, C., To€ano, G., 1990. Regulation of
the synthesis and metabolism of striatal dopamine after disruption of nerve conduction in the medial forebrain bundle. Br. J.
Pharmacol. 99, 741±749.
Cooper, J.R., Meyer, E.M., 1984. Possible mechanisms involved in
99
the release and modulation of release of neuroactive agents.
Neurochem. Int. 6, 419±433.
Cragg, S., Rice, M.E., Green®eld, S.A., 1997. Heterogeneity of electrically evoked dopamine release and reuptake in substantia
nigra, ventral tegmental area, and striatum. J. Neurophysiol. 77,
863±873.
Cragg, S.J., Holmes, C., Hawkey, C.R., Green®eld, S.A., 1998.
Dopamine is release spontaneously from developing midbrain
neurons in organotypic culture. Neuroscience 84, 325±330.
Crespi, D., Mennini, T., Gobbi, M., 1997. Carrier-dependent and
Ca(2+)-dependent 5-HT and dopamine release induced by
(+)amphetamine, 3,4-methylendioxymethamphetamine, p-chloroamphetamine and (+)-fen¯uramine. Br. J. Pharmacol. 121,
1735±1743.
Cuello, A.C., Iversen, L.L. 1978. In: Garattini, S., Pujol, J.F.,
Samanin, R., (Eds.) Interactions of Dopamine with Other
Neurotransmitters in the Rat Substantia Nigra: a Possible
Functional Role of Dendritic Dopamine. New York, pp. 127±
149.
Cuello, A.C., 1983. Nonclassical neuronal communications.
Federation Proc. 42, 2912±2922.
Daoust, M., Moore, N., Saligaut, C., Lhuintre, J.P., Chretien, P.,
Boismare, F., 1986. Striatal dopamine does not appear involved
in the voluntary intake of ethanol by rats. Alcohol 3, 15±17.
David, D.J., Zahniser, N.R., Ho€er, B.J., Gerhart, G.A., 1998. In
vivo electrochemical studies of dopamine clearance in subregions
of rat nucleus accumbens: di€erential properties of the core and
shell. Exp. Neurol. 153, 277±286.
Debler, E.A., Hashim, A., Lajtha, A., Sershen, H., 1988. Ascorbic
acid and striatal transport of [3H]1-methyl-4-phenylpyridine
(MPP+)and [3H]dopamine. Life Sci. 42, 2553±2559.
Debler, E.A., Sershen, H., Hashim, A., Lajtha, A., Reith, M.E.A.,
1991. Carrier mediated e‚ux of [3H]dopamine and [3H]1-methyl4-phenylpyridine: e€ect of ascorbic acid. Synapse 7, 99±105.
de Deurwaerdere, P., Bonhomme, N., Le Moal, M., Spampinato, U.,
1995. d-Fen¯uramine increases striatal extracellular dopamine in
vivo independently of serotoninergic terminals or dopamine or
dopamine uptake sites. J. Neurochem. 65, 1100±1108.
Del Castillo, J., Katz, B., 1956. Biophysical aspects of neuromuscular
transmission. Prog. Biophys. Biophys. Chem. 6, 121±170.
Descarries, L., Beaudet, A., Watkins, K.C., 1975. Serotonin nerve
terminals in adult rat neocortex. Brain Res. 100, 563±588.
Descarries, L., Bosler, O., Berthelet, F., Des Rosiers, M.H., 1980.
Dopaminergic nerve endings visualised by high resolution autoradiography in adult rat neostriatum. Nature 284, 620±622.
Descarries, L., Watkins, K.C., Garcia, S., Bosler, O., Doucet, G.,
1996. Dual character, asynaptic and synaptic, of the dopamine innervation in adult rat neostriatum: a quantitative autoradiographic and immunocytochemical anlysis. J. Comp. Neurol. 375,
167±186.
Desce, J.M., Godeheu, G., Galli, T., Artaud, F., Cheramy, A.,
Glowinski, J., 1992. L-glutamate evoked release of dopamine
from synaptosomes of the rat striatum: involvement of AMPA
and N-methyl-D-aspartate receptors. Neuroscience 47, 333±339.
Desce, J.M., Godeheu, G., Galli, T., Glowinski, J., Cheramy, A.,
1993. Opposite presynaptic regulations by glutamate through
NMDA receptors of dopamine synthesis and release in rat striatal
synaptosomes. Brain Res. 640, 205±214.
Dickinson, S.D., Sabeti, J., Larson, G.A., Giardina, K., Rubinstein,
M., Kelly, M.A., Grandy, D.K., Low, M.J., Gerhart, G.A.,
Zahniser, N.R., 1999. Dopamine D2 receptor de®cient mice exhibit decreased dopamine transporter function but no changes in
dopamine release in dorsal striatum. J. Neurochem. 72, 148±156.
di Giovanni, G., de Deurwaerdere, P., Di Mascio, M., Di Matteo,
V., Esposito, E., Spampinato, U., 1999. Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal
100
V. Leviel / Neurochemistry International 38 (2001) 83±106
dopaminergic function: a combined in vivo electrophysiological
and microdialysis study. Neuroscience 91, 587±597.
Diliberto, P.A., Garret, L.J., James, M.K., Cubeddu, L.X., 1987.
Ionic mechanism of dopaminergic and muscarinic auto and heteroreceptot activation in superfused striatal slices: role of extracellular chloride. J. Pharm. Exp. Therap. 240, 795±801.
Diliberto, P.A., Je€s, R.A., Cubeddu, L.X., 1989. E€ects of low
extracellular chloride on dopamine release and the dopamine
transporter. J. Pharm. Exp. Therap. 248, 644±653.
Dismukes, K., 1977. New look at the aminergic nervous system.
Nature 269, 557±558.
Disshon, K.A., Boja, J.W., Dluzen, D.E., 1998. Inhibition of striatal
dopamine transporter activity by 17b-estradiol. Eur. J. Pharm.
345, 207±211.
Donnan, G.A., Kaczmarczyk, S.J., Paxinos, G., Chilco, P.J.,
Kalnins, R.M., Woodhouse, D.G., Mendelsohn, F.A., 1991.
Distribution of catecholamine uptake sites in human brain as
determined by quantitative [3H]mazindol autoradiography. J.
Comp. Neurol. 304, 419±434.
Du, X.J., Woodcock, E.A., Little, P.J., Esler, M.D., Dart, A.M.,
1998. Protection of neuronal uptake-1 inhibitors in ischemic and
anoxic hearts by norepinephrine-dependent and -independent
mechanisms. J. Cardiovasc. Pharmacol. 32, 621±628.
Earl, C.D., Sautter, J., Xie, J., Kruk, Z.L., Kupsch, A., Oertel,
W.H., 1998. Pharmacological characterization of dopamine over¯ow in the striatum of the normal and MPTP-treated common
marmoset, studied in vivo using fast cyclic voltametry, nomifensine and sulpiride. J. Neurosci. Meth. 85, 201±209.
Elghozi, J.L., Le Quan-Bui, K.H., Devynck, M.A., Meyer, P., 1983.
Nomifensine antagonizes the ouabain-induced increase in dopamine metabolites in cerebrospinal ¯uid of the rat. Eur. J.
Pharmacol. 90, 279±282.
Elverfors, A., Nissbrandt, H., 1991. Reserpine-insensitive dopamine
release in the substantia nigra. Brain Res. 557, 5±12.
Erecinska, M., Pastuszko, A., Wilson, D.F., Nelson, D., 1987.
Ammonia induced release of neurotransmoitters from rat brain
synaptosomes: di€erences between the e€ects on amines and
amino acids. J. Neurochem. 49, 1258±1265.
Espino, A., Cutillas, B., Tortosa, A., Ferrer, I., Bartrons, R.,
Ambrosio, S., 1995. Chronic e€ects of single intrastriatal injections of 6-hydroxydopamine or 1-methyl-4-phenylpyridinium studied by microdialysis in freely moving rats. Brain Res. 695, 151±
157.
Fairbrother, I.S., Arbuthnott, G.W., Kelly, J.S., Butcher, S.P., 1990.
In vivo mechanisms underlying dopamine release from rat nigrostriatal terminals. Part II: Studies using potassium and tyramine.
J. Neurochem. 54, 1844±1851.
Ferger, B., Eberhardt, O., Teismann, P., de Groote, C., Schultz, J.B.,
1999. Malonate-induced generation of reactive oxygen species in
rat striatum depends on dopamine release but not on NMDA
receptor activation. J. Neurochem. 73, 1329±1332.
Fillenz, M., 1993. Short-term control of transmitter synthesis in central catecholaminergic neurones. Prog. Biophys. Molec. Biol. 60,
29±46.
Filloux, F., Townsend, J.J., 1993. Pre and post synaptic neurotoxic
e€ects of dopamine demonstrated by intrastriatal injection. Exp.
Neurol. 119, 79±88.
Fischer, J.F., Cho, A.K., 1976. Properties of dopamine e‚ux from
rat striatal tissue caused by amphetamine and parahydroxyamphetamine. Proc. West. Pharmacol. Soc. 19, 179±182.
Fischer, J.F., Cho, A.K., 1979. Chemical release of dopamine from
striatal homogenate: evidence for an exchange di€usion model. J.
Pharm. Exp. Therap. 208, 203±209.
Fung, Y.K., Uretsky, N.J., 1982. The importance of calcium in the
amphetamine-induced stimulation of dopamine synthesis in
mouse striata in vivo. J. Pharm. Exp. Therap. 223, 477±482.
Fuxe, K., Ungerstedt, U., 1968. Histochemical studies on the e€ect
of (+)-amphetamine, drugs of the imipramine group and tryptamine on central catecholamine and 5-hydroxytryptamine neurons
after intraventricular injection of catecholamines and 5-hydroxytryptamine. Eur. J. Pharm. 1, 135±144.
Fuxe, K., Agnati, L.F., 1991. Two principal modes of electrochemical communication in the brain: volume versus wiring transmission. In: Fuxe, K., Agnati, L.F. (Eds.), Volume Transmission
in the Brain. Novel Mechanism for Neural Transmission,
Advances in Neuroscience, vol. 1. Raven Press, New York, pp.
1±9.
Garris, P.A., Ciolkowski, E.L., Pastore, P., Wightman, R.M., 1994.
E‚ux of dopamine from the synaptic cleft in the nucleus accumbens of the rat brain. J. Neurosci. 14, 6084±6093.
Garris, P.A., Walker, Q.D., Wightman, R.M., 1997. Dopamine
release and uptake rates both decrease in the partially denervated
striatum in proportion to the loss of dopamine terminals. Brain
Res. 753, 225±234.
Ge€en, L.B., Jessell, T.M., Cuello, A.C., Iversen, L.L., 1976. Release
of DA from dendrites in rat SN. Nature 260, 258±260.
Gerhart, G.A., Cass, W.A., Hudson, J., Henson, M., Zhang, Z.,
Ovadia, A., Ho€er, B.J., Gash, D.M., 1996. In vivo electrochemical studies of dopamine over¯ow and clearance in the striatum of
normal and MPTP-treated rhesus monkeys. J. Neurochem. 66,
579±587.
Giorguie€, M.F., Kemel, M.L., Glowinski, J., 1977. Presynaptic
e€ect of L-glutamic acid on the release of dopamine in rat striatal
slices. Neurosci. Lett. 6, 73±77.
Giros, B., Caron, M.G., 1993. Molecular characterization of the
dopamine transporter. Trends Pharmac. Sci. 14, 43±49.
Giros, B., Jaber, M., Jones, S.R., Wightman, R.M., Caron, M.G.,
1996. Hyperlocomotion and indi€erence to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379,
606±612.
Globus, M.Y.T., Busto, R., Dietrich, W.D., Martinez, E., Valdes, I.,
Ginsberg, M.D., 1988. Intra-ischemic extracellular release of
dopamine and glutamate is associated with striatal vulnerability
to ischemia. Neurosci. Lett. 91, 36±40.
Glowinski, J., Kopin, I., Axelrod, J., 1965. Metabolism of
[3H]norepinephrine in the rat brain. J. Neurochem. 12, 25±30.
Glowinski, J., Axelrod, J., Iversen, L.L., 1966. Regional studies of
catecholamines in the rat brain. Part IV: e€ects of drugs on the
disposition and metabolism of 3H-norepinephrine and 3H-dopamine. J. Pharm. Exp. Ther. 153, 30±41.
Glowinski, J., 1975. Properties and functions of intraneuronal monoamine compartments in central aminergic neurons. In: Iversen,
L.L., Iversen, S.D., Snyder, S.H. (Eds.), Handbook of
Psychopharmacology. Plenum Press, New York, pp. 139±167.
Gobert, A., Guibert, B., Lenoir, V., Kerdelhue, B., Leviel, V., 1992.
GnRH-associated peptide (GAP) is present in the rat striatum
and a€ects the synthesis and release of dopamine. J. Neurosci.
Res. 31, 354±359.
Gotow, T., Miyaguchi, K., Hashimoto, P.H., 1991. Cytoplasmic
architecture of the axon terminal: ®lamentous strands speci®cally
associated with synaptic vesicles. Neuroscience 40, 587±598.
Grace, A.A., 1991. Phasic versus tonic release and the modulation of
dopamine system responsitivity: a hypothesis for etiology of
schizophrenia. Neuroscience 41, 1±24.
Gracz, L.M., Madras, B.K., 1995. [3H]WIN 35, 428 ([3H]CFT) binds
to multiple charge-states of the solubilized dopamine transporter
in primate striatum. J. Pharm. Exp. Therap. 273, 1224±1234.
Green®eld, S.A., 1985. The signi®cance of dendritic release of transmitter and protein in the substantia nigra. Neurochem. Int. 7,
887±890.
Groppetti, A., Algeri, S., Cattabeni, F., Digiulio, A.M., Galli, C.L.,
Ponzio, F., Spano, P.F., 1977. Changes in speci®c activity of
dopamine metabolites as evidence of a multiple compartmentation of dopamine in striatal neurons. J. Neurochem. 28, 193±197.
V. Leviel / Neurochemistry International 38 (2001) 83±106
Groves, P.M., Wilson, C.J., Young, S.J., Rebec, G.V., 1975. Self inhibition by dopaminergic neurons. Science 190, 522±529.
Groves, P.M., Linder, J.C., 1983. Dendro-dendritic synapses in substantia nigra: descriptions based on analysis of serial sections.
Exp. Brain Res. 49, 209±217.
Groves, P.M., 1983. A theory of the functional organization of the
neostriatum and the neostriatal control of voluntary movement.
Brain Res. Rev. 5, 109±132.
Haass, M., Hock, M., Richardt, G., SchoÈmig, A., 1989.
Neuropeptide Y di€erentiates between exocytotic and nonexocytotic noradrenaline release in guinea-pig heart. Naunyn
Schmiedeberg's Arch. Pharmacol. 340, 509±515.
Hantraye, P., Khalili-Varasteh, M., Peschanski, M., Maziere, M.,
1990. MPTP: meÂcanismes biologiques et limites d'un modeÁle expeÂrimental de la maladie de Parkinson. Circul. et meÂtab. du
Cerveau. 7, 15±19.
Hastings, T.G., Lewis, D.A., Zigmond, M.J., 1996. Role of oxidation
in the neurotoxic e€ects of intrastriatal dopamine injections.
Proc. Natl. Acad. Sci. USA 93, 1956±1961.
HaÈusser, M., Stuart, G., Racca, C., Sakmann, B., 1995. Axonal initiation and active dendritic propagation of action potentials in
substantia nigra neurons. Neuron 15, 637±647.
Heeringa, M.J., Abercrombie, E.D., 1995. Biochemistry of somatodendritic dopamine release in substantia nigra: an in vivo comparison with striatal dopamine release. J. Neurochem. 65, 192±
200.
Hefti, F., Melamed, E., Wurtman, R.J., 1980. Partial lesion of the
dopamine nigrostriatal system in rat brain: biochemical characterization. Brain Res. 195, 123±137.
Henry, J.P., SagneÂ, C., Bedet, C., Gasnier, B., 1998. The vesicular
monoamine transporter: from chroman granule to brain.
Neurochem. Int. 32, 227±246.
Herdon, H., Srupish, J., Nahorski, S.R., 1985. Di€erences between
the release of radiolabelled and endogenous dopamine from
superfused rat brain slices: e€ects of depolarizing stimuli, amphetamine and synthesis inhibition. Brain Res. 348, 309±320.
Hersch, S.M., Yi, H., Heilman, C.J., Edwards, R.H., Levey, A.I.,
1997. Subcellular localization and molecular topology of the
dopamine transporter in the striatum and substantia nigra. J.
Comp. Neurol. 388, 211±227.
Hollerman, J.R., Grace, A.A., 1990. The e€ects of dopamine-depleting brain lesions on the electrophysiological activity of rat substantia nigra dopamine neurons. Brain Res. 533, 203±212.
Horn, A.S., 1973. Structure activity relationships for inhibition of
catecholamine uptake into synaptosomes from NE and DA neurons in rat brain. Brit. J. Pharmacol. 47, 332±338.
Hoyt, K.R., Reynolds, I.J., Hasting, T.G., 1997. Mechanisms of
dopamine induced cell death in cultured rat forebrain neurons: interactions with and di€erences from glutamate-induced cell death.
Exp. Neurol. 143, 269±281.
Hubbard, J.I., 1970. Mechanism of transmitter release. Prog.
Biophys. 21, 33±124.
Hunt, P., Kennengiesser, M.H., Raynaud, J.P., 1974. Nomifensine: a
new potent inhibitor of dopamine uptake into synaptosomes
from rat brain corpus striatum. J. Pharm. Pharmacol. 26, 370±
371.
Hunt, P., Raynaud, J.P., Leven, M., Schacht, U., 1979. Dopamine
uptake inhibitors and releasing agents di€erentiated by the use of
synaptosomes and ®eld-stimulated brain slices in vitro. Biochem.
Pharmacol. 28, 2011±2016.
Hurd, Y.L., Ungerstedt, U., 1989a. In vivo neurochemical pro®le of
dopamine uptake inhibitors and releasers in rat caudate-putamen.
Eur. J. Pharmacol. 166, 251±260.
Hurd, Y.L., Ungerstedt, U., 1989b. Ca2+ dependence of the amphetamine nomifensine and Lu19005 e€ect on in vivo dopamine
transmission. Eur. J. Pharmacol. 166, 261±269.
Hurd, Y.L., Ungerstedt, U., 1989c. In¯uence of a carrier transport
101
process on the in vivo release and metabolism of dopamine:
dependence on extracellulat Na+. Life Sci. 45, 283±293.
Ikeda, M., Fahien, L.A., Udenfriend, S., 1966. A kinetic study of
bovine adrenal tyrosine hydroxylase. J. Biol. Chem. 241, 4452±
4456.
Inoue, H., Ochi, M., Shibata, S., Watanabe, S., 1995. E€ects of
transcient forebrain ischemia on long term enhancement of dopamine release in rat striatal slices. Brain Res. 671, 95±99.
Iravani, M.M., Kruk, Z.L., 1996. Real-time e€ects of N-methyl-Daspartic acid on dopamine release in slices of rat caudate putamen: a study using fast cyclic voltametry. J. Neurochem. 66,
1076±1085.
Iwasaki, Y., Ikeda, K., Shiojima, T., Kinoshita, M., 1992. Increased
plasma concentrations of aspartate, glutamate and glycine in
Parkinson's disease. Neurosci. Lett. 145, 175±177.
Jacocks, H.M., Cox, B.M., 1992. Serotonin-stimulated release of
[3H]dopamine via reversal of the dopamine transporter in rat
striatum and nucleus accumbens: a comparison with release elicited by potassium, N-methyl-D-aspartic acid, glutamic acid and
D-amphetamine. J. Pharm. Exp. Therap. 262, 356±364.
Johnson, R.G., 1988. Accumulation of biological amines into chroman granules; a model for hormone and neurotransmitter
transport. Physiol. Rev. 68, 232±307.
Kahn, R.A., Weinberger, J., Brannan, T., Prikhojan, A., Reich,
D.L., 1995. Nitric oxyde modulates dopamine release during global temporary cerebral ischemia. Anesth. Analg. 80, 1116±1121.
Kalivas, P.W., Du€y, P., 1991. A comparison of axonal and somatodendritic dopamine release using in vivo dialysis. J. Neurochem.
56, 961±967.
Kamal, L.A., Arbilla, S., Langer, S.Z., 1981. Presynaptic modulation
of the release of dopamine from the rabbit caudate nucleus:
di€erences between electrical stimulation, amphetamine and tyramine. J. Pharm. Exp. Therap. 216, 592±598.
Kamal, L.A., Arbilla, S., Galzin, A.M., Langer, S.Z., 1983.
Amphetamine inhibits the electrically evoked release of
[3H]dopamine from slices of the rabbit caudate. J. Pharm. Exp.
Therap. 227, 446±458.
Kapatos, G., Zigmond, M., 1977. Dopamine biosynthesis from Ltyrosine and L-phenylalanine in rat brain synaptosomes: preferential use of newly accumulated precursors. J. Neurochem. 28,
1109±1119.
Kebabian, J.W., Saavedra, J.M., 1976. Dopamine sensitive adenylate
cyclase occurs in a region of substantia nigra containing dopaminergic dendrites. Science 193, 683±685.
Keefe, K.A., Zigmond, M.J., Abercrombie, E.D., 1992. Extracellular
dopamine in striatum: in¯uence of nerve impulse activity in medial forebrain bundle and local glutamatergic input. Neuroscience
47, 325±332.
Keefe, K.A., Zigmond, M.J., Abercrombie, E.D., 1993. In vivo regulation of extracellular dopamine in the neostriatum: in¯uence of
impulse activity and local excitatory amino acids. J. Neural.
Trans. 91, 223±240.
Kim, K.W., Kim, D.C., Kim, H.Y., Eun, Y.A., Kim, H.I., Cho,
K.P., 1995. Ca2+-dependent and -independent mechanisms of
ischaemia-evoked release of [3H]-dopamine from rat striatal slices.
Clin. Exp. Pharmac. Physiol. 22, 301±302.
Kitayama, S., Dohi, T., Uhl, G.R., 1994. Phorbolesters alters functions of the expressed dopamine transporter. Eur. J. Pharmacol.
268, 115±119.
Kogure, K., Scheinberg, P., Matsumoto, A., Busto, R., Reinmuth,
O.M., 1975. Catecholamines in experimental brain ischemia.
Arch. Neurol. 32, 21±24.
Kopin, I., Breese, G.R., Krauss, K.R., Weise, V.K., 1968. Selective
release of newly synthesized norepinephrine from the cat spleen
during sympathetic nerve stimulation. J. Pharm. Exp. Therap.
161, 271±278.
Kuczenski, R., 1975. E€ects of catecholamine releasing agents on
102
V. Leviel / Neurochemistry International 38 (2001) 83±106
synaptosomal dopamine biosynthesis: multiple pools of dopamine
or multiple forms of tyrosine hydroxylase. Neuropharmacology
14, 1±10.
Kuczenski, R., Segal, D.S., Manley, L.D., 1990. Apomorphine does
not alter amphetamine induced dopamine release measured in
striatal dialysates. J. Neurochem. 54, 1492±1499.
Kuhr, W.G., Ewing, A.G., Near, J.A., Wightman, R.M., 1985.
Amphetamine attenuates the stimulated release of dopamine in
vivo. J. Pharm. Exp. Therap. 232, 388±394.
Kula, N.S., Baldessarini, R.J., 1991. Lack of increase in dopamine
transporter binding or function in rat b rain tissue after treatment
with
blockers
of
neuronal
uptake
of
dopamine.
Neuropharmacology 30, 89±92.
L'hirondel, M., CheÂramy, A., Godeheu, G., Glowinsky, J., 1995.
E€ects of arachidonic acid on dopamine synthesis, spontaneous
release, and uptake in striatal synaptosomes from the rat. J.
Neurochem. 64, 1406±1409.
Langer, S.Z., Arbilla, S., 1984. The amphetamine paradox in dopaminergic neurotransmission. Trends Pharmacol. Sci. 5, 387±390.
Lavyne, M.H., Moskowitz, M.A., Larin, F., Zervas, N.T., Wurtman,
R.J., 1975. Brain H-3-catecholamine metabolism in experimental
cerebral ischemia. Neurology 25, 483±485.
Levi, G., Rusca, G., Raiteri, M., 1976. Diaminobutyric acid: a tool
for dicriminating between carrier-mediated and non carriermediated release of GABA from synaptosomes. Neurochem. Res.
1, 581±590.
Levi, G., Raiteri, M., 1993. Carrier-mediated release of neurotransmitters. Trends Neurosci. 16, 415±419.
Leviel, V., Cheramy, A., Glowinski, J., 1979. Role of the dendritic
release of dopamine in the reciprocal control of the two nigrostriatal dopaminergic pathways. Nature 280, 237±239.
Leviel, V., Guibert, B., 1987. Involvement of intraterminal dopamine
compartments in the amine release in the cat striatum. Neurosci.
Lett. 76, 197±202.
Leviel, V., Gobert, A., Guibert, B., 1989. Direct observation of
dopamine compartmentation in striatal nerve terminal by in vivo
measurement of the speci®c activity of released dopamine. Brain
Res. 499, 205±213.
Leviel, V., Gobert, A., Guibert, B., 1990. The glutamate-mediated
release of dopamine in the rat striatum: further characterization
of the dual excitatory-inhibitory function. Neuroscience 39, 305±
312.
Leviel, V., Gobert, A., Guibert, B., 1991. Speci®cally evoked release
of newly synthesized or stored dopamine by di€erent treatments.
In: Bernardi, G., Carpenter, M.B., Di Chiara, G., Mirelli, M.,
Stanzione, P. (Eds.), The Basal Ganglia III. Plenum, New York,
London, pp. 407±416.
Leviel, V., Olivier, V., Guibert, B., 1994. The role of calcium ions in
dopamine synthesis and dopamine release. In: Percheron, G.,
McKensie, J.S., Feger, J. (Eds.), The Basal Ganglia IV. Plenum,
New York, London, pp. 403±409.
Liang, N.Y., Rutledge, C., 1982. Evidence for carrier-mediated e‚ux
of dopamine from corpus striatum. Biochem. Pharmac. 31, 2479±
2484.
Lin, A.M., Chai, C.Y., 1995. Dynamic analysis of ethanol e€ects on
NMDA-evoked dopamine over¯ow in rat striatum. Brain Res.
696, 15±20.
Lin, A.M., Chai, C.Y., 1998. Role of dopamine uptake in NMDA
modulated K(+)-evoked dopamine over¯ow in rat striatum: an
in vivo electrochemical study. Neurosci. Res. 31, 171±177.
Llinas, R., Green®eld, S.A., Jahnsen, H., 1984. Electrophysiology of
pars compacta cells in the in vitro substantia nigra Ð a possible
mechanism for dendritic release. Brain Res. 294, 127±132.
Llinas, R., 1988. The intrinsic electrophysiological properties of
mammalian neurons: insight into central nervous function.
Science 242, 1654±1664.
Lonart, G., Johnson, K.M., 1994. Inhibitory e€ects of nitric oxide
on the uptake of [3H]dopamine and [3H]glutamate by striatal
synaptosomes. J. Neurochem. 63, 2108±2117.
Lonart, G., Zigmond, M.J., 1990. N-Methyl-D-aspartate evokes
dopamine release from rat striatum via dopamine uptake system.
Soc. Neurosci. Abs. 16, 552.
Lonart, G., Zigmond, M.J., 1991. High glutamate concentrations
evoke Ca++ independent dopamine release from striatal slices, a
possible role of reverse dopamine transport. J. Pharm. Exp.
Therap. 256, 1132±1138.
Lucas, G., de Deurwaerdere, P., Caccia, S., Spampinato, U., 2000.
The e€ect of serotoninergic agents on haloperidol-induced striatal
dopamine release in vivo: opposite role of 5-HT(2A) and 5HT(2C) receptor subtypes and signi®cance of the haloperidol
dose used. Neuropharmacology 39, 1053±1063.
Luthman, J., Friedemann, M.N., Ho€er, B.J., Gerhardt, G.A., 1993.
In vivo electrochemical measurements of exogenous dopamine
clearance in normal and neonatal 6-hydroxydopamine treated rat
striatum. Exp. Neurol. 122, 273±282.
Lynch, M.A., Littleton, J.M., 1983. Possible association of alcohol
tolerance with increased synaptic Ca2+ sensitivity. Nature 303,
175±176.
Maker, H.S., Weiss, C., Brannan, T.S., 1986. Amine mediated toxicity. The e€ects of dopamine, norepinephrine, 5-hydroxytryptamine, 6-hydroxydopamine, ascorbate, glutathione and peroxide
on the in vivo activities of creatine and adenylate kinases in the
brain of the rat. Neuropharmacology 25, 25±32.
Maley, B.E., Engle, M.G., Humphreys, S., Vascik, D.A., Howes,
K.A., Newton, B.W., Elde, R.P., 1990. Monoamine synaptic
structure and localization in the central nervous system. J. Electr.
Microsc. Tech. 15, 20±33.
Maloteaux, J.M., Vanisberg, M.A., Laterre, C., Javoy-Agid, F.,
Agid, Y., Laduron, P.M., 1988. [3H]GBR12935 binding to dopamine uptake sites: subcellular localization and reduction in parkinson's disease and prograssive supranuclear palsy. Eur. J.
Pharmacol. 156, 331±340.
Marie, C., Mossiat, C., Beley, A., Bralet, J., 1992. Alpha-methylpara-tyrosine pretreatment protect from striatal neuronal death
induced by four-vessel occlusion in the rat. Neurochem. Res. 17,
961±965.
Matsumoto, M., Togashi, H., Mori, K., Ueno, K., Miyamoto, A.,
Yoshioka, M., 1999. Characterization of endogenous serotoninmediated regulation of dopamine release in the rat prefrontal cortex. Eur. J. Pharmacol. 383, 39±48.
Maurin, Y., Banzeres, B., Menetrey, A., Mailly, P., Deniau, J.M.,
1999. Three dimensional distribution of nigrostriatal neurons in
the rat: relation to the topography of striatonigral projections.
Neuroscience 91, 891±909.
Maus, M., Premont, J., Glowinski, J., 1990. In vitro e€ects of 17 boestradiol on the sensitivity of receptors coupled to adenylate
cyclase on striatal neurons in primary culture. In: Steroids and
Neuronal Activity, CIBA Foundation Symposium 153. Wiley,
New York, pp. 145±153.
May, L.J., Wightman, R.M., 1989. E€ects of D2 antagonists on frequency dependent stimulated dopamine over¯ow in nucleus
accumbens and caudate putamen. J. Neurochem. 53, 898±906.
McMahon, H.T., Barrie, A.P., Lowe, M., Nicholls, D.G., 1989.
Glutamate release from guinea-pig synaptosomes: stimulation by
reuptake-induced depolarization. J. Neurochem. 53, 71±79.
McMillen, B.A., German, D.C., Shore, P.A., 1980. Functional and
pharmacological signi®cance of brain dopamine and norepinephrine storage pools. Biochem. Pharmacol. 29, 3045±3050.
Meiergerd, S.M., Patterson, T.P., Schenk, J.O., 1993. D2 receptors
may modulate the function of the striatal transporter for dopamine kinetic evidence from studies in vitro and in vivo. J.
Neurochem. 61, 764±767.
Mennicken, F., Savasta, M., Peretti, R.R., Feuerstein, C., 1992.
V. Leviel / Neurochemistry International 38 (2001) 83±106
Autoradiographic localization of dopamine uptake sites in the rat
brain with [3H]-GBR12935. J. Neural. Trans. 87, 1±14.
Meshul, C.K., Emre, N., Nakamura, C.M., Allen, C., Donohue,
M.K., Buckman, J.F., 1999. Time dependent changes in striatal
glutamate synapses following a 6-hydroxydopamine lesion.
Neuroscience 88, 1±16.
Michael, A.C., Ikeda, M., Justice, J.B., 1987. Mechanisms contributing to the recovery of striatal releasable dopamine following
MFB stimulation. Brain Res. 421, 325±335.
Miller, H.H., Shore, P.A., Clarke, D.E., 1980. In vivo monoamine
oxydase inhibition by d-amphetamine. Biochem. Pharmacol. 29,
1347±1354.
Miller, H.H., Shore, P.A., 1982. E€ects of amphetamine and amfonelic acid on the disposition of striatal newly synthesyzed dopamine. Eur. J. Parmacol. 78, 33±44.
Milusheva, E.A., Doda, M., Pasztor, E., Lajtha, A., Sershen, H.,
Vizi, E.S., 1992. Regulatory interactions among axon terminal
a€ecting the release of di€erent transmitters from rat striatal
slices under hypoxic and hypoglycemic conditions. J. Neurochem.
59, 946±952.
Milusheva, E.A., Doda, M., Baranyi, M., Vizi, E.S., 1996. E€ect of
hypoxia and glucose deprivation on ATP level, adenylate energy
charge and [Ca2+]-dependent and independent release of
[3H]dopamine in rat striatal slices. Neurochem. Int. 28, 501±507.
Mirenowicz, J., Schultz, W., 1996. Preferential activation of midbrain
dopamine neurons by appetitive rather than aversive stimuli.
Nature 379, 449±451.
Moghadam, B., Gruen, R.J., Roth, R.H., Bunney, B.S., Adams,
R.N., 1990. E€ect of L-glutamate on the release of striatal dopamine: in vivo dialysis and electrochemical studies. Brain Res. 518,
55±60.
Nagatsu, T., Levitt, M., Udenfriend, S., 1964. Tyrosine hydroxylase:
the initial step in norepinephrine biosynthesis. J. Biol. Chem. 239,
2910±2917.
Nash, J.F., Brodkin, J., 1991. Microdialysis studies on 3,4-methylenedioxymethamphetamine induced dopamine release: e€ect of
dopamine uptake inhibitors. J. Pharm. Exp. Therap. 259, 820±
825.
Nemeth, G., Cintra, A., Herb, J.M., Ding, A., Goldstein, M.,
Agnati, L.F., Hoyer, S., Fuxe, K., 1991. Changes in striatal dopamine neurohistochemistry and biochemistry after incomplete
transcient cerebral ischemia in the rat. Exp. Brain Res. 86, 545±
554.
Nicolaysen, L.C., Justice Jr., J.B., 1988. E€ects of cocaine on release
and uptake of dopamine in vivo: di€erentiation by mathematical
modeling. Pharmacol. Biochem. and Behav. 31, 327±335.
Niddam, R., Arbilla, S., Scatton, B., Dennis, T., Langer, S.Z., 1985.
Amphetamine induced release of endogenous dopamine in vitro is
not reduced following pretreatment with reserpine. Naumyn
Schmiedeberg's Arch. Pharmacol. 329, 123±127.
Nieoullon, A., Cheramy, A., Glowinski, J., 1977. Release of DA in
vivo from cat SN. Nature 266, 375±377.
Nirenberg, M.J., Vaughan, R.A., Uhl, G.R., Kuhar, M.J., Pickel,
V.M., 1996. The dopamine transporter is localized to dendritic
and axonal plasma membranes of nigrostriatal dopaminergic
neurons. J. Neurosci. 16, 436±447.
Nissbrandt, H., Pileblad, E., Carlsson, A., 1985. Evidence for DA
release and metabolism beyond the control of nerve impulses and
DA receptors in rat substantia nigra. J. Pharm. Pharmacol. 37,
884±889.
Ng, N.K., Lee, H.S., Wong, P.T., 1999. Regulation of striatal dopamine release through 5-HT1 and 5-HT2 receptors. J. Neurosci.
Res. 55, 600±607.
Nowycky, M.C., Roth, R.H., 1978. Dopaminergic neurons: role of
presynaptic receptors in the regulation of transmitter biosynthesis.
Prog. Neuro-Psychopharmac. 2, 139±158.
Nurse, B., Russel, V.A., Taljaard, J.J., 1988. Characterization of the
103
e€ects of serotonin on the release of [3H]dopamine from rat
nucleus accumbens and striatal slices. Neurochem. Res. 13, 403±
407.
Oh, J.D., Russel, D.S., Vaughan, C.L., Chase, T.N., 1998. Enhanced
tyrosine phosphorylation of striatal NMDA receptor subunits:
e€ect of dopaminergic denervation and L-DOPA administration.
Brain Res. 813, 150±159.
Okada, M., Mine, K., Fujiwara, M., 1990. The Na+ d ependent
release of endogenous dopamine and noradranaline from rat
brain synaptosomes. J. Pharm. Exp. Therap. 252, 1283±1288.
Ole®rowicz, T.M., Ewing, A.G., 1990. Dopamine concentration in
the cytoplasmic compartment of single neurons determined by
capillary electrophoresis. J. Neurosci. Methods 34, 11±15.
Olivier, V., Guibert, B., Leviel, V., 1995. Direct in vivo comparison
of two mechanisms releasing dopamine in the rat striatum. Brain
Res. 695, 1±9.
Olivier, V., Gobert, A., Guibert, B., Leviel, V., 1999. The in vivo
modulation of dopamine synthesis by calcium ions: in¯uences on
the calcium independent release. Neurochem. Int. 35, 431±438.
Ooboshi, H., Sadoshima, S., Yao, H., Nakahara, T., Uchimura, H.,
Fujishima, M., 1992. Inhibition of ischemia-induced dopamine
release by omega-conotoxin, a calcium channel blocker, in the
striatum of spontaneously hypertensive rats: in vivo brain dialysis
study. J. Neurochem. 58, 298±303.
Parsons, L.H., Schad, C.A., Justice Jr., J.B., 1993. Co-administration
of the D2 antagonist pimozide inhibits up-regulation of dopamine
release and uptake induced by repeated cocaine. J. Neurochem.
60, 376±379.
Parker, E.M., Cubeddu, L.X., 1986a. E€ects of d-amphetamine and
dopamine synthesis inhibitors on dopamine and acetylcholine
neurotransmission in the striatum. I Release in the absence of
vesicular transmitter stores. J. Pharm. Exp. Therap. 237, 179±192.
Parker, E.M., Cubeddu, L.X., 1986b. E€ects of d-amphetamine and
dopamine synthesis inhibitors on dopamine and acetylcholine
neurotransmission in the striatum. II Release in the presence of
vesicular transmitter stores. J. Pharm. Exp. Therap. 237, 193±203.
Parker, E.M., Cubeddu, L.X., 1988. Comparative e€ects of amphetamine, phenylethylamine and related drugs on dopamine e‚ux,
dopamine uptake and mazindol binding. J. Pharm. Exp. Therap.
245, 199±210.
Pasqualini, C., Guibert, B., Leviel, V., 1993. Short-term inhibitory
e€ect of estradiol on tyrosine hydroxylase activity in tuberoinfundibular dopaminergic neurons in vitro. J. Neurochem. 60, 1707±
1713.
Pasqualini, C., Guibert, B., Frain, O., Leviel, V., 1994. Evidence for
protein kinase C involvement in the short term activation by prolactin of tyrosine hydroxylase in tuberoinfundibular dopaminergic
neurons. J. Neurochem. 62, 967±977.
Pasqualini, C., Olivier, V., Guibert, B., Frain, O., Leviel, V., 1995.
Acute stimulatory e€ect of estradiol on striatal dopamine synthesis. J. Neurochem. 65, 1651±1657.
Pastuszko, A., Wilson, D.F., Erecinska, M., 1982. Neurotransmitter
metabolism in rat brain synaptosomes: e€ect of anoxia and pH.
J. Neurochem. 38, 1657±1667.
Paton, D.M., 1973a. Evidence for a carrier-mediated e‚ux of noradrenaline from the axoplasm of adrenergic nerves in rabbit atria.
J. Pharm. Pharmac. 25, 265±267.
Paton, D.M., 1973b. Mechanism of e‚ux of noradrenaline from
adrenergic nerves in rabbit atria. Br. J. Pharm. 49, 614±627.
Philips, S.R., Robson, A.M., 1983. In vivo release of endogenous
dopamine from rat caudate nucleus by phenylethylamine.
Neuropharmacology 22, 1297±1301.
Phillipson, O.T., Horn, A.S., 1976. Substantia nigra of the rat contains a dopamine sensitive adenylate-cyclase. Nature 261, 418±
420.
Pickel, V.M., Joh, T.H., Reiss, D.J., 1977. Regional and ultrastructural localization of tyrosine hydroxylase by immunocytochem-
104
V. Leviel / Neurochemistry International 38 (2001) 83±106
istry. In: Costa, E., Gessa, G.L. (Eds.), Dopaminergic Neurons,
of the Mesolimbic and the Nigrostriatal System. Raven Press,
New York, pp. 321±329.
Pickel, V.M., Beckley, S.C., Joh, T.H., Reis, D.J., 1981.
Ultrastructural immunocytochemical localization of tyrosine hydroxylase in the neostriatum. Brain Res. 225, 373±385.
Pogun, S., Baumann, M.H., Kuhar, M.J., 1994. Nitric oxide inhibits
[3H]dopamine uptake. Brain Res. 641, 83±91.
Premont, J., Thierry, A.M., Tassin, J.P., Glowinski, J., Blanc, G.,
Bokaert, J., 1976. Is the dopamine sensitive adenylate cyclase in
the rat substantia nigra coupled with autoreceptors? Fed. Eur.
Biochem. Soc. Lett. 68, 99±104.
Pulsinelli, W.A., 1985. Selective neuronal vulnerability: morphological and molecular characteristics. Prog. Brain Res. 63, 29±37.
Raiteri, M., Del Carmine, R., Bertollini, A., Levi, G., 1977. E€ects
of desmethyl imipramine on the release of [3H]norepinephrine
induced by various agents in hypothalamic synaptosomes. Mol.
Pharmacol. 13, 746±758.
Raiteri, M., Levi, G., 1978. Release mechanism for catecholamine
and serotonine in synaptosomes. In: Ehrenpreis, S., Kopin, I.J.
(Eds.), Reviews of Neuroscience. Raven Press, New York, pp.
77±130.
Raiteri, M., Cerrito, F., Cervoni, A.M., Levi, G., 1979. Dopamine
can be release by two mechanisms di€erentially a€ected by the
dopamine transport inhibitor nomifensine. J. Pharm. Exp.
Therap. 208, 195±202.
Rajanna, B., Hobson, M., Harris, L., Ware, L., Chetty, C.S., 1990.
E€ects of cadmium and mercury on Na+±K+ ATPase and
uptake of 3H-dopamine in rat brain synaptosomes. Arch. Int.
Physiol. Biochem. 98, 291±296.
Ramirez, V.D., Kim, K., Dluzen, D.E., 1985. Progesterone action on
the LHRH and the nigrostriatal dopamine neuronal systems: in
vitro and in vivo studies. Recent Prog. Horm. Res. 41, 421±472.
Remblier, C., Jolimay, N., Wahl, A., Pariat, C., Piriou, A., Huguet,
F., 1998. Extracellular dopamine and catabolite in rat striatum
during lactic acid perfusion as determined by in vivo microdialysis. Brain Res. 804, 224±230.
Remblier, C., Pontcharraud, R., Tallineau, C., Piriou, A., Huguet,
F., 1999a. Lactic acid-induced increase of extracellular dopamine
measured by microdialysis in rat striatum: evidence for glutamatergic and oxydative mechanisms. Brain Res. 837, 22±28.
Remblier, C., Pontcharraud, R., Vandel, B., Piriou, A., Huguet, F.,
1999b. Origin of extracellular increase induced by lactic acid striatal perfusion monitored by microdialysis in the awake rat.
NeuroReport 10, 1961±1964.
Rice, M.E., Cragg, S.J., Green®eld, S.A., 1997. Characteristics of
electrically evoked somatodendritic dopamine release in substantia nigra and ventral tegmental area in vitro. J. Neurophysiol. 77,
853±862.
Richard, M.G., Bennett, J.P., 1995. NMDA receptor blockade
increases in vivo striatal dopamine synthesis and release in rats
and mice with incomplete, dopamine depleting, nigrostriatal
lesions. J. Neurochem. 64, 2080±2086.
Richter, J.A., Bare, D.J., Yu, H., Ghetti, B., Simon, J.R., 1995.
Dopamine transporter-dependent and independent endogenous
dopamine release from weaver mouse striatum in vitro. J.
Neurochem. 64, 191±198.
Roberts, P.J., Shari€, N.A., 1978. E€ects of L-glutamate and related
amino acids upon the release of [3H]dopamine from rat striatal
slices. Brain Res. 157, 391±395.
Roberts, M.M., Patrick, R.L., 1979. Amphetamine and phenylethylamine-induced alterations in dopamine synthesis regulation in rat
brain striatal synaptosomes. J. Pharm. Exp. Therap. 209, 104±
110.
Roberts, P.J., Anderson, S.D., 1979. Stimulatory e€ect of L-glutamate and related amino acids on [3H]dopamine release from rat
striatum: an in vitro model for glutamic actions. J. Neurochem.
32, 1539±1545.
Robinson, T.E., Whishaw, I.Q., 1988. Normalization of extracellular
dopamine in striatum following recovery from a partial unilateral
6-OHDA lesion of the substantia nigra: a microdialysis study in
freely moving rats. Brain Res. 450, 209±224.
Ro‚er-Tarlov, S., Pugatch, D., Graybiel, A.M., 1990. Patterns of
cell and ®ber vulnerability in the mesostriatal system of the
mutant mouse weaver. II. High anity uptake, sites for dopamine. J. Neurosci. 10, 734±740.
Ross, S.B., Renyi, A.L., 1964. Blocking action of sympathomimetic
amines on the uptake of NE by mouse cerebral cortex. Acta
Pharmacol. Toxicol. 31, 226±239.
Ross, S.B., Renyi, A.L., 1966. Uptake of some tritiated sympathomimetic amines by mouse brain cortex slices in vitro. Acta
Pharmacol. Toxicol. 24, 297±309.
Roth, R.H., Murrin, L.C., Walters, J.R., 1976. Central dopaminergic
neurons: e€ects of alterations in impulse ¯ow on the accumulation of dihydroxyphenylacetic acid. Eur. J. Pharmacol. 36, 163±
171.
Rudnick, G., Wall, S.C., 1992. The molecular mechanism of `ectasy'
[3,4-methylenedioxymethamphetamine (MDMA)]: serotonine
transporters are targets for MDMA induced serotonin release.
Proc. Natl. Acad. Sci., USA 89, 1817±1821.
Rueux, A., Schultz, W., 1980. Dopaminergic activation of reticulata neurons in the substantia nigra. Nature 285, 240±241.
Rutledge, C.O., 1970. The mechanism by which amphetamine inhibits oxydative deamination of norepinephrine in brain. J. Pharm.
Exp. Therap. 171, 188±195.
Samuel, D., Errami, M., Nieoullon, A., 1990. Localization of Nmethyl-D-aspartate receptors in the rat striatum: e€ects of speci®c
lesions on the [3H]3-(2-carboxypiperazin-4)propyl-1-phosphonic
acid binding. J. Neurochem. 54, 1926±1933.
Santiago, M., Westerink, B.H.C., 1991. Characterization and pharmacological reponsivness of dopamine release recorded by microdialysis in the substantia nigra of conscious rats. J. Neurochem.
57, 738±747.
Santos, M.S., Moreno, A.J., Carvalho, A.P., 1996. Relationships
between ATP depletion, membrane potential, and the release of
neurotransmitters in rat nerve terminals. An in vitro study under
conditions that mimic anoxia, hypoglycemia, and ischemia.
Stroke 27, 941±950.
Sarre, S.P., Herregodts, P., Deleu, D., Devrieze, A., De Klippel, N.,
Ebinger, G., Michotte, Y., 1992. Biotransformation of L-DOPA
in striatum and substantia nigra of rats with a unilateral, nigrostriatal lesion: a microdialysis study. Naumyn Schmiedeberg Arch.
Pharmacol. 346, 277±285.
Schacht, U., Leven, M., Backer, G., 1977. Studies on brain metabolism of biogenic amines. Br. J. Clin. Pharmacol. 4, 77S±87S.
Schmidt, C.J., Black, C.K., 1989. The putative 5HT3 agonist phenylbiguanide induces carrier-mediated release of [3H]dopamine. Eur.
J. Pharmac. 167, 309±310.
Schoemaker, H., Nickolson, V.J., 1983. Dopamine uptake by rat
striatal synaptosomes: a compartmental analysis. J. Neurochem.
41, 684±690.
SchoÈmig, A., Dart, A.M., Dietz, R., Mayer, E., Kubler, W., 1984.
Release of endogenous catecholamines in the ischemic myocardium of the rat. Part A: locally mediated release. Circ. Res. 55,
689±701.
SchoÈmig, A., Fischer, S., Kurz, S., Richardt, G., SchoÈmig, E., 1987.
Nonexocytotic release of endogenous noradrenaline in the
ischemic and anoxic rat heart: mechanisms and metabolic requirements. Circ. Res. 60, 194±205.
SchoÈmig, A., Kurz, S., Richardt, G., SchoÈmig, E., 1988. Neuronal
sodium homeostasis and axoplasmic amine concentration determine calcium-independent noradrenaline release in normoxic and
ischemic rat heart. Circ. Res. 63, 214±226.
V. Leviel / Neurochemistry International 38 (2001) 83±106
Schuldiner, S., Steiner-Mordoch, S., Yelin, R., Wall, S.C., Rudnick,
G., 1993. Amphetamine derivatives interact with both plasma
membrane and secretory vesicle biogenic amine transporters.
Mol. Pharmac. 44, 1227±1231.
Schultz, W., 1986. Response of midbrain dopamine neurons to behavioral trigger stimuli in the monkey. J. Neurophysiol. 56, 1439±
1461.
Schwartz, R.D., Uretsky, N.J., Bianchine, J.R., 1980. The relationship between the stimulation of dopamine synthesis and release
produced by amphetamine and high potassium in striatal slices. J.
Neurochem. 35, 1120±1127.
Sedvall, G.G., Weise, V.K., Kopin, I.J., 1968. The rate of norepinephrine synthesis measured in vivo during short intervals: in¯uence of adrenergic nerve impulse activity. J. Pharm. Exp. Therap.
159, 274±282.
Sershen, H., Debler, E.A., Lajhta, A., 1987. E€ect of ascorbic acid
on the synaptosomal uptake of [3H]MPP+, [3H]dopamine, and
[3H]GABA. J. Neurosci. Res. 17, 298±301.
Shimada, S., Kitayama, S., Lin, C.L., Patel, A., Nanthakumar, E.,
Gregor, P., Kuhar, M., Uhl, G., 1991. Cloning and expression of
a cocaine sensitive dopamine transporter complementary DNA.
Science 254, 576±578.
Sill, T.L., Greenshaw, A.J., Baker, G.B., Fletcher, P.J., 1999. Acute
¯uoxetine treatment potentiates amphetamine hyperactivity and
amphetamine-induced nucleus accumbens dopamine release: possible pharmacokinetic interaction. Psychopharmacology 141, 421±
427.
Simon, J.R., Yu, H., Richter, J.A., Vasko, M.R., Ghetti, B., 1991.
In vitro release of endogenous dopamine from the striatum of the
Weaver mutant mouse. J. Neurochem. 57, 1478±1482.
Sirinathsinghji, D.J.S., Heavens, R.P., Sikdar, S.K., 1988. In vivo
studies on the dopamine reuptake mechanism in the striatum of
the rat: e€ects of benztropine, sodium and ouabain. Brain Res.
438, 399±403.
Smolen, T.N., Howerton, T.C., Collins, A.C., 1984. E€ects of ethanol and salsolinol on catecholamine function in LS and SS mice.
Pharmacol. Biochem. Behav. 20, 125±131.
Snape, B.M., Engel, J.A., 1988. Ethanol enhances the calcium-dependent stimulus induced release of endogeneous dopamine from
slices of rat striatum and nucleus accumbens in vitro.
Neuropharmacology. 27, 1097±1101.
Snyder, G., Keller, R.W., Zigmond, M.J., 1990. Dopamine e‚ux
from striatal slices after intracerebral 6-hydroxydopamine: evidence for compensatory hyperactivity of residual terminals. J.
Pharm. Exp. Therap. 253, 867±876.
Soares da Silva, P., Garret, M.C., 1990. Over¯ow of endogenous
dopamine and 34 dihydroxyphenylacetic acid from tissues of the
rat brain, elicited by electrical stimulation, depolarization by potassium
ans
activation
of
carrier-mediated
release.
Neuropharmacology 29, 1151±1159.
Sotelo, C., 1971. The ®ne structural localization of
norepinephrine-3H in the substantia nigra and area postrema of
the rat: an autoradiographic study. J. Ultrastruc. Res. 36, 824±
841.
Spatz, M., Yasuma, Y., Strasser, A., Kawai, N., Stanimirovic, D.,
McCarron, R., 1995. Modulation of striatal dopamine release in
cerebral ischemia by L-arginine. Neurochem. Res. 20, 491±496.
Stachowiak, M.K., Keller, R.W., Stricker, E.M., Zigmond, M.J.,
1987. Increased dopamine e‚ux from striatal slices during development and after nigrostriatal bundle damage. J. Neuroscience 7,
1648±1654.
Stamford, J.A., Kruk, Z.L., Millar, J., Wightman, R.M., 1984.
Striatal dopamine uptake in the rat: in vivo analysis by fast cyclic
voltametry. Neurosci. Lett. 51, 133±138.
Stamford, J.A., Isaac, D., Hicks, C.A., Ward, M.A., Osborne, D.J.,
O'Neill, M.J., 1999. Ascorbic acid is neuroprotective against glo-
105
bal ischemia in striatum but not hippocampus: histological and
voltametric data. Brain Res. 835, 229±240.
Standaert, D.G., Testa, C.M., Rudolph, G.D., Hollingsworth, Z.R.,
1996. Inhibition of N-methyl-D-aspartate glutamate receptor subunit expression by antisens oliginucleotids reveals their role in
striatal motor regulation. J. Pharm. Exp. Therap. 276, 342±352.
Stein, W.D., 1967. The Movement of Molecules Across Cell
Membranes. Academic Press, New York, pp. 177±206.
Stein, W.D., 1990. Channels, Carriers, and Pumps. Academic Press,
New York.
Stuart, G.J., Sakmann, B., 1994. Active propagation of somatic potentials into neocortical pyramidal cell dendrites. Nature 367, 69±
72.
Stute, N., Trendelenburg, U., 1984. The outward transport of axoplasmic noradrenaline induced by a rise of the sodium concentration in the adrenergic nerve endings of the rat vas deferens.
Naunyn Schmiedeberg's Arch. Pharmacol. 327, 124±132.
Suaud-Chagny, M.F., Dugast, C., Chergui, K., Msghina, M.,
Gonon, F., 1995. Uptake of dopamine released by impulse ¯ow
in the rat mesolimbic and striatal systems in vivo. J. Neurochem.
65, 2603±2611.
Sulzer, D., Rayport, S., 1990. Amphetamine and other psychostimulants reduce pH gradients in midbrain dopaminergic neurons and
chroman granules: a mechanism of action. Neuron 5, 797±808.
Sulzer, D., Maidment, N.T., Rayport, S., 1993. Amphetamine and
other weak bases act to promote reverse transport of dopamine
in ventral midbrain neurons. J. Neurochem. 60, 527±535.
Sulzer, D., Chen, T., Lau, Y.Y., Kristensen, H., Rayport, S., Ewing,
A., 1995. Amphetamine redistributes dopamine from synaptic
vesicles to the cytosol and promotes reverse transport. J.
Neurosci. 15, 4102±4108.
Sweadner, K.J., 1985. Ouabain evoked norepinephrine release from
intact rat sympathetic neurons: evidence of carrier mediated
release. J. Neurosci. 5, 2397±2406.
Tauc, L., 1982. Nonvesicular release of neurotransmitter. Physiol.
Rev. 62, 857±892.
Tennyson, V.M., Heikkila, R., Mytilineou, C., CoteÂ, L., Cohen, G.,
1974. 5-hydroxydopamine ``tagged'' neuronal boutons in rabbit
neostriatum: interrelationship between vesicles and axonal membrane. Brain Res. 82, 341±348.
Thoenen, H., Hurlimann, A., Haefely, W., 1969. Cation dependence
of the noradrenaline releasing action of tyramine. Eur. J.
Pharmacol. 6, 29±37.
Toner, C.C., Stamford, J.A., 1999. E€ects of metabolic alterations
on dopamine release in an in vitro model of neostriatal ischaemia.
Brain Res. Bull. 48, 395±399.
Udenfriend, S., Zaltman-Niremberg, P., Nagatsu, T., 1965.
Inhibitors of puri®ed beef adrenal tyrosine hydroxylase. Biochem.
Pharmacol. 14, 837±845.
Ulas, J., Cotman, C.W., 1996. Dopaminergic denervation of striatum
results in elevated expression of NR2A subunit. NeuroReport 7,
1789±1793.
Uretsky, N.J., Snodgrass, S.R., 1977. Studies on the mechanism of
stimulation of dopamine synthesis by amphetamine in striatal
slices. J. Pharm. Exp. Therap. 202, 565±580.
Uretsky, N.J., Kamal, L., Snodgrass, S.R., 1979. E€ects of divalent
cations on amphetamine induced stimulation of [3H]catechol synthesis in the striatum. J. Neurochem. 32, 951±960.
Uvnas, B., Aborg, C.H., 1984. Cation exchange Ð a common mechanism in the storage and release of biogenic amines stored in
granules (vesicles). Acta Physiol. Scand. 120, 99±107.
Vizi, E.S., 1980. Nonsynaptic modulation of transmitter release:
pharmacological implications. TIPS 2, 172±175.
Vizi, E.S., 1984. Non-Synaptic Interactions between Neurons:
Modulation of Neurochemical Transmission. Wiley, Chichester.
Vizi, E.S., 1998. Di€erent temperature dependence of carriermediated (cytoplasmic) and stimulus-evoked (exocytotic) release
106
V. Leviel / Neurochemistry International 38 (2001) 83±106
of transmitter: a simple method to separate the two types of
release. Neurochem. Int. 33, 359±366.
Vizi, E.S., 2000. Role of high-anity receptors and membrane transporters in non synaptic communication and drug action in the
central nervous system. Pharmacol. Rev. 52, 63±89.
Vizi, E.S., Bernath, S., Kapocsi, J., Serfozo, P., 1986. Transmitter
release from the cytoplasm is of physiological importance but no
subject to presynaptic modulation. J. Physiol., Paris 81, 283±288.
Vizi, E.S., Kiss, J.P., 1998. Neurochemistry and pharmacology of the
major hippocampal transmitter systems: synaptic and non-synaptic interactions. Hippocampus 8, 566±607.
Vizi, E.S., Labos, E., 1991. Nonsynaptic interactions at presynaptic
level. Prog. Neurobiol. 37, 145±163.
Walker, J.H., Agoston, D.V., 1987. The synaptic vesicle and the
cytoskeleton. Biochem. J. 247, 249±258.
Wang, Y., Wang, S.D., Lin, S.Z., Liu, J.C., 1994. Restoration of
dopamine over¯ow and clearance from the 6-hydroxydopamine
lesioned rat striatum reinnervated by fetal mesencephalic grafts.
J. Pharm. Exp. Therap. 270, 814±821.
Wang, Y., Palmer, M.R., Cline, E.J., Gerhardt, G.A., 1997. E€ects
of ethanol on striatal dopamine over¯ow and clearance: an in
vivo electrochemical study. Alcohol 14, 593±601.
Wassef, M., Berod, A., Sotelo, C., 1981. Dopaminergic dendrites in
the pars reticulata of the rat substantia nigra and their striatal
input. Combined immunocytochemical localization of tyrosine
hydroxylase and anterograde degeneration. Neuroscience 6, 2125±
2139.
Weihmuller, F.B., Ulas, J., Nguyen, L., Cotman, C.W., Marshall,
J.F., 1992. Elevated NMDA receptors in parkinsonian striatum.
NeuroReport 3, 977±980.
Welch, S.M., Justice Jr., J.B., 1996. Regulation of dopamine uptake
in rat striatal tissue by NMDA receptors as measured using rotating disk electrode voltametry. Neurosci. Lett. 217, 184±188.
Werling, L.L., Hoener, P.J., Hurt, K.J., Fox, L.G., Blanck, T.J.,
Rosenthal, R.E., Fiskum, G., 1994. Increased activation of L-type
voltage dependent calcium channels is associated with glycine
enhancement of N-methyl-D-aspartate-stimulated dopamine
release in global cerebral ischemia/reperfusion. J. Neurochem. 63,
215±221.
Westerink, B.H.C., Damsma, G., De Vries, J.B., 1989. E€ect of ouabain applied by intrastriatal microdialysis on the in vivo release
of dopamine, acetylcholine, and aminoacids in the brain of conscious rats. J. Neurochem. 52, 705±712.
Wheeler, D.D., Edwards, A.M., Chapman, B.M., Ondo, J.G., 1993.
A model of the sodium dependence of dopamine uptake in rat
striatal synaptosomes. Neurochem. Res. 18, 927±936.
Wieczorek, W.J., Kruk, Z.L., 1994. A quantitative comparison on
the e€ects of benztropine, cocaine and nomifensine on electrically
evoked dopamine over¯ow and rate of Te-uptake in the caudate
putamen and nucleus accumbens in the rat brain slice. Brain Res.
657, 42±50.
Wiener, H.L., Hashim, A., Lajtha, A., Sershen, H., 1989. Chronic Ldeprenyl-induced up-regulation of the dopamine uptake carrier.
Eur. J. Pharmacol. 163, 191±194.
Wightman, R.M., Amatore, C., Engstrom, R.C., Hale, P.D.,
Kristensen, E.W., Kuhr, W.G., May, L.J., 1988. Real time
characterization of dopamine over¯ow and uptake in the rat
striatum. Neuroscience 25, 513±523.
Wightman, R.M., Zimmerman, J.B., 1990. Control of dopamine
extracellular concentration in rat striatum by impulse ¯ow and
uptake. Brain Res. Rev. 15, 135±144.
Wolf, M.E., Roth, R.H., 1987. Dopamine autoreceptors. In: Creese,
I., Fraser, C.M. (Eds.), Dopamine Receptors. Alan R. Liss, New
York, pp. 45±96.
Woodward, J.J., Gonzales, R.A., 1990. Ethanol inhibition of
NMDA-stimulated endogenous dopamine release from rat striatal
slices: reversal by glycine. J. Neurochem. 54, 712±715.
Wullner, U., Testa, C.M., Catania, M.V., Young, A.B., Penney Jr.,
J.B., 1994. Glutamate receptors in striatum and substantia nigra:
e€ects of medial forebrain bundle lesions. Brain Res. 645, 98±102.
Yadid, G., Pacak, K., Kopin, I.J., Goldstein, D.S., 1994.
Endogenous serotonin stimulates striatal dopamine release in conscious rats. J. Pharm. Exp. Therap. 270, 1158±1165.
Yi, S., Gi€ord, A.N., Johnson, K.M., 1991. E€ect of cocaine and
5HT3 receptor antagonists on 5HT-induced [3H]dopamine release
from rat striatal synaptosomes. Eur. J. Pharm. 199, 185±189.
Zaczek, R., Culp, S., De Souza, E.B., 1990. Intrasynaptosomal
sequestration of [3H]amphetamine and [3H]methylenedioxyamphetamine: characterization suggests the presence of a factor
responsible for maintaining sequestration. J. Neurochem. 54,
195±204.
Zaczek, R., Culp, S., De Souza, E.B., 1991. Interactions of
[3H]amphetamine with rat brain synaptosomes. II Active transport. J. Pharm. Exp. Therap. 257, 830±835.
Zahniser, N.A., Gerhardt, G.A., Ho€man, A.F., Lupica, C.R., 1998.
Voltage-dependency of the dopamine transporter in rat brain.
Adv. Pharmac. 42, 195±198.
Zahniser, N.A., Larson, G.A., Gerhardt, G.A., 1999. In vivo dopamine clearance rate in rat striatum: regulation by extracellular
dopamine concentration and dopamine transporter inhibitors. J.
Pharm. Exp. Therap. 289, 266±277.
Ziance, R.J., Azzaro, A.J., Rutledge, C.O., 1972. Characteristic of
amphetamine induced release of norepinephrine from rat cerbral
cortex in vitro. J. Pharm. Exp. Therap. 182, 284±294.
Ziance, R.J., Rutledge, C.O., 1972. A comparison of the e€ects of
fen¯uramine and amphetamine on uptake, release and catabolism
of norepinephrine in rat brain. J. Pharm. Exp. Therap. 180, 118±
126.
Zigmond, M.J., Stricker, E.M., 1988. Animal models of parkinsonism using selective neurotoxins: clinical and basic implications.
In: Bradley, R.J. (Ed.), International Review of Neurobiology.
Academic Press, New York.
Zigmond, M.J., Abercrombie, E.D., Berger, T.W., Grace, A.A.,
Stricker, E.M., 1990. Compensatory changes after lesions of central dopaminergic neurons: some clinical and basis implications.
Trends Neurosci. 13, 290±295.
Zhang, W.Q., Tilson, H.A., Nanry, K.P., Hudson, P.M., Hong, J.S.,
Stachowiak, M.K., 1988. Increased dopamine release from striata
of rats after unilateral nigrostriatal bundle damage. Brain Res.
461, 335±342.
Zoli, M., Torri, C., Ferrari, R., Jansson, A., Zini, I., Fuxe, K.,
Agnati, L.F., 1998. The emergence of the volume transmission
concept. Brain Res. Rev. 26, 136±147.