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Vol. 58, Issue 2, 312-318, August 2000
-Bungarotoxin-Sensitive Nicotinic Receptors Indirectly
Modulate [3H]Dopamine Release in Rat Striatal Slices via
Glutamate Release
Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
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Abstract |
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 Top
 Abstract
 Introduction
Experimental Procedures
Results
Discussion
References
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Nicotinic agonists elicit the release of dopamine from striatal
synaptosomes by acting on presynaptic nicotinic acetylcholine receptors
(nAChRs) on dopamine nerve terminals. Both 
3
2* and 42 nAChR
subtypes (but not 7* nAChRs) have been implicated. Here, we compared
nAChR-evoked [3H]dopamine release from rat striatal
synaptosome and slice preparations by using the nicotinic agonist
anatoxin-a. In the more integral slice preparation, the
concentration-response curve for anatoxin-a-evoked [3H]dopamine release was best fitted to a two-site model,
giving EC50 values of 241 nM and 5.1 µM, whereas only the
higher-affinity component was observed in synaptosome preparations
(EC50 = 134 nM). Responses to a high concentration of
anatoxin-a (25 µM) in slices (but not in synaptosomes) were partially
blocked by ionotropic glutamate receptor antagonists (kynurenic acid,
6,7-dinitroquinoxaline-2,3-dione) and by 7*-selective nAChR
antagonists (-bungarotoxin, -conotoxin-ImI, methyllycaconitine)
in a nonadditive manner. In contrast, the 32-selective nAChR
antagonist -conotoxin-MII partially inhibited [3H]dopamine release from both slice and synaptosome
preparations, stimulated with both low (1 µM) and high (25 µM)
concentrations of anatoxin-a. Antagonism by -conotoxin-MII was
additive with that of 7*-selective antagonists. These data support a
model in which 7* nAChRs on striatal glutamate terminals elicit
glutamate release, which in turn acts at ionotropic glutamate receptors on dopamine terminals to stimulate dopamine release. In addition, non-7* nAChRs on dopamine terminals also stimulate dopamine release. These observations have implications for the complex cholinergic modulation of inputs onto the major efferent neurons of the striatum.
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Introduction |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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The
dorsal striatum is concerned with the control of movement. The
principal output neurons from the striatum, the GABAergic medium spiny
neurons, receive glutamatergic afferents from the cortex and thalamus
and dopaminergic inputs from the substantia nigra (Smith and Bolam,
1990
). Cholinergic interneurons also synapse onto the medium spiny
neurons. In addition to these well-established synaptic relationships,
there is increasing evidence for neurochemical cross talk between the
terminals of afferent neurons via presynaptic receptors. This may
provide a basis for new therapeutic approaches for the treatment of
movement disorders that arise from the degeneration of neuronal
subpopulations (Parkinson's and Huntington's diseases) or as a side
effect of clinical treatments (tardive dyskinesia).
In vitro, glutamate stimulates the release of
[3H]dopamine from rat striatal slices (Roberts
and Anderson, 1979), and this effect appears to be mediated by both
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate
and N-methyl-D-aspartate (NMDA)
receptors present on dopaminergic nerve terminals (Wang, 1991; Desce et al., 1992). Consistent with this view, in vivo infusion into the striatum via a microdialysis probe of either NMDA (Keefe et al., 1992;
Morari et al., 1993; Kendrick et al., 1996) or AMPA (Kendrick et al.,
1996; Smolders et al., 1996) increased local release of dopamine. There
also is strong evidence for the presence on dopamine terminals of
nicotinic acetylcholine receptors (nAChRs) capable of enhancing the
basal release of dopamine (Wonnacott, 1997). These nAChRs appear to be
heterogeneous, composed of subtypes containing 3 and 2 subunits
(32* nAChRs; Kulak et al., 1997; Kaiser et al., 1998) and 4
and 2 subunits (42 nAChRs; Sharples et al., 2000).
Furthermore, locally applied (
)-nicotine in vivo has been shown to
increase striatal levels of dopamine (Marshall et al., 1997) and
glutamate (Toth et al., 1993) in a mecamylamine-sensitive manner.
Moreover, the local application of NMDA antagonists diminished the
ability of locally applied ()-nicotine to elicit dopamine release in
vivo (Toth et al., 1992). These data lead to the hypothesis that
()-nicotine can also act at presynaptic nAChRs on striatal glutamatergic nerve terminals to release glutamate, which in turn stimulates the release of dopamine via presynaptic ionotropic glutamate
receptors on dopaminergic terminals. Recent electrophysiological recordings from striatum in situ are consistent with this argument (García-Muñoz et al., 1996).
Here, we examined the relationship between nAChRs, glutamate receptors,
and dopamine release in the striatum in vitro. Comparative experiments
using perfused synaptosomes (which represent isolated nerve terminals
with low probability of neurochemical cross-talk) and slices (which
preserve some of the anatomical integrity of the striatum) provide
evidence for a component of [3H]dopamine
release in slices, but not in synaptosomes, that is sensitive to
glutamate receptor antagonists and 7*-selective nAChR antagonists.
These results are consistent with an indirect modulation of dopamine
release in striatum via 7* nAChRs on striatal glutamatergic nerve terminals.
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Experimental Procedures |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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Materials.
Adult male Sprague-Dawley rats were obtained from
the University of Bath Animal House breeding colony.
[7,8-3H]Dopamine (1.78 TBq/mmol) was purchased
from Amersham International (Buckinghamshire, UK). -Conotoxin-MII
(CTx-MII) was synthesized with correct disulfide bond formation as
previously described (Cartier et al., 1996; Kaiser et al., 1998).
(±)-Anatoxin-a (AnTx-a), 6,7-dinitroquinoxaline-2,3-dione (DNQX), and
kynurenic acid were obtained from Tocris Cookson (Bristol, UK).
-Conotoxin-ImI (CTx-ImI) was obtained from Calbiochem (San Diego,
CA). Methyllycaconitine (MLA) and 4-aminopyridine were purchased from
Research Biochemicals International (Natick, MA). -Bungarotoxin
(-Bgt), mecamylamine, pargyline, and nomifensine were purchased from
Sigma Chemical Co. (Poole, Dorset, UK). All other chemicals used were
of analytical grade and were obtained from standard commercial sources.
Superfusion of Rat Striatal Slices and Synaptosomes.
Male
Sprague-Dawley rats (approximately 250 g) were sacrificed by
cervical dislocation and decapitated, and brain striata (180-240 mg
tissue wet wt./rat) were rapidly dissected. P2 synaptosomes were
prepared by differential centrifugation as previously described (Soliakov et al., 1995). Synaptosomes were loaded with
[3H]dopamine (0.1 µM, 0.132 MBq/ml) for 15 min at 37°C and superfused in open chambers (Soliakov et al., 1995).
All superfusion experiments were performed in Krebs-bicarbonate buffer
of the following composition: 118 mM NaCl, 2.4 mM KCl, 2.4 mM
CaCl2, 1.2 mM MgSO4, 1.2 mM
KH2PO4, 25 mM
NaHCO3, and 10 mM glucose, buffered to pH 7.4 with 95% O2, 5% CO2 and
supplemented with 1 mM ascorbic acid, 8 µM pargyline, and 0.5 µM
nomifensine to prevent dopamine degradation and reuptake.
) using a McIlwain tissue chopper. Striatal tissue prisms were washed twice with Krebs-bicarbonate buffer and
loaded with [3H]dopamine (0.1 µM, 0.132 MBq/ml) for 15 min at 37°C. After two washes, slices were resuspended
in Krebs' buffer and loaded into superfusion chambers (approximately
45-50 mg of slices per chamber). Superfusion of synaptosomes (open
chambers) or slices (closed chambers) was performed as previously
described (Soliakov et al., 1995; Marshall et al., 1996) in a Brandel
Superfusion Apparatus model SF-12 (Montreal, Quebec, Canada), using
Krebs-bicarbonate buffer at 37°C and a flow rate of 0.5 ml/min; 2-min
fractions were collected.
Chambers containing either synaptosomes or slices were washed for 20 min with Krebs-bicarbonate buffer, followed by a further 10 min with
normal buffer or buffer containing antagonist (112 nM Ctx-MII, 1 µM Ctx-ImI, 50 nM MLA, 10 µM mecamylamine, 500 µM kynurenic
acid, 100 µM DNQX). In the case of -Bgt (40 nM) the preincubation
time was extended to 1 h. Then, the nicotinic agonist AnTx-a or
general depolarizing agent (KCl or 4-aminopyridine) was applied for
40 s in the presence or absence of antagonist. The 40-s drug pulse
was separated from the bulk buffer flow by 10-s air bubbles.
Fractions were counted in a Packard TRI-CARB Liquid Scintillation
Counter (model 1500; counting efficiency 48%). Evoked tritium release
above baseline was calculated as a percent of the total radioactivity
present in the synaptosomes immediately before stimulation (Soliakov et
al., 1995). To estimate the radioactivity remaining in slices at the
end of the experiment, superfusion was continued for 30 min with 10 mM
HCl to lyse the slices (Marshall et al., 1996). Aliquots (1 ml) of the
lysates were counted for radioactivity. Total radioactivity in slices
at the time of stimulation was calculated as the sum of subsequently
released [3H]dopamine plus lysate.
Data Analysis.
The baseline was derived by fitting the
following double exponential decay equation to the data using Sigma
Plot Version 2.0 for Windows:
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![y={a/[1+(k1/x)<SUP>n1</SUP>]}+{b/[1+(k2/x)<SUP>n2</SUP>]}](/content/vol58/issue2/fulltext/312/img002.gif)
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Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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Effect of Ionotropic Glutamate Receptor Antagonists on
[3H]Dopamine Release from Striatal Slices.
The
nonselective glutamate receptor antagonist kynurenic acid significantly
inhibited [3H]dopamine release from striatal
slices, evoked by modest concentrations of the depolarizing agents KCl
and 4-aminopyridine (Fig. 1, a and b).
Kynurenic acid was used at a concentration (500 µM) sufficient to
maximally inhibit AMPA/kainate and NMDA receptors and decreased [3H]dopamine release by 21.0 ± 0.3% and
23.0 ± 6.0%, respectively, when slices were stimulated by 23.5 mM KCl and 1 mM 4-aminopyridine. A higher concentration (800 µM) of
kynurenic acid did not produce any greater degree of inhibition. These
data are consistent with previous reports (Wang, 1991; Desce et al.,
1992) that presynaptic ionotropic glutamate receptors on striatal
dopamine terminals positively modulate dopamine release: in the present
experiments, the depolarizing agents released glutamate to activate
these receptors.
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;
Sharples et al., 2000). Initially, it was used at a concentration (1 µM) previously shown to elicit maximum
[3H]dopamine release from striatal synaptosomes
(Soliakov et al., 1995; see Fig. 2,
inset): this concentration evokes about 30% of the response achieved
with 23.5 mM KCl or 1 mM 4-aminopyridine. In contrast to the results
from slices, kynurenic acid had no effect on AnTx-a-evoked
[3H]dopamine release from striatal synaptosomes
(Fig. 1d). These results are consistent with the hypothesis that in
addition to activating nAChRs on dopaminergic nerve terminals, AnTx-a
acts at nAChRs that provoke the release of glutamate, which in turn elicits [3H]dopamine release.
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Pharmacological Characterization of nAChRs Modulating
[3H]Dopamine Release in Striatal Slices.
To
characterize the nAChR subtypes involved in the modulation of striatal
[3H]dopamine release, several nicotinic
antagonists were compared for their abilities to inhibit release evoked
by 1 µM and 25 µM AnTx-a, in both slices and synaptosomes (Fig.
4). In agreement with our previous
findings (Kaiser et al., 1998), a maximally effective concentration
(112 nM) of the 32-selective toxin Ctx-MII (Cartier et al.,
1996) partially inhibited [3H]dopamine release
evoked by AnTx-a in both slices and synaptosomes. The latter
preparation was inhibited to a greater extent by Ctx-MII than
slices, as we have noted previously (Kaiser et al., 1998).
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7*-selective nAChR antagonist MLA (50 nM; Alkondon et al., 1992;
Wonnacott et al., 1993) was perfused for 10 min: this concentration was
predicted to fully block 7* nAChRs in this protocol without
activating other nAChR subtypes. Unexpectedly, [3H]dopamine release evoked by 1 µM AnTx-a
was decreased 39.1 and 31.3% by MLA in synaptosomes and slices,
respectively (Fig. 4). Other concentrations of MLA were compared for
their effect on [3H]dopamine release from
synaptosomes stimulated with 1 µM AnTx-a: 10 nM MLA gave 37.1 ± 9.9% inhibition, comparable with that of 50 nM MLA, whereas 500 nM MLA
produced significantly greater inhibition of 60.6 ± 7.0% (data
not shown). However, responses to 25 µM AnTx-a in synaptosomes were
not significantly affected by 50 nM MLA (Fig. 4b); thus, the inhibition
by 50 nM MLA disappeared with increasing agonist concentration in
synaptosomes, perhaps reflecting a surmountable mode of antagonism.
However, in slices this toxin inhibited the response to 25 µM AnTx-a
by 42.7% (Fig. 4a), demonstrating an increase in the percent
inhibition with increasing agonist concentration.
To further explore the possible involvement of the 7* subtype of
nAChRs in the nicotinic stimulation of
[3H]dopamine release from striatal slices, we
examined the effect of the 7*-selective Ctx-ImI (1 µM; Johnson
et al., 1995; Pereira et al., 1996). This toxin decreased
[3H]dopamine release from slices elicited by 25 µM AnTx-a by 31.9% (Fig. 4a), comparable with the effect of 50 nM
MLA. In synaptosomes stimulated with 25 µM AnTx-a, 1 µM Ctx-ImI
had no significant effect (Fig. 4b), consistent with results for
()-nicotine-evoked [3H]dopamine release from
synaptosomes (Kulak et al., 1997). Thus, at the higher agonist
concentration, an 7-like component is clearly demonstrable in slices
but not in synaptosomes. The involvement of 7* nAChRs was confirmed
by the ability of 40 nM -Bgt, perfused for 1 h at 37°C before
stimulation with 25 µM AnTx-a, to inhibit [3H]dopamine release from slices by 39.8%
(Fig. 4a).
Thus, three structurally unrelated 7*-selective nAChR antagonists
block [3H]dopamine release from slices in
response to the higher concentration of AnTx-a to a comparable extent
(30-40%; Table 1). This level of
inhibition is similar to that obtained in the presence of ionotropic glutamate receptor antagonists (Fig. 3). Coapplication of antagonists showed that neither 40 nM -Bgt plus 100 µM DNQX, nor 50 nM MLA plus 100 µM DNQX, achieved any additional inhibition above that of
any of the antagonists applied alone (Table 1). In contrast, -Bgt
plus 112 nM Ctx-MII and MLA plus 112 nM Ctx-MII resulted in
clearly additive inhibition, decreasing the release of
[3H]dopamine from slices in response to 25 µM
AnTx-a by about 70% (Table 1).
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Discussion |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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In this study, we have shown that the ionotropic glutamate
receptor antagonists kynurenic acid and DNQX and the 7*-selective nAChR antagonists -Bgt, Ctx-ImI, and MLA partially inhibit
[3H]dopamine release from striatal slices
elicited by the potent and specific nicotinic agonist AnTx-a. When
applied together, glutamate receptor antagonists and 7*-selective
nAChR antagonists were not additive in their inhibition and generally
were without effect in corresponding experiments on synaptosome
preparations. In contrast, AnTx-a-evoked
[3H]dopamine release from both slices and
synaptosomes was partially inhibited by the 32-selective nAChR
antagonist Ctx-MII, and this inhibition was additive with that of
7*-selective nAChR antagonists. These findings are consistent with
the hypothesis that 7* nAChRs are present on striatal glutamatergic
terminals and promote the release of glutamate, which in turn activates presynaptic ionotropic glutamate receptors on striatal dopaminergic nerve terminals (Fig. 5).
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Glutamate Heteroreceptors on Dopaminergic Terminals.
The
ability of the nonselective ionotropic glutamate receptor antagonist
kynurenic acid to significantly decrease
[3H]dopamine release from striatal slices,
evoked by the depolarizing agents KCl and 4-aminopyridine (Fig. 1, a
and b) is consistent with other studies (Jin and Fredholm, 1994) and is
compatible with evidence that glutamate can influence dopamine release
via heteroreceptors on dopaminergic terminals (Wang, 1991; Desce et al., 1992). The similar finding using AnTx-a in place of a general depolarizing agent (Fig. 1c) suggests that nAChR activation can also
evoke glutamate release. The lack of effect of kynurenic acid on
AnTx-a-evoked [3H]dopamine release from
synaptosomes (Fig. 1d) supports this interpretation and, importantly,
excludes the possibility that kynurenic acid was exerting a nonspecific
action directly at nAChRs on dopaminergic terminals.
). In that report, NMDA alone was ineffective,
attributed to Mg2+ block of NMDA receptors,
whereas activation of AMPA/kainate receptors could overcome this
inhibition. Indeed, it has been proposed that ACh or ()-nicotine,
acting at presynaptic nAChRs on dopaminergic terminals, can also
relieve the Mg2+ block of NMDA receptors, to give
a synergistic effect on dopamine release when ()-nicotine and NMDA
are applied together in the presence of 1 µM glycine (Chéramy
et al., 1996). However, in the present study, NMDA receptors are
unlikely to contribute because the experiments were conducted in
nominally glycine-free conditions, and glycine is an obligatory
coagonist of NMDA receptors (Kleckner and Dingledine, 1988; Vyklicky et
al., 1990). In support of this interpretation, we have found that under
the conditions used in this study, 1 mM NMDA alone failed to stimulate
[3H]dopamine release from striatal slices, and
release evoked by 10 µM ()-nicotine was not enhanced by
coapplication with NMDA. When this experiment was repeated in the
presence of 1 µM glycine (and 1 µM strychnine to block glycine
receptors), NMDA alone was again without effect, but NMDA applied
together with ()-nicotine significantly increased
[3H]dopamine release by 52 ± 7%
(n = 4) compared with ()-nicotine alone (S. Kaiser
and S. Wonnacott, unpublished results). Thus, we can conclude that the
effects of kynurenic acid and DNQX on AnTx-a-evoked
[3H]dopamine release reported herein reflect
the participation of AMPA/kainate receptors; any role of NMDA receptors
was not disclosed under the experimental conditions used.
Subtypes of Presynaptic nAChRs.
Impetus for this investigation
came from our observation (Kaiser et al., 1998) that although
AnTx-a-evoked [3H]dopamine release in both
synaptosome and slice preparations was partially inhibited by
Ctx-MII, the proportion of release attributable to 32* nAChRs
was significantly less in slices. This suggested the contribution of
additional nAChRs in the more integral preparation. A comparison of the
dose-response curves for AnTx-a in synaptosomes and slices shows a
distinct difference in the profiles, with a second, lower-affinity
component in the slice preparation (Fig. 2). The suppression of this
low-affinity component by glutamate receptor antagonists and 7*
nAChR antagonists, in a nonadditive manner (Figs. 2 and 4, Table 1), is
consistent with an additional nicotinic component indirectly enhancing
[3H]dopamine release, via the release of
glutamate. The ability to fit a two-site model to the slice data is
fortuitous, reflecting the good separation of affinities for AnTx-a of
the high- and low-affinity components, together with the relatively low
efficacy of AnTx-a at presynaptic nAChRs on dopaminergic terminals,
demonstrated in synaptosome preparations (Sharples et al., 2000). We
have observed that concentration-response curves for ()-nicotine in
both synaptosome and slice preparations conform to a single-site model,
but higher concentrations of nicotine (30-100 µM) produce relatively
greater amounts of [3H]dopamine release in the
slice preparation, and this increment can be blocked by DNQX (Wonnacott
et al., 2000). Thus, the phenomenon described in detail here is also
observed with other nicotinic agonists.
). In
synaptosomes, this component reflects the contribution of at least two
nAChR subtypes, currently considered to be 32* and 42
nAChRs (Kulak et al., 1997; Kaiser et al., 1998; Sharples et al.,
2000). 7* nAChRs are not thought to be present on dopamine terminals, because -Bgt and Ctx-ImI fail to antagonize
()-nicotine-evoked dopamine release from synaptosomes (Rapier et al.,
1990; Grady et al., 1992; Kulak et al., 1997; A. Mogg and S. Wonnacott,
unpublished observations). Therefore, inhibition by 50 nM MLA of
[3H]dopamine release evoked by 1 µM AnTx-a
was unexpected, as this concentration of MLA was assumed to be
selective for 7* nAChRs (Wonnacott et al., 1993). However, Clarke
and Reuben (1996) reported an IC50 value of 38 nM
for MLA inhibition of ()-nicotine-stimulated [3H]dopamine release from striatal
synaptosomes. A possible explanation of the "surmountable"
antagonism of nicotinic agonist-evoked
[3H]dopamine release from synaptosomes is that
MLA may also interact with high affinity with combinations of nAChR
subunits that have not yet been examined but that are activated by
lower agonist concentrations than 7* nAChRs. This observation
emphasizes that antagonists presumed to be subtype-selective may not be
definitive when used in heterogeneous systems.
However, the ability of three structurally unrelated 7*
nAChR-selective antagonists to partially inhibit (to the same extent) the release of [3H]dopamine in slices
stimulated with 25 µM AnTx-a provides compelling evidence for the
involvement of 7* nAChRs. Indeed, the apparent EC50 value of 5.1 µM determined for the
low-affinity component of the AnTx-a concentration-response curve in
slices (Fig. 2) is strikingly similar to the EC50
value of 3.9 µM reported for -Bgt- and MLA-sensitive type IA
currents in hippocampal neurons (Alkondon and Albuquerque, 1993). The
most parsimonious interpretation of the data is that 7* nAChRs
reside on striatal glutamatergic nerve terminals and directly modulate
glutamate release (see Fig. 5). There is precedent for such an
arrangement from some elegant electrophysiological studies in other
brain regions in the rat (Alkondon et al., 1996; Radcliffe and Dani,
1998). Furthermore, the stimulatory effect of nicotine on dopamine
output in the nucleus accumbens, monitored by microdialysis, has been
attributed to enhanced glutamate transmission via presynaptic 7*
nAChRs in the ventral tegmentum (Schilstrom et al., 1998). Reports to
date suggest that presynaptic nAChRs modulating glutamate release may be exclusively of the 7 subtype. There is good rationale for this
association: the relatively low affinity for ACh, rapid
desensitization, and modulation by choline (Alkondon et al., 1999) of
these receptors render them most suitable for the regulation of the
release of the major excitatory transmitter whose levels must be
rigorously controlled and limited to avoid the risk of overexcitation
and Ca2+-associated neurotoxicity.
Although it would be desirable to demonstrate directly that nicotinic
agonists elevate glutamate release from in vitro preparations, attempts
to do this have been unsuccessful (Wonnacott et al., 1995). In addition
to practical difficulties in measuring transmitter glutamate release,
the rapid desensitization of 7* nAChRs may confound the ability to
observe release evoked by nicotinic agonists using a superfusion
protocol with relatively poor temporal resolution (Kaiser and
Wonnacott, 1999).
Physiological Implications of Transmitter Cross-Talk.
This
study used pharmacological tools to dissect a relationship among
glutamate, dopamine, and presynaptic nAChRs in the rat striatum.
Although axo-axonic synapses between dopaminergic and cortical
afferents have not been demonstrated in the striatum, these inputs form
synapses in close proximity to each other on the dendrites and
dendritic spines of the GABAergic medium spiny neurons (Smith and
Bolam, 1990; see Fig. 5). Thus, glutamate would have to diffuse only a
relatively short distance to influence neighboring dopaminergic
terminals. The source of ACh (or choline) for activation of nAChRs is
currently less clear. The medium spiny neurons are the major synaptic
target for cholinergic interneurons (Izzo and Bolam, 1988), but the
spatial relationship between these synapses and those using dopamine
and glutamate as transmitters has not yet been established. However,
less than 10% of cholinergic varicosities in the rat striatum appeared
to be synaptic (Contant et al., 1996), consistent with volume
transmission, a concept that is gaining currency. This interplay
between transmitters at the level of the nerve terminal (illustrated in
the model in Fig. 5) will constitute a subtle means of local
coordination and modulation. This may be reflected in altered levels of
basal (tonic) transmitter release, as recorded in this study, but may
also govern other regulatory mechanisms (Radcliffe and Dani, 1998),
perhaps by interfacing with second messenger cascades via the
Ca2+ permeabilities of neuronal nAChRs.
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Footnotes |
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Received March 13, 2000; Accepted May 8, 2000
1 Present address: Department of Biology, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0357.
This work was supported by grants from the Biological and Biotechnological Sciences Research Council and European Community.
Send reprint requests to: Dr. S. Wonnacott, Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK. E-mail: s.wonnacott{at}bath.ac.uk
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Abbreviations |
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AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;
AnTx-a, (±)-anatoxin-a;
-Bgt, -bungarotoxin;
NMDA, N-methyl-D-aspartate;
Ctx-MII, -conotoxin-MII;
Ctx-ImI, -conotoxin-ImI;
DNQX, 6,7-dinitroquinoxaline-2,3-dione;
MLA, methyllycaconitine;
nAChR, nicotinic acetylcholine receptor.
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References |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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-Bungarotoxin-sensitive nicotinic receptors in olfactory bulb neurons and presynaptic modulation of glutamate release.
J Pharmacol Exp Ther
278:
1460-1471-conotoxin which targets 32 nicotinic acetylcholine receptors.
J Biol Chem
271:
7522-7528-Conotoxin IMI exhibits subtype-specific nicotinic acetylcholine receptor blockade: preferential inhibition of homomeric 7 and 9 receptors.
Mol Pharmacol
48:
194-199[Abstract].-conotoxin-MII of the nicotinic stimulation of [3H]dopamine release from rat striatal synaptosomes and slices.
J Neurochem
70:
1069-1076[Medline].-Conotoxin MII blocks nicotine-stimulated dopamine release in rat striatal synaptosomes.
J Neurosci
17:
5263-5270-Conotoxin-ImI: A competitive antagonist at -bungarotoxin-sensitive neuronal nicotinic receptors in hippocampal neurons.
J Pharmacol Exp Ther
278:
1472-148342 subtype in the modulation of dopamine release from rat striatal synaptosomes.
J Neurosci
20:
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 M. Solinas, M. Scherma, L. Fattore, J. Stroik, C. Wertheim, G. Tanda, W. Fratta, and S. R. Goldberg Nicotinic {alpha}7 Receptors as a New Target for Treatment of Cannabis Abuse J. Neurosci., May 23, 2007; 27(21): 5615 - 5620. [Abstract] [Full Text] [PDF]
|
|
|
|
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|
 J. Barik and S. Wonnacott Indirect Modulation by {alpha}7 Nicotinic Acetylcholine Receptors of Noradrenaline Release in Rat Hippocampal Slices: Interaction with Glutamate and GABA Systems and Effect of Nicotine Withdrawal Mol. Pharmacol., February 1, 2006; 69(2): 618 - 628. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. van Nierop, S. Bertrand, D. W. Munno, Y. Gouwenberg, J. van Minnen, J. D. Spafford, N. I. Syed, D. Bertrand, and A. B. Smit Identification and Functional Expression of a Family of Nicotinic Acetylcholine Receptor Subunits in the Central Nervous System of the Mollusc Lymnaea stagnalis J. Biol. Chem., January 20, 2006; 281(3): 1680 - 1691. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hamada, J. P. Hendrick, G. R. Ryan, M. Kuroiwa, H. Higashi, M. Tanaka, A. C. Nairn, P. Greengard, and A. Nishi Nicotine Regulates DARPP-32 (Dopamine- and cAMP-Regulated Phosphoprotein of 32 kDa) Phosphorylation at Multiple Sites in Neostriatal Neurons J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 872 - 878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Escubedo, C. Chipana, M. Perez-Sanchez, J. Camarasa, and D. Pubill Methyllycaconitine Prevents Methamphetamine-Induced Effects in Mouse Striatum: Involvement of {alpha}7 Nicotinic Receptors J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 658 - 667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Quik, S. Vailati, T. Bordia, J. M. Kulak, H. Fan, J. M. McIntosh, F. Clementi, and C. Gotti Subunit Composition of Nicotinic Receptors in Monkey Striatum: Effect of Treatments with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine or L-DOPA Mol. Pharmacol., January 1, 2005; 67(1): 32 - 41. [Abstract] [Full Text] [PDF]
|
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S. L. Parker, Y. Fu, K. McAllen, J. Luo, J. M. McIntosh, J. M. Lindstrom, and B. M. Sharp Up-Regulation of Brain Nicotinic Acetylcholine Receptors in the Rat during Long-Term Self-Administration of Nicotine: Disproportionate Increase of the {alpha}6 Subunit Mol. Pharmacol., March 1, 2004; 65(3): 611 - 622. [Abstract] [Full Text] [PDF]
|
|
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|
V. P. Grinevich, P. A. Crooks, S. P. Sumithran, A. J. Haubner, J. T. Ayers, and L. P. Dwoskin N-n-Alkylpyridinium Analogs, a Novel Class of Nicotinic Receptor Antagonists: Selective Inhibition of Nicotine-Evoked [3H]Dopamine Overflow from Superfused Rat Striatal Slices J. Pharmacol. Exp. Ther., September 1, 2003; 306(3): 1011 - 1020. [Abstract] [Full Text] [PDF]
|
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|
|
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N. Champtiaux, C. Gotti, M. Cordero-Erausquin, D. J. David, C. Przybylski, C. Lena, F. Clementi, M. Moretti, F. M. Rossi, N. Le Novere, et al. Subunit Composition of Functional Nicotinic Receptors in Dopaminergic Neurons Investigated with Knock-Out Mice J. Neurosci., August 27, 2003; 23(21): 7820 - 7829. [Abstract] [Full Text] [PDF]
|
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L. Zhang and R. A. Warren Muscarinic and Nicotinic Presynaptic Modulation of EPSCs in the Nucleus Accumbens During Postnatal Development J Neurophysiol, December 1, 2002; 88(6): 3315 - 3330. [Abstract] [Full Text] [PDF]
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) or presence of 10 µM mecamylamine
(mec, 
) or 500 µM kynurenic acid (KyA, 
). Antagonists were
introduced into the perfusion buffer 10 min before the agonist pulse.
[3H]Dopamine released above baseline is expressed as a
percent of the response to stimulation with 1 µM AnTx-a, taken as a
control and included in every assay. Values are the mean ± S.D.
from at least three independent determinations. The
concentration-response data for synaptosomes are fitted to a one-site
Hill equation, giving an apparent EC50 value of 134 ± 26 nM, whereas the data for slices are fitted to a two-site model (see
Experimental Procedures), giving apparent
EC50 values of 241 ± 36 nM and 5.1 ± 0.3 µM.
**, significantly different from corresponding responses to AnTx-a
in the absence of kynurenic acid, P < .01, one-way
ANOVA, Dunnett's test.
