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 Previous Article | Next Article 
The Journal of Neuroscience, May 15, 1999, 19(10):4123-4131
Opposing Role of Dopamine D1 and D2 Receptors in Modulation of
Rat Nucleus Accumbens Noradrenaline Release
Louk J. M. J.
Vanderschuren,
George
Wardeh,
Taco J.
De Vries,
Arie
H.
Mulder, and
Anton N. M.
Schoffelmeer
Research Institute Neurosciences Vrije Universiteit, Department of
Pharmacology, Medical Faculty, Free University, Amsterdam, The
Netherlands
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ABSTRACT |
The role of dopamine receptors in the modulation of nucleus
accumbens noradrenaline release was investigated in superfused rat
brain slices. At concentrations of  1 µM, dopamine
enhanced, whereas at higher concentrations dopamine inhibited
electrically evoked [3H]noradrenaline
release. The D1 receptor agonist SKF-38393 increased, whereas
the D2 agonist quinpirole inhibited evoked
[3H]noradrenaline release. These effects were
attenuated by the D1 antagonist SCH-23390 and the D2 antagonist
( )-sulpiride, respectively, indicating that accumbens noradrenaline
release is regulated by stimulatory D1 and inhibitory D2 receptors.
Whereas ()-sulpiride enhanced, SCH-23390 did not reduce evoked
accumbens [3H]noradrenaline release, indicating a
tonic activation of D2 receptors only. Given the similar apparent
affinity of dopamine for D1 and D2 receptors in striatal slices, the
lack of tonic D1 receptor activation suggests that D1, unlike D2,
receptors are extrasynaptically localized. No dopaminergic modulation
of noradrenaline release was observed in rat medial prefrontal cortex
or amygdala slices. To examine the regulation of accumbens
noradrenaline release under conditions of increased dopaminergic
activity, measurements were made using slices of amphetamine-pretreated
rats. In these slices, the electrically evoked release of
[3H]dopamine and
[3H]noradrenaline was enhanced. The increasing
effect of ()-sulpiride on noradrenaline release was augmented, and
SCH-23390 almost completely reversed this enhancement of
[3H]noradrenaline release. These data suggest that
whereas although under a moderate dopaminergic tone, accumbens
noradrenaline release is mainly regulated by inhibitory D2 receptors,
under circumstances of increased dopaminergic activity, recruitment of
extrasynaptic stimulatory D1 receptors contributes to enhancement of
noradrenaline release.
Key words:
noradrenaline release; nucleus accumbens; dopamine
release; dopamine D1 receptor; dopamine D2 receptor; amphetamine
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INTRODUCTION |
Because of extensive and reciprocal
connections with limbic and motor systems, the nucleus accumbens (NAcc)
is thought to be important for the generation of motor responses to
emotionally relevant environmental stimuli (Mogenson, 1987 ; Kalivas et
al., 1993). The dopaminergic projection from the ventral tegmental area
to the NAcc, part of the so-called mesolimbic dopamine (DA) system, has
received particular attention in this respect. For instance, NAcc DA
neurotransmission has been shown to be involved in exploratory
behavior, in the psychomotor and reinforcing effects of drugs of abuse,
and in appetitive and preparatory behaviors. This has led to the
general assumption that the mesolimbic DA system plays a key role in
goal-directed and motivational behavior (Le Moal and Simon, 1991;
Phillips et al., 1991; Koob, 1992; Amalric and Koob, 1993; Salamone,
1994; Schultz et al., 1997).
Interactions between the various inputs into the NAcc can be expected
to serve to optimize information flow necessary for the generation of
adaptive motor responses. In this respect, it has been shown recently
that the shell portion of the NAcc receives a dense noradrenaline
(NA)-containing projection, originating primarily in the nucleus
tractus solitarius (NTS) (Berridge et al., 1997; Delfs et al., 1998).
Because there is very little information on the possible interaction
between NAcc NA and DA systems (Nurse et al., 1984; Yavich et al.,
1997), we investigated here the role of DA receptor stimulation on
electrically evoked NA release from rat NAcc slices in
vitro.
Extracellular concentrations of NAcc DA and NA are enhanced by
systemically and locally applied psychostimulant drugs, such as
amphetamine and cocaine (Di Chiara and Imperato, 1988; Seiden et al.,
1993; McKittrick and Abercrombie, 1997; Reith et al., 1997), and
psychostimulant-induced locomotion is known to rely on increases in
NAcc DA neurotransmission (Kelly et al., 1975; Pijnenburg et al., 1975;
Delfs et al., 1990; Amalric and Koob, 1993). In addition, involvement
of NA in the psychomotor effects of amphetamine and cocaine has also
been demonstrated (Snoddy and Tessel, 1985; Dickinson et al., 1988;
Harris et al., 1996). With regard to repeated exposure to
psychostimulants, there is ample evidence that this causes NAcc DA
nerve terminals to become hypersensitive (Kalivas and Stewart, 1991;
Nestby et al., 1997; Pierce and Kalivas, 1997). If NAcc NA
neurotransmission is modulated by DA, this regulation might be altered
as a result of psychostimulant-induced increase in DA tone.
Therefore, we also investigated the effects of DA receptor activation
on NA release in NAcc slices of rats repeatedly treated with
amphetamine. This is of particular interest given the notion that the
neuroadaptations occurring after repeated psychostimulant exposure are
involved in drug-induced addiction and psychosis (Robinson and Becker,
1986; Robinson and Berridge, 1993).
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MATERIALS AND METHODS |
Animals and drug pretreatments. All experiments were
approved by the Animal Care Committee of the Free University of
Amsterdam. Male Wistar rats (Harlan CPB, Zeist, The Netherlands),
weighing 180-200 gm at the time of arrival in the laboratory, were
housed two per cage in Macrolon cages under controlled
conditions (lights on from 7:00 A.M. to 7:00 P.M.) for 1 week
before use. Food and water were available ad libitum.
Animals receiving drug pretreatment were briefly handled on the 2 d preceding the beginning of treatment. Pretreatment consisted of
intraperitoneal injections with 2.5 mg/kg (+)-amphetamine or
saline, administered once daily on 5 consecutive days. Three days after
the last injection, the animals were killed, and
neurotransmitter release was determined as described below.
Determination of neurotransmitter release. Rats were
decapitated, their brains were rapidly removed, and NAcc (including
core and shell), medial prefrontal cortex, or amygdala were dissected from a 1-mm-thick coronal slice using the atlas of Paxinos and Watson
(1986). Slices (0.3 × 0.3 × 1 mm) were prepared using a McIlwain tissue chopper and incubated and superfused as described previously (Schoffelmeer et al., 1994). Briefly, slices were washed twice with Krebs'-Ringer's bicarbonate medium containing (in
mM) 121 NaCl, 1.87 KCl, 1.17 KH2PO4, 1.17 MgSO4,
1.22 CaCl2, 25 NaHCO3, and 10 D-(+)-glucose and subsequently incubated for 15 min in this
medium under a constant atmosphere of 95% O2-5%
CO2 at 37°C. After preincubation, the slices were rapidly
washed and incubated for 15 min in 2.5 ml of medium containing 5 µCi
of [3H]NA or, in one set of experiments, 5 µCi
of [3H]DA under an atmosphere of 95%
O2-5% CO2 at 37°C. Because the brain areas
investigated have both dense dopaminergic and noradrenergic innervations, 1 µM GBR-12909 was added to the
medium during incubation to prevent accumulation of
[3H]NA in DA nerve terminals, or 3 µM desipramine was added during incubation to prevent
accumulation of [3H]DA in NA nerve terminals.
After labeling, the slices were rapidly washed and transferred to each
of 24 chambers of a superfusion apparatus (~4 mg of tissue in 0.2 ml
of volume) and superfused (0.20 ml/min) with medium gassed with 95%
O2-5% CO2 at 37°C. The superfusate was
collected as 10 min samples after 40 min of superfusion (t = 40 min). Ca2+-dependent
neurotransmitter release was induced during superfusion by exposing the
slices to electrical biphasic block pulses (1 Hz, 10 mA, 2 msec pulses
to evoke release of [3H]NA, and 1 Hz, 30 mA, 2 msec pulses to evoke release of [3H]DA) for 10 min
at t = 50 min (electrical field stimulation). ()-Sulpiride or SCH-23390 were added 30 min before, and DA,
SKF-38393, quinpirole, or
N6-cyclopentyladenosine (CPA) were added 20 min before electrical field stimulation. In the experiments
investigating the effects of DA on [3H]NA release,
3 µM desipramine was present during superfusion to
prevent uptake of DA into noradrenergic nerve terminals. Drugs remained
present until the end of the experiment. In each experiment, quadruplicate observations were made.
Calculation of release data. The radioactivity remaining at
the end of the experiment was extracted from the tissue with
0.1N HCl. The radioactivity in superfusion fractions and tissue
extracts was determined by liquid scintillation counting. The efflux of radioactivity during each collection period was expressed as a percentage of the amount of radioactivity in the slices at the beginning of the respective collection period. The electrically evoked
release of neurotransmitter was calculated by subtracting the
spontaneous efflux of radioactivity from the total overflow of
radioactivity during stimulation and the next 10 min. A linear decline
from the 10 min interval before to the 20-30 min after the start of
stimulation was assumed for calculation of the spontaneous efflux of
radioactivity. The release evoked was expressed as percentage of the
content of radioactivity of the slices at the start of the stimulation
period. Effects of drugs were calculated as percentages of control and
analyzed using one-way ANOVA and, where appropriate, followed by
Student-Newman-Keuls tests. Curve fitting was done by nonlinear
regression analysis.
Radiochemicals and drugs.
[3H]Noradrenaline (39 Ci/mmol) and
[3H]dopamine (47 Ci/mmol) were purchased from the
Radiochemical Center (Amersham, Buckinghamshire, UK). DA and
()-sulpiride were purchased from Sigma (St. Louis, MO), and
SKF-38393, SCH-23390, quinpirole, GBR-12909, and CPA were purchased
from Research Biochemicals (Natick, MA). Desipramine was a gift from
Ciba-Geigy (Basel, Switzerland). (+)-Amphetamine-sulfate was purchased
from O.P.G. (Utrecht, The Netherlands) and dissolved in sterile saline.
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RESULTS |
DA modulates NAcc NA release through stimulatory D1 and inhibitory
D2 receptors
DA had a biphasic effect on the electrically evoked
[3H]NA release (F(6,142) = 10.78; p < 0.001). A concentration of 0.3 µM slightly increased and 1 µM
significantly increased the evoked release of
[3H]NA from superfused rat NAcc slices by ~15%.
At a concentration of 3 µM, DA had no effect on
[3H]NA release, and at 10 and 30 µM,
DA appeared to suppress the electrically evoked release of
[3H]NA by 20-25% (Fig.
1).
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Figure 1.
Effect of DA on the electrically evoked release of
[3H]NA from superfused slices of rat NAcc. The
slices were superfused in the presence of 3 µM
desipramine to prevent uptake of DA into noradrenergic nerve terminals
and were stimulated electrically at t = 50 min for
10 min. DA was added to the superfusion medium 20 min before
depolarization. Control [3H]NA release, in the
presence of 3 µM desipramine, amounted to 5.8 ± 0.4%. The data, expressed as percent of control release, represent
means ± SEM of 24 observations. *p < 0.05 compared with control values (Student-Newman-Keuls test).
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To investigate the contribution of D1 and D2 receptors to the effects
of DA on [3H]NA release, selective D1 and D2
agonists and antagonists were applied. The DA D1 agonist SKF-38393
dose-dependently increased electrically evoked
[3H]NA release (F(5,46) = 7.06; p < 0.0001). The maximal effective concentration
of SKF-38393 (1 µM) caused an increase of
[3H]NA release of ~35% above control (Fig.
2A). In contrast, the evoked release of [3H]NA was dose-dependently
inhibited by the D2 agonist quinpirole (F(5,63) = 14.52; p < 0.0001); a 40% inhibition was observed
at a concentration of 1 µM quinpirole (Fig.
2B). When the effects of the D1 and D2 antagonists
SCH-23390 and ()-sulpiride, respectively, were tested, it appeared
that 0.3 µM SCH-23390 tended to increase [3H]NA release by ~10%
(F(1,53) = 3.74; p = 0.06) (Fig.
2C). ()-Sulpiride potently increased evoked
[3H]NA release, with a 65% increase above control
values observed with 1 µM ()-sulpiride
(F(1,39) = 109.00; p < 0.0001)
(Fig. 2C).
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Figure 2.
Effects of the D1 agonist SKF-38393
(A), the D2 agonist quinpirole
(B), the D1 antagonist SCH-23390
(C; hatched bar), and the D2 antagonist
()-sulpiride (cross-hatched bar) on the electrically
evoked release of [3H]NA from superfused slices of
rat NAcc. The slices were superfused and stimulated electrically at
t = 50 min for 10 min. SKF-38393 and quinpirole
were added to the superfusion medium at 20 min, and SCH-23390 and
()-sulpiride were added 30 min before depolarization. Control
[3H]NA release amounted to 4.7 ± 0.3%. The
data, expressed as percent of control release, represent means ± SEM of 8-28 observations. *p < 0.05 compared with
control values (Student-Newman-Keuls test); **p < 0.001 compared with control values (ANOVA).
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Consistent with the previous experiment, 1 µM SKF-38393
increased electrically evoked [3H]NA release by
33%, whereas 1 µM quinpirole suppressed it by 32% (Fig.
3, left). In the presence of
0.3 µM SCH-23390, the increasing effect of SKF-38393 on
[3H]NA release was significantly attenuated, from
33% in the absence of to 10% in the presence of respective control
values of SCH-23390 (F(1,37) = 15.53;
p < 0.001) (Fig. 3, middle). In contrast,
0.3 µM SCH-23390 did not at all affect the effect of
quinpirole on electrically evoked [3H]NA release;
in both the absence and presence of SCH-23390, 1 µM
quinpirole inhibited [3H]NA release by 32%
(F(1,35) = 0.02; NS) (Fig. 3,
middle). Exactly the opposite effect was found with
()-sulpiride. In a concentration of 1 µM,
()-sulpiride significantly antagonized the inhibitory effect of
quinpirole on evoked [3H]NA release; the decrease
in [3H]NA release induced by quinpirole was 32%
in the absence of and 11% in the presence of ()-sulpiride
(F(1,26) = 11.65; p < 0.01) (Fig. 3, right). In contrast, the increase in
[3H]NA release induced by SKF-38393 was not
affected by ()-sulpiride (F(1,27) = 0.28; NS)
(Fig. 3, right).
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Figure 3.
Effect of 0.3 µM SCH-23390
(middle) and 1 µM ()-sulpiride
(right) on the quinpirole-induced decrease and the
SKF-38393-induced increase of electrically evoked
[3H]NA release in superfused rat NAcc slices. The
slices were superfused and stimulated electrically at
t = 50 min for 10 min. SCH-23390 or ()-sulpiride
were added 30 min before depolarization, and SKF-38393 or quinpirole
were added to the superfusion medium at 20 min before depolarization.
Control [3H]NA release amounted to 4.7 ± 0.3% of total tissue radioactivity in the absence of antagonists,
5.1 ± 0.3% in the presence of SCH-23390, and 7.7 ± 0.5%
in the presence of ()-sulpiride, respectively. Data, expressed as
percent of respective control release, represent means ± SEM of
24 observations. Open bars represent
[3H]NA release under control conditions,
hatched bars represent release in the presence of 1 µM quinpirole, and cross-hatched bars
represent release in the presence of 1 µM SKF-38393.
*p < 0.05; **p < 0.001 compared with control values; ##p < 0.001 compared
with same condition without antagonist (ANOVA).
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In the presence of 1 µM ()-sulpiride, DA potently
increased electrically evoked [3H]NA release
(F(5,91) = 7.85; p < 0.0001).
The dose-effect curve of DA was shifted leftward, as apparent from the
finding that the lowest concentration of DA to significantly increase
NA release was decreased from 1 µM to 30 nM.
In addition, the dose-response curve of DA was also shifted upward,
because the maximal effect of DA was increased from 15% in the absence
of to 35% in the presence of ()-sulpiride (Fig.
4). It should be noted that the increase in [3H]NA release induced by DA in the presence of
()-sulpiride was of a similar magnitude as that induced by SKF-38393
(compare Figs. 2A, 4). Experiments on the effects of
DA in the presence of SCH-23390 yielded inconsistent results, probably
because of the fact that the selectivity of SCH-23390 for D1 over D2
receptors in brain slices is less than 10-fold (Plantjé et al.,
1984). Indeed, concentrations of SCH-23390 >0.3 µM
caused a marked enhancement of [3H]NA release
(data not shown), as observed with ()-sulpiride.
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Figure 4.
Effect of DA in the absence (compare with Fig. 1;
open circles) and in the presence of 1 µM
()-sulpiride (closed circles) on the electrically
evoked [3H]NA release of superfused rat NAcc
slices. The slices were superfused in the presence of 3 µM desipramine to prevent uptake of DA into noradrenergic
nerve terminals and were stimulated electrically at
t = 50 min for 10 min. ()-Sulpiride was added to
the superfusion medium at 30 min before depolarization, and DA was
added at 20 min before depolarization. Control
[3H]NA release amounted to 5.8 ± 0.4% of
total tissue radioactivity in the absence of and 7.2 ± 0.5% in
the presence of ()-sulpiride, respectively. Data, expressed as
percent of control release, represent means ± SEM of 24 observations. *p < 0.05 compared with control
values in the presence of ()-sulpiride (Student-Newman-Keuls
test).
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The effects of D1 receptor stimulation on NAcc NA release are not
secondary to extracellular conversion of cAMP to adenosine
Stimulation of D1 receptors enhances adenylate cyclase activity
(Stoof and Kebabian, 1984). It has been described recently that certain
effects of D1 receptor stimulation are the consequence of extracellular
conversion of cAMP to adenosine, which, through stimulation of
adenosine A1 receptors, alters neuronal activity (Bonci and Williams,
1996; Harvey and Lacey, 1997). To investigate whether the effect of D1
receptor activation on NAcc [3H]NA release was
caused by such a mechanism, the effect of the adenosine A1 agonist CPA
was investigated. CPA did not mimic the effect of SKF-38393. On the
contrary, CPA appeared to suppress the electrically evoked
[3H]NA release by 13% at a concentration of 0.1 µM and by 19% at a concentration of 1 µM
(F(2,33) = 5.67; p < 0.01; data
not shown).
DAergic regulation of NA release does not occur within medial
prefrontal cortex and amygdala
Regulation by DA of NA release has been reported previously to
occur in the hypothalamus (Misu et al., 1985) and hippocampus (Jackisch
et al., 1985), but, in those areas only a D2-mediated inhibition of NA
release was found. To investigate whether the opposite regulation of NA
release by D1 and D2 receptors also occurred in other limbic areas, we
studied the effects of SKF-38393 and quinpirole on NA release in slices
of medial prefrontal cortex and amygdala. In slices of medial
prefrontal cortex, 1 µM SKF-38393 slightly, but not
significantly (12% above control), increased electrically evoked
[3H]NA release (F(1,23) = 2.17; NS). Quinpirole, at a concentration of 1 µM, did
not affect medial prefrontal cortex [3H]NA release
(F(1,23) = 0.05; NS) (Fig.
5, left). In rat amygdala slices, SKF-38393 (1 µM) did not at all affect
electrically evoked [3H]NA release
(F(1,23) = 0.04; NS), whereas quinpirole (1 µM) caused a slight (12%) nonsignificant inhibition of
evoked [3H]NA release
(F(1,22) = 1.19; NS) (Fig. 5,
right).
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Figure 5.
Effects of SKF-38393 (1 µM) and
quinpirole (1 µM) on the electrically evoked release of
[3H]NA from superfused slices of rat medial
prefrontal cortex (MPFC; left) or
amygdala (right). The slices were superfused and
stimulated electrically at t = 50 min for 10 min.
SKF-38393 and quinpirole were added to the superfusion medium at 20 min
before depolarization. Control [3H]NA release
amounted to 4.1 ± 0.3% in medial prefrontal cortex slices and
3.0 ± 0.2% in amygdala slices. Data, expressed as percent of
control release, represent means ± SEM of 11-12 observations.
Open bars represent [3H]NA release
under control conditions, hatched bars represent release
in the presence of 1 µM quinpirole, and
cross-hatched bars represent release in the presence of
1 µM SKF-38393.
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Altered modulation of NAcc NA release by DA in slices of
amphetamine-pretreated rats
In NAcc slices of amphetamine-pretreated animals, the electrically
evoked release of [3H]DA was augmented by 73%
(F(1,15) = 61.25; p < 0.0001)
(Fig. 6A), and the
electrically evoked [3H]NA release was increased
by 22% (F(1,23) = 7.34; p < 0.05) (Fig. 6B). Whereas in slices of
saline-pretreated rats 1 µM ()-sulpiride caused a 46%
increase in evoked NAcc [3H]NA release (data not
shown, but see Fig. 2C), in slices of amphetamine-pretreated rats, 1 µM ()-sulpiride enhanced evoked
[3H]NA release by 92%. Thus, in the presence of 1 µM ()-sulpiride, the relative enhancement of evoked
[3H]NA release in slices of
amphetamine-pretreated rats was 60% (F(1,45) = 74.37; p < 0.0001)
(Fig. 6C) compared with 22% in the absence of sulpiride
(Fig. 6B), indicating enhanced D2 receptor activation
in slices of amphetamine-pretreated rats. SCH-23390 (0.3 µM) slightly enhanced evoked
[3H]NA release in NAcc slices of saline-pretreated
animals, but in slices of amphetamine-pretreated rats, SCH-23390
suppressed [3H]NA release by 20% (data not
shown). However, these data cannot be interpreted unambiguously because
0.3 µM SCH-23390 may be expected to partially block D2
receptors (Plantjé et al., 1984). Therefore, the effect of
SCH-23390 was investigated in the presence of 1 µM
()-sulpiride. Interestingly, under circumstances of D2 receptor blockade, 0.3 µM SCH-23390 appeared to diminish the
increase in NAcc [3H]NA release after previous
amphetamine treatment to 15% (F(1,22) = 6.20;
p < 0.05) (Fig. 6D). Thus,
SCH-23390 almost abolished the increase in electrically evoked
[3H]NA release observed in slices of rats
preexposed to amphetamine.
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Figure 6.
A, Electrically evoked release of
[3H]DA from superfused NAcc slices of rats
pretreated with amphetamine (5 × 2.5 mg/kg, i.p.; hatched
bar) or saline (open bar) 3 d after
treatment. [3H]DA release amounted to 1.0 ± 0.1% in slices of saline-pretreated rats. B,
Electrically evoked release of [3H]NA from
superfused NAcc slices of rats pretreated with amphetamine (5 × 2.5 mg/kg, i.p.; hatched bar) or saline (open
bar) 3 d after treatment. [3H]NA
release amounted to 4.1 ± 0.2% in slices of saline-pretreated
rats. C, Electrically evoked release of
[3H]NA from superfused NAcc slices of rats
pretreated with amphetamine (5 × 2.5 mg/kg, i.p.; hatched
bar) or saline (open bar) in the presence of 1 µM ()-sulpiride 3 d after treatment.
[3H]NA release amounted to 6.0 ± 0.3% in
slices of saline-pretreated rats. D, Electrically evoked
release of [3H]NA from superfused NAcc slices of
rats pretreated with amphetamine (5 × 2.5 mg/kg, i.p.;
hatched bar) or saline (open bar) in the
presence of 1 µM ()-sulpiride and 0.3 µM
SCH-23390 3 d after treatment. [3H]NA release
amounted to 7.8 ± 0.4% in slices of saline-pretreated rats. NAcc
slices were superfused and stimulated electrically at
t = 50 min for 10 min. ()-Sulpiride and SCH-23390
were added to the superfusion medium at 30 min before depolarization.
Note that the data are expressed as percent of respective control
release in slices of saline-pretreated rats. The basic effects of
()-sulpiride and SCH-23390 (Fig. 2C) are therefore not
shown. Data represent means ± SEM of 8-23 observations.
*p < 0.05; ***p < 0.0001 compared with saline pretreatment (ANOVA).
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DISCUSSION |
The present data demonstrate that NA release in the rat NAcc is
under the opposing influence of stimulatory DA D1 and inhibitory DA D2
receptors. These NA release-modulatory DA receptors are presumably
localized on nerve terminals of NA neurons originating in the NTS
(Delfs et al., 1998). Although occurrence of presynaptic receptors on
central nerve terminals has indeed been demonstrated (Fisher et al.,
1994; Sesack et al., 1994; Hersch et al., 1995), the involvement of
indirect or transsynaptic regulation of neurotransmitter release cannot
be excluded, even in superfused brain slices. It is therefore possible
that DA indirectly affects NAcc NA release through modulation of
excitatory or inhibitory neurotransmission. In this respect,
electrophysiological experiments have shown that, in the NAcc,
stimulation of presynaptic D1 receptors depresses both inhibitory and
excitatory transmission (Pennartz et al., 1992; Harvey and Lacey, 1996;
Nicola and Malenka, 1997, 1998), whereas activation of presynaptic D2
receptors suppresses excitatory transmission (O'Donnell and Grace,
1994). Microdialysis studies have shown that D1 receptor stimulation
actually enhances NAcc GABA release, whereas D2 receptor stimulation
appears to inhibit glutamate release in the NAcc (Kalivas and Duffy,
1997). Thus, some of these data seem to fit with the present
observations of stimulatory effects of D1 receptors and inhibitory
effects of D2 receptor stimulation, but others do not. The present data
can therefore not be explained solely on the basis of DA effects on excitatory and inhibitory inputs into the NAcc rather than direct DA
effects on NA varicosities. Neurotransmission-modulatory effects of D1
receptor stimulation may also be indirectly mediated by the release of
adenosine (Bonci and Williams, 1996; Harvey and Lacey, 1997), but the
selective adenosine A1 receptor agonist CPA appeared not to mimic the
stimulatory effects of D1 receptor stimulation but even slightly
decreased NAcc [3H]NA release. This suggests that,
although release-inhibitory adenosine A1 receptors may be present on
NAcc NA nerve terminals, the stimulatory effect of D1 receptor
activation is not mediated indirectly through activation of adenosine
receptors. Together, although possible indirect effects of D1 and D2
receptor stimulation cannot be ruled out, it is most likely that the
release-modulatory DA receptors are located on NAcc NA varicosities.
With regard to the tonic activation of these DA receptors, the D2
antagonist ()-sulpiride strongly increased NAcc NA release, whereas
the D1 antagonist SCH-23390 did not reduce NA release. Thus, released
endogenous DA tonically inhibits NAcc NA release through stimulation of
D2 receptors, whereas the stimulatory D1 receptors are not activated
under the present in vitro conditions. Because one of our
previous studies showed that, in superfused rat striatal slices,
exogenous and endogenous DA displays an identical apparent affinity to
D1 and D2 receptors (Schoffelmeer et al., 1994), differences in
apparent affinity for DA cannot account for these findings. A more
likely explanation is that D1 and D2 receptors are differentially
located on or near NA nerve terminals. We hypothesize that D2 receptors
are located near active zones formed by DA and NA nerve terminals,
whereas D1 receptors are located more distal from the site of DA
release (Fig. 7, top). Indeed,
such a differential localization of D1 and D2 receptors is supported by
ultrastructural studies indicating that NAcc D1 receptors are mainly
localized extrasynaptically (Smiley et al., 1994; Hersch et al., 1995;
Caillé et al., 1996), whereas D2 receptors can be found near
DAergic nerve terminals (Fisher et al., 1994; Sesack et al., 1994;
Hersch et al., 1995; Delle Donne et al., 1996). Interestingly,
voltammetric measurements of synaptic DA efflux showed that
extrasynaptic DA neurotransmission occurs in the NAcc (Garris et al.,
1994) and that excitatory signals can be conveyed by extrasynaptic D1
receptors activated by released DA, diffusing up to 12 µM
away from release sites (Gonon, 1997). In the case of DA modulation of
NAcc NA release, this would imply that DA released from mesolimbic
neurons preferentially interacts with D2 receptors, located in the
vicinity of the site of release. D1 receptors, located further away,
might be stimulated in case of higher rates of release and/or during
later phases of neurotransmission by DA that has diffused away from the
synapse (Fig. 7, bottom). The biphasic effects of
exogenously applied DA, activating both D1 and D2 receptors
(Schoffelmeer et al., 1994), could be the consequence of such a
different role of D1 and D2 receptors. For instance, when low
concentrations of exogenous DA are applied, the possible inhibitory
effect of this exogenous DA could be masked by the tonic D2
receptor-mediated inhibition of NA release, causing the D1
receptor-mediated increasing effect to prevail (Fig. 1). It is also
worth noting that, in the presence of ()-sulpiride when DA will only
stimulate D1 receptors, the dose-response curve of DA was shifted
upward, as well as leftward, closely resembling the dose-response
curve of SKF-38393 (compare Figs. 4, 2A).
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Figure 7.
Hypothetical model of the modulation of NAcc NA
release by DA and alterations therein after repeated exposure to
amphetamine. DA ( ), released from mesolimbic projections, is able to
modulate NA ( ) release in two directions: stimulation through D1
receptors and inhibition through D2 receptors. In drug-naive animals,
released DA will tonically inhibit NA release via stimulation of
inhibitory D2 receptors, whereas D1 receptors do not seem to be
involved in the tonic DAergic regulation of NA release. We suggest that
this is because of differential localization of D1 and D2 receptors on
or near NA varicosities (top). In the case of enhanced
DA overflow (e.g., caused by repeated exposure to amphetamine in
vivo), the D2 receptor-mediated suppression of NA release will
increase. In addition, excess DA will diffuse further away from the
site of release and stimulate D1 receptors as well, causing NA release
to become enhanced (bottom).
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Both the medial prefrontal cortex and the amygdala represent limbic
brain areas that, similar to the NAcc, receive dense DA and NA
innervations (Ungerstedt, 1971; Moore and Bloom, 1978, 1979; Le Moal
and Simon, 1991). However, [3H]NA release in
slices of these areas does not seem to be modulated by DA. A possible
explanation for this difference is that the NA projection to the NAcc
originates mainly in the NTS (Delfs et al., 1998), whereas medial
prefrontal cortex and amygdala receive a NA innervation from the locus
ceruleus (Ungerstedt, 1971; Moore and Bloom, 1979). Similar phenomena
have been observed with regard to the modulation of NA release by
opioid receptors, which also seems to differ between different regions
of origin (Heijna et al., 1991). The present data add to a growing body
of evidence that NAcc NA release may be modulated in a unique manner.
For instance, we have shown recently that, unlike in most other brain areas receiving NA input, NAcc NA release is not under the inhibitory influence of  2-autoreceptors (Schoffelmeer et al.,
1998).
The physiological relevance of the opposite regulation of NAcc NA
release by D1 and D2 receptors remains to be elucidated. Coordinated
activity of NAcc NA and DA neurotransmission may be necessary for
adequate processing of motivational, visceral, and autonomic stimuli
into behavioral responses (Le Moal and Simon, 1991; Phillips et al.,
1991; Salamone, 1994; Schultz et al., 1997; Delfs et al., 1998). The
subtle interregulation of NAcc NA and DA release therefore suggests the
existence of a catecholaminergic fine-tuning mechanism modulating
the generation of adaptive behavioral responses. In this respect, it is
of interest to note that recent electrophysiological experiments have
shown that, while in the NAcc DA, via D1 receptors, inhibits both
excitatory and inhibitory transmission; NA, via -receptors only
inhibited excitatory, but not inhibitory, transmission (Nicola and
Malenka, 1998). This suggests that the balance of DA and NA
neurotransmission in the NAcc might determine whether
excitatory or inhibitory input into NAcc neurons will prevail.
In addition, the entwinement of NAcc DA and NA systems could be
involved in certain phenomena associated with drug abuse, such as
psychostimulant sensitization and opiate withdrawal (Harris and
Aston-Jones, 1994). In parallel to the effects on NAcc NA release
described here, administration of D2 agonists into the NAcc shell has
been shown to inhibit, and administration of a D1 agonist has been
shown to enhance naloxone-evoked opiate withdrawal effects, whereas an
intra-NAcc D2 antagonist appeared to evoke opiate withdrawal phenomena
(Harris and Aston-Jones, 1994). Because increased NA activity
accompanies opiate withdrawal (Akaoka and Aston-Jones, 1991; De Vries
et al., 1993), it is likely that the effects of intra-NAcc-applied
DAergic drugs on opiate withdrawal involve modulation of NAcc NA release.
In NAcc slices of amphetamine-pretreated rats, the electrically evoked
release of both [3H]NA and
[3H]DA was enhanced. Moreover, the increase in
[3H]NA release induced by D2 receptor blockade
with ()-sulpiride was enhanced, indicating an increase in the tonic
D2-mediated suppression of NA release. Remarkably, SCH-23390 primarily
antagonized this augmentation of NAcc NA release induced by amphetamine
preexposure. These data indicate that, under conditions of different
dopaminergic tone in the accumbens, NA release is differentially
regulated by DA receptors. In addition, they are consistent with our
hypothesis that D1 receptors represent extrasynaptic receptors,
particularly stimulated under conditions of increased DA release. Thus,
under circumstances of moderate DA tone, released DA, stimulating D2 receptors, tonically suppresses NAcc NA release, whereas
extrasynaptically located D1 receptors play a less prominent role
in the regulation of NA release (Fig. 7, top). When DA
tone is increased, such as in amphetamine-pretreated rats, enhanced
DA release from mesolimbic terminals increases the tonic
D2-receptor-mediated suppression of NA release. In addition, augmented
DA release will also stimulate extrasynaptic D1 receptors, resulting in
a net increase in NAcc NA release (Fig. 7, bottom). Assuming
that the balance between NAcc DA and NA activity is relevant for the
formation of adequate adaptive behavioral responses, this
amphetamine-induced disbalance in catecholamine neurotransmission could
represent a substrate for the distorted motivational and affective
behaviors characteristic for drug-induced addiction and psychosis.
| |
FOOTNOTES |
Received Nov. 23, 1998; revised Feb. 22, 1999; accepted March 2, 1999.
This work was supported by the Netherlands Organization for Scientific
Research (NWO) Grant 903-42-007.
Correspondence should be addressed to Dr. Louk J. M. J. Vanderschuren, Research Institute Neurosciences Vrije Universiteit, Department of Pharmacology, Medical Faculty, Free University, Van der
Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
| |
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ABSTRACT
INTRODUCTION
