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The Journal of Neuroscience, April 15, 2002, 22(8):3293-3301
Changes in Extracellular Dopamine Induced by Morphine and
Cocaine: Crucial Control by D2 Receptors
Françoise
Rougé-Pont1, *,
Alessandro
Usiello3, *,
Marianne
Benoit-Marand2, *,
François
Gonon2,
Pier Vincenzo
Piazza1, and
Emiliana
Borrelli3
1 Institut National de la Santé et de la
Recherche Médicale (INSERM) U259, Université Victor
Segalen Bordeaux 2, 33077 Bordeaux Cedex, France, 2 Centre
National de la Recherche Scientifique (CNRS) Unité Mixte de
Recherche 5541, Université V. Segalen Bordeaux 2, 33076 Bordeaux,
France, and 3 Institut de Génétique et de
Biologie Moléculaire et Cellulaire, INSERM, CNRS,
Université Louis Pasteur, 67404 Illkirch Cedex, Communauté
Urbaine de Strasbourg, France
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ABSTRACT |
An increase of extracellular dopamine (DA) concentration is a major
neurobiological substrate of the addictive properties of drugs of
abuse. In this article we investigated the contribution of the DA D2
receptor (D2R) in the control of this response. Extracellular DA levels
were measured in the striatum of mice lacking D2R expression (D2R /)
by in vivo microdialysis after administration of the psychostimulant cocaine and the opioid morphine. Interestingly, the
increase in extracellular DA induced by both drugs was strikingly higher in D2R/ than in wild-type littermates. This indicates that
D2Rs play a key role in the modulation of DA release in response to
drugs of abuse. Furthermore, this observation prompted us to investigate the dopaminergic autoreceptor function in the absence of D2
receptor in D2R/ mice. Results obtained using complementary microdialysis and voltammetry analyses show that the autoreceptor function regulating DA release is totally abolished in the absence of
D2R, despite unchanged DA uptake and basal DA efflux. Finally, we
propose that the short isoform D2S receptor of the D2 receptors is the
one controlling change in DA release induced by drugs of abuse. Indeed,
the neurochemical effects of cocaine and morphine are unchanged in
animals with a selective deletion of the long isoform D2L receptor.
Thus, deregulated expression of D2R isoforms might be involved in the
vulnerability of an individual to drug abuse.
Key words:
dopamine; D2 receptors; knock-out mice; dopaminergic
autoreceptors; microdialysis; voltammetry; addictive drugs
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INTRODUCTION |
Dopaminergic (DAergic) pathways
regulate diverse physiological functions ranging from locomotion to
motivated behaviors and pituitary hormone release (Jackson and
Westlind-Danielsson, 1994 ). An altered DAergic neurotransmission seems
implicated in several neuropathologies, such as Parkinson's disease
and schizophrenia (Seeman and Kapur, 2000). The relevance of a
controlled dopamine (DA) release is highlighted by the physiological
consequences of the intake of addictive drugs. Practically, all drugs
of abuse share the common feature of increasing extracellular
concentration of DA in the striatal complex (Di Chiara, 1995; Berke and
Hyman, 2000). Individuals with higher predisposition to develop
addiction show a higher drug-induced DA release (Piazza and Le Moal,
1996, 1998). Suppression or reduction of drug-induced DA release
profoundly decreases the reinforcing effects of drugs (Wise, 1996).
Therefore, the molecular identification of the factors modulating the
increase in extracellular DA induced by drugs of abuse is a fundamental step in the understanding of the pathophysiological basis of addiction.
At least two types of proteins participate in the regulation of the
extracellular concentration of DA induced by drugs of abuse. The DA
transporter (DAT), which re-uptakes DA from the synaptic cleft into
DAergic neurons (Graefe and Bonish, 1988; Giros et al., 1996) and the
DA autoreceptors. DA autoreceptors once activated by extracellular DA
inhibit the firing of DA neurons, as well as DA synthesis and release
(Roth, 1984; Starke et al., 1989). DA D2 and D3 receptors (D2R, D3R)
have been postulated to have autoreceptor functions (Jackson and
Westlind-Danielsson, 1994; Shafer and Levant, 1998). Although it has
been possible to define the implication of the DAT in drug abuse by
analyzing DAT/ mice (Giros et al., 1996; Sora et al., 1998), the
role of the autoreceptors has been postulated (White and Kalivas,
1998).
In this report we have analyzed the role played by DA D2 autoreceptors
in response to systemic administration of the psychostimulant cocaine
and the opioid morphine. In vivo microdialysis was used to
assess variations in the extracellular concentrations of DA, elicited
by these drugs. Experiments were performed using DA D2R mutants in
comparison to wild-type (WT) littermates. Two different D2R mutant mice
were compared, those lacking both isoforms of the receptor (D2L and
D2S) (Baik et al., 1995) and D2L/ mice (Usiello et al., 2000) in
which only the expression of the long isoform is missing. These studies
indicate that the D2 receptors directly and firmly regulate the
increase in extracellular DA concentrations elicited by morphine and
cocaine. We also show, using microdialysis and voltammetry, that
deletion of the D2R is a sufficient condition to totally suppress
autoreceptor-mediated inhibition of DA release both in the striatum and
in the shell of the nucleus accumbens (AcbSh). These results suggest
that among the D2-like receptor family, the expression of the D2
receptor is a necessary condition to ensure a functional autoreceptor
mediated regulation of this function. Finally, parallel analyses
performed on D2L knock-out (KO) mice, in which only the D2S
isoform of the D2R is expressed, suggest that the D2L receptor does not
control the increase in extracellular DA induced by cocaine and
morphine. The latest results suggest that the D2S receptor is the DA
autoreceptor involved in the control of DA levels after administration
of addictive drugs.
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MATERIALS AND METHODS |
Animals
Animals were bred and raised under standard animal housing
conditions, in a 12 hr light/dark cycle (lights on between 8:00 A.M.
and 8:00 P.M.). Food and water were available ad libitum. D2R/ (Baik et al., 1995) and D2L/ mice (Usiello et al., 2000) and the respective WT littermates were used. All mice were in a mixed
genetic background (25% 129/Sv and 75% C57BL/6J) All the experiments
were performed in accordance with French (Ministère de
l'Agriculture et de la Forêt, 87-848) and European Economic Community (EEC, 86-6091) guidelines for care of laboratory animals.
Drugs
Cocaine (20 and 40 mg/kg), quinpirole (0.3 mg/kg), and
haloperidol (0.5 mg/kg) were injected intraperitoneally; morphine
sulfate (9, 18 mg/kg) was injected subcutaneously. Urethane was
dissolved in distilled water and injected intraperitoneally.
For microdialysis, all drugs were injected after three stable baseline
points (<10% variation) were observed. Drugs concentration for
cocaine and morphine were in the range of those inducing unambiguous behavioral effects. For quinpirole and haloperidol the dose used are
among the most used for the neurochemical characterization of the
presynaptic effect of these drugs.
Microdialysis
The microdialysis procedure used has been previously described
(Rouge-Pont et al., 1993). Briefly, anesthetized mice (chloral hydrate;
400 mg/kg, i.p.) were implanted with a guide cannula (CMA-Carnegie
Medicin-Sweden) in the striatum. Damage to the target site was
minimized by implanting the tips of the guide cannula 2 mm above the
desired site. The coordinates (in mm), were: anteroposterior, +1;
mediolateral, 1.9; and dorsoventral, 2.5 relative to bregma according
to the atlas of Franklin and Paxinos (1997). Dialysis experiments were
conducted in freely moving mice. Seven days after surgery, the
microdialysis probe (CMA/11; 2 mm cuprophane membrane length) was
inserted through the guide cannula, and the animals returned to their
home cage. Animals were transferred to the microdialysis test cage
(Phymep, Paris, France) 24 hr after probe implantation. Probes were
then connected to a syringe pump (Harvard 22; Harvard Apparatus, South
Natick, MA) and perfused at a perfusion rate of 1 µl/min with a
modified artificial CSF containing (in mM): NaCl,
145; KCl, 2.7; CaCl2, 1.2;
MgCl2, 1;
Na2HPO4/NaH2PO4
(buffer), 2, pH 7.4. Microdialysis samples (20 µl) were automatically
injected in the HPLC every 20 min using a fully automated on-line
system. HPLC coupled to a coulometric detector (Coulochem II;
ESA, Bedford, MA) was used to detect DA (detection limit: 0.3 pg/20
µl sample). Cannula placements were verified histologically on 30 µm coronal sections using thionine staining. Data were expressed as
percentage of baseline. Baseline was defined as the average of the last
three preinjection values. At the end of each experiment animals were killed and the brain was removed, frozen at 20°C, and
cryostat-sectioned into 30-µm-thick sections collected on
gelatin-coated slides. Sections were colored with toluidine blue for
anatomical observations. Only animals with corrected placed probes
(Fig. 1) were used in data analysis.
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Figure 1.
Position of the microdialysis probe in the dorsal
striatum. Coronal section (30 µm) of a mouse brain showing the
implantation site of a dialysis probe, in the dorsal striatum
(arrow), and the area within which all probes were
contained (rectangle).
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In vivo voltammetry
MFB electrical stimulation. Adult mice were
anesthetized with urethane (1.8 gm/kg, i.p.), fixed in a stereotaxic
frame using a mouse adapter (Stoelting Co., Wood Dale, IL),
positioned according to the atlas of Franklin and Paxinos (1997), and
maintained at 37°C. In each animal a concentric bipolar stimulating
electrode (SNEX-200; Rhodes Medical Instruments) was implanted in the
medial forebrain bundle (MFB) 2.1 mm posterior to bregma and either 1.1 or 0.8 mm lateral to medial line to evoke DA release in the striatum or
in the AcbSh, respectively. The depth of the stimulating electrode was
adjusted for each experiment so that the DA response was maximal. Stimulation pulses (0.5 msec, 300 µA) were applied using an isolated stimulator (DS2; Digitimer, Hertfordshire, UK) triggered by a MacLab/2e
system (ADInstrument, Castle Hill, New South Wales, Australia).
Electrochemical techniques. The electrochemical technique
used here, continuous amperometry with untreated carbon fiber
electrodes, provides excellent time resolution and sensitivity.
Unfortunately, this technique exhibits a poor chemical resolution as
compared with fast scan cyclic voltammetry and can be only used to
monitor DA overflow evoked by brief MFB electrical stimulations (Dugast et al., 1994; Michael and Wightman, 1999). However, with respect to
brief DA overflow in anesthetized rodents, the validity of this
approach has been confirmed by anatomical, pharmacological and
physiological data (Dugast et al., 1994; Suaud-Chagny et al., 1995;
Benoit-Marand et al., 2000). Moreover, results obtained with this
technique are in excellent agreement with similar observations provided
by fast scan cyclic voltammetry (Garris and Wightman, 1994; Michael and
Wightman, 1999).
Measuring electrodes, whose active surface was a carbon fiber 8 µm in
diameter and 250-µm-long (AGT 10000; SOFICAR, Saint Maurice, France),
were implanted either in striatum (1.7 mm lateral to medial line, 1.1 mm anterior to bregma, and 2.75-3.25 mm below the cortical surface) or
in AcbSh (0.6 mm lateral, 1.1 mm anterior to bregma, and 4.25-4.75 mm
below the cortical surface). The dura mater was punctured by a used
carbon fiber electrode, and the new electrode was lowered through this
hole. The reference electrode was a silver wire coated with AgCl and
was maintained in contact with the skull by a sponge moistened with a
0.9% NaCl solution. A two electrode potentiostat (AMU 130; Radiometer
Analytical, Villeurbanne, France) was used to apply +0.4 V to the
carbon fiber electrode versus the reference electrode and to record the
current passing through them. The amplified signal was digitized by a MacLab/2e system coupled to a Macintosh computer running the
"Scope" program (ADInstruments). Train pulses stimulations
consisting of four pulses at 100 Hz (see Fig. 6) or of 10 pulses at 15 Hz (see Fig. 4) and the sequence of three train stimulations shown in
Figure 5 were applied every 15 sec. Ten consecutive responses to these
stimulations were recorded and averaged on-line. Only averaged
responses were stored for subsequent analysis. Time intervals between
consecutive train pulse stimulations were chosen after preliminary
experiments so that consecutive individual evoked responses were stable
in terms of kinetics and amplitude. For each type of stimulation the
current was also recorded while the carbon fiber electrode was held at
0 V. Because at this potential DA was not oxidized, only transient
electrical artifacts caused by the stimulation were recorded (Dugast et
al., 1994). To improve the recording of oxidation currents, these
artifacts were removed by subtracting data obtained at 0 V from those
recorded at +0.4 V.
In the dorsal striatum variations in the oxidation current were
estimated in terms of changes in DA extracellular concentration on the
basis of in vitro calibration of the carbon fiber electrode performed after in vivo measurement as described (Dugast et
al., 1994). To perform this measure it was impossible to verify the exact location of the electrode tip in this structure. Indeed, the
exact location of the electrode tip can be visualized only inducing an
electrolytic lesion that damages the carbon fiber electrode. To ensure
a correct placement of the electrode, the exact position of the tip was
verified by performing an electrolytic lesion (+5 V for 4 sec) in three
animals before the start of the actual experiments and then in two
animals at the end of the experiments. All the tip placements verified
this way were in the area of the dorsal striatum shown in Figure
4D. Animals used to verify the tip position were not
used for data analysis. This strategy was possible because the striatum
is a large and relatively homogenous structure. However, in the case of
the nucleus AcbSh that is a much smaller brain area the anatomical
location of the recording electrode was checked after each experiment
by inducing an electrolytic lesion as described above. Because
this manipulation forbids the in vitro calibration of the
electrode, DA overflow evoked in AcbSh was expressed in picoamperes.
Animals in which the recording site was not localized in AcbSh close to
islands of Calleja were discarded.
For all the histological verifications the brain was removed, frozen at
20°C, and cryostat sectioned into 15-µm-thick sections collected
on gelatin-coated slides. Sections were colored with toluidine blue for
anatomical observations.
Data analysis. Two parameters were measured from evoked
overflow using the "Scope" software. The maximal amplitude of the overflow was expressed in changes in DA concentration. The DA half-life
corresponded to the time to 50% decay from the point where the maximal
overflow was reached. In the experiment described in Figure 5,
autoreceptors were activated by DA whose release was evoked by a
conditioning stimulation (Sc) consisting of four pulses at 15 Hz. Test
stimulations S1 and S2 consisted of three pulses at 100 Hz and were
respectively applied 4 sec before Sc and 300 msec after the end of Sc.
The amplitude of the DA overflow evoked by S2 was expressed as a
percentage of the overflow evoked by S1 and was used to measure the
inhibition of DA release induced by Sc. Because DA clearance is slower
in AcbSh than in striatum, the recording of DA overflow evoked by S2 in
AcbSh overlapped with that evoked by Sc. To accurately measure from
averaged recordings the amplitude of the overflow evoked by S2, the
curve corresponding to a similar overflow evoked by Sc, but not
followed by S2 and obtained in the same experiment, was subtracted.
Statistical analysis
All data were analyzed using ANOVA followed by appropriate
post hoc comparisons. Analyses were performed on raw data.
For microdialysis, genotype and treatment were used as between-factors and time as within-factor. For in vivo voltammetry, genotype
was used as between-factor and time or treatment as within-factors (haloperidol effect, autoinhibition induced by Sc).
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RESULTS |
The DAergic response to cocaine and morphine are controlled by
D2 receptors
D2R/ mice represent a useful model to assess the role of D2R
in the control of DA release in the striatum after drug challenge. These mice lack the expression of both the isoforms (D2L and D2S) of
the D2R (Baik et al., 1995). Cocaine and morphine effects on the
extracellular DA levels were analyzed in WT and D2R/ mice. Cocaine
acts directly on DAergic neurons by blocking the activity of DAT.
Morphine, conversely has an indirect effect and evokes DA release by
relieving the inhibition of mesencephalic GABAergic interneurons on
DAergic cells.
Changes in the extracellular level of DA were evaluated in the striatum
(Fig. 1) in freely moving mice of both genotypes by means of
microdialysis. The mean baseline concentration (in picograms per 20 min ± SEM) of DA in striatal dialysates was similar (ANOVA group
effect, F(1,69) = 0.32;
p > 0.57) in WT (5.12 ± 0.42; n = 32) and D2R/ (5.58 ± 0.65; n = 39) mice.
Cocaine administration induced a dose- and time-dependent (dose × time interaction, F(10,125) = 3.39;
p < 0.001) increase in striatal DA in animals of both
genotypes (Fig. 2A).
However, this increase was dramatically higher in D2R/ mutants as
compared with WT animals (genotype × time interaction,
F(5,125) = 3.97; p < 0.002). The higher concentration of extracellular DA in D2R-null mice
was observed for both cocaine doses
(F(5,90) = 4.88; p = 0.0006) (Fig. 2A), but the two groups did not differ
in response to saline (F(5,35) = 1.37;
p > 0.25). Interestingly, the response of D2R/
mice to 20 mg/kg of cocaine almost doubled that of WT mice at 40 mg/kg.
Accordingly, the response of mutant mice to 40 mg/kg was particularly
impressive and to our knowledge well above the range of increases
normally observed in WT animals.
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Figure 2.
Cocaine- and morphine-induced changes in
extracellular concentration of dopamine in WT and D2R/ mice.
A, The administration of cocaine (20 and 40 mg/kg, i.p)
induced a higher increase in dopamine in D2R/ than in WT animals.
B, The administration of morphine (9 and 18 mg/kg, s.c.)
induced a higher increase in dopamine in D2R/ than in WT mice.
Dialysates were collected in the striatum of freely moving animals
every 20 min, and data are expressed as mean ± SEM of changes
from baseline.
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We then assessed DA release elicited by morphine in animals of both
genotypes (Fig. 2B). Similar to what has been
observed in response to cocaine, morphine also drastically increased
extracellular DA levels in D2R/ mice in comparison with WT siblings
(genotype × time interaction,
F(5,110) = 9.13; p < 0.0001) (Fig. 2B). Strikingly, although
administration of morphine at 9 mg/kg failed to induce a significant
elevation of DA levels in WT animals
(F(8,32) = 0.33; p > 0.27), it induced a maximal response in mutant mice (Fig.
2B). Indeed, morphine at 9 mg/kg
(F(8,48) = 10.23; p < 0.0001) and 18 mg/kg (F(8,48) = 10.97;
p < 0.0001) elicited a similar increase of DA
extracellular levels in D2R/ mice
(F(1,12) = 0.23; p > 0.63). In contrast, in WT mice a significant effect of morphine on DA
release was only observed at 18 mg/kg
(F(8,48) = 3.58; p < 0.003). However, even at this dose, the increase of DA levels in WT was
half that induced in D2R/ mice by 9 mg/kg of morphine.
Haloperidol and quinpirole effects on DA release are suppressed in
D2R null mice
The striking effects of drug-induced changes in extracellular DA
level in D2R/ mice prompted us to analyze to which extent D2R
participates to the DAergic autoreceptor functions. Indeed, although it
is well established that the DA autoreceptor belongs to the D2-like
family (comprising D2, D3, and D4 receptors), the respective role
played by each one of these receptors in this function is still
controversial. In particular, D2 receptors and D3 receptors have been
supposed to serve autoreceptor functions because of their localization
on mesencephalic DAergic neurons (Jackson and Westlind-Danielsson,
1994; Diaz et al., 2000).
To investigate the role played by D2R in mediating autoreceptor
functions, the effect on DA release of systemic injections of a D2-like
specific receptor antagonist (haloperidol) and agonist (quinpirole)
were analyzed. Haloperidol and quinpirole are known to respectively
increase and decrease DA release by acting on DA autoreceptors. As
expected, in vivo microdialysis in WT mice showed that
haloperidol (0.5 mg/kg) significantly increased
(F(8,24) = 17.69; p < 0.0001) extracellular DA levels, whereas quinpirole (0.3 mg/kg)
significantly decreased it (F(8,48) = 56.28; p < 0.0001). In contrast neither haloperidol
(F(8,32) = 0.66; p > 0.71) nor quinpirole (F(8,48) = 0.97;
p > 0.46) exerted a significant effect on DA release
in D2R/ mice (Fig. 3).
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Figure 3.
Quinpirole- and haloperidol-induced changes in
extracellular concentration of dopamine in WT and D2R/ mice. The
D2-specific agonist (quinpirole) and antagonist (haloperidol) were
administered in WT and D2R/ mice. Quinpirole and haloperidol,
respectively, decrease and increased DA release in WT animals. In
contrast, the two drugs had no effects in D2R / mice. Dialysates
were collected in the striatum of freely moving animals every 20 min,
and data are expressed as mean ± SEM of changes from
baseline.
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To extend these findings we also studied the effects of haloperidol on
the release of DA evoked by MFB electrical stimulation. DA release was
recorded in anesthetized mice by carbon fiber electrodes implanted
either in the striatum or in the AcbSh (Fig.
4D). We extended the
study to the AcbSh because this brain structure is the one expressing
the highest concentration of D3 receptors. The AcbSh was studied only
by voltammetry because the small extension of this brain region in mice
makes it of very difficult access by a microdialysis probe. As
previously reported (Dugast et al., 1994; Benoit-Marand et al., 2000),
prolonged electrical stimulation of the MFB (10 pulses at 15 Hz) evoked
a DA overflow in WT animals, which reached a plateau from the third
pulse in striatum (Fig. 4A) and from the sixth in
AcbSh (Fig. 4B). This plateau was attributable to DA
reuptake and to autoregulation by D2-like receptors (Suaud-Chagny et
al., 1995; Benoit-Marand et al., 2000). Because DA reuptake is slower
in nucleus AcbSh than in the striatum (Suaud-Chagny et al., 1995), the
plateau was reached later in this structure. When autoreceptor
functions were blocked by haloperidol in WT mice, this plateau was not
observed (Fig. 4A,B). Interestingly, after
haloperidol injection (Fig. 4A-C) the maximal
amplitude of the evoked DA overflow was enhanced in comparison with the baseline only in WT mice by +354% in the striatum and by +189% in
AcbSh (ANOVA genotype × haloperidol interaction,
F(1,8) = 83.3, p < 0.0001 and F(1,8) = 24.0, p < 0.002 in striatum and in AcbSh, respectively).
Indeed haloperidol had no significant effect in D2R/ animals (Fig.
4A-C) either in striatum or in AcbSh. Importantly, under basal condition, the shape of DA overflow recorded in the striatum and AcbSh of D2R/ mice was similar to the one observed in
WT animals after haloperidol (no plateau phase) (Fig.
4A,B). It is also larger than the one observed in WT
animals before haloperidol (290 and 208% in striatum and AcbSh,
respectively; p < 0.02) (Fig. 4A,B).
These observations show that in WT animals, the DA released by the
first pulses stimulated D2 autoreceptors and inhibited the DA release
evoked by the last pulses in striatum as well as in AcbSh, although the
amplitude of this autoregulation appears more pronounced in the
striatum.
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Figure 4.
Effect of haloperidol on the DA overflow evoked by
prolonged stimulations in striatum and AcbSh of WT and D2R/ mice.
Typical recordings of the effect of haloperidol on DA overflow in one
WT mouse and one D2R / mouse before (Baseline) and
20 min after haloperidol (0.5 mg/kg, s.c.). DA overflow was evoked by
MFB stimulation consisting of 10 pulses at 15 Hz. The DA overflow
recorded in striatum (A) was expressed in terms
of changes in DA concentration by in vitro calibration
of the electrode. In AcbSh (B), because the
carbon fiber electrode was not calibrated after each experiment, the DA
overflow was expressed in terms of changes in oxidation current. The
maximal amplitude of the DA overflow observed 20 min after haloperidol
was expressed as a percentage of that observed before injection
(C). Data are given as mean ± SEM (5 animals in each group in the striatum, 6 WT and 4 D2R/ mice in
AcbSh). Anatomical location of the electrode tip in the dorsal striatum
and accumbens shell (D).
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Autoinhibition of DA release is suppressed in D2R null mice
To complete the characterization of autoreceptor function in D2R
null mice, we studied the inhibition by endogenous DA of its own
release. This phenomenon was studied in the dorsal striatum and in the
nucleus AcbSh by applying paired test stimulations (S1 and S2) of the
MFB, one of which was preceded by a conditioning stimulation (Sc). The
conditioning stimulation (four pulses at 15 Hz) used was
physiologically relevant and mimicked a burst of action potentials,
typically generated by dopaminergic neurons (Grace and Bunney, 1984).
The test stimulation (three pulses at 100 Hz) was selected as the
minimal brief stimulation evoking an accurately measurable DA overflow.
In the striatum of WT and D2R/ mice, in the absence of conditioning
stimulation (no Sc) both test stimulations (S1 and S2) evoked DA
overflow of the same maximal amplitude (Fig.
5A,C). In the dorsal striatum
of WT mice, the DA released by the conditioning stimulation inhibited
further DA release because the DA overflow evoked by S2 was about half of that evoked by S2 in the absence of Sc (Fig. 5A,C). In
contrast, this autoinhibition was not observed in the dorsal striatum
of D2R/ mice (Fig. 5A,C) (p > 0.1) (ANOVA genotype × Sc interaction, F(1,12) = 41.68; p < 0.0001).
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Figure 5.
Autoregulation of the evoked DA release in
striatum and AcbSh of WT and D2R/ mice. The DA overflow was evoked
in striatum (A) and AcbSh
(B) by MFB electrical stimulation. Test
stimulations S1 and S2 consisted of three pulses at 100 Hz and were
applied 4 sec apart. The conditioning stimulation (Sc)
consisted of four pulses at 15 Hz, and the delay between the end of Sc
and S2 was 300 msec. The amplitude of the DA overflow evoked by S2 was
expressed as a percentage of the overflow evoked by S1 and reflected
the inhibition of DA release induced by Sc. The data are given as
mean ± SEM (8 WT and 6 D2R/ in striatum, 6 WT and 5 D2R/
in the shell). In the absence of conditioning stimulation (noSc), S1
and S2 were similar in WT and D2R/ mice. In WT mice the DA overflow
evoked by Sc inhibited DA release evoked by S2 (*p < 0.002). In contrast, in D2R / mice Sc did not modify further DA
release.
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In the AcbSh of WT mice in the absence of conditioning stimulation, S2
evoked a slightly lower DA overflow than that evoked by S1 (Fig.
5B,C). The DA release evoked by conditioning stimulation (Sc) inhibited further DA release in the AcbSh of WT mice (Fig. 5B). In contrast, this autoinhibition was not observed in
the AcbSh of D2R / mice (Fig. 5B,C)
(p = 0.13) (ANOVA genotype × Sc
interaction, F(1,9) = 38.54;
p < 0.0002). The autoinhibition induced by Sc in WT
mice was higher in striatum than in AcbSh (p < 0.005) (Fig. 5C).
DA clearance and DA release per pulse in basal conditions
are unaltered in D2R null mice
To provide a quantitative estimate of DA uptake and a relative
estimate of DA release in D2R/ mice, DA overflow was evoked by
brief MFB electrical stimulations consisting of four pulses at 100 Hz.
These conditions were required for a reliable quantification of DA
overflow (Garris and Wightman, 1994; Benoit-Marand et al., 2000). The striatal DA half-life was
similar in D2R/ mice and WT littermates (Fig. 6, Table
1) and well correlated to that previously
found in C57/Bl6 mice (Benoit-Marand et al., 2000) and rats
(Suaud-Chagny et al., 1995). Although the DA half-life recorded from
D2R/ mice was slightly longer in duration as compared with WT
siblings, this difference did not reach statistical significance (F(1,12) = 3.00; p > 0.1). DA clearance depends on DA reuptake, this result suggests that in
our experimental conditions there are no major modifications of the DA
transporter function in D2R/ mice. The maximal amplitudes of the DA
overflow evoked by a brief stimulation showed a nonsignificant genotype
effect (F(1,8) = 3.56;
p = 0.096) (Fig. 6, Table 1). The evoked DA overflow
reflects DA release per pulse (multiplied by the number of pulses)
minus DA clearance by reuptake (Garris and Wightman, 1994;
Benoit-Marand et al., 2000). Because DA clearance is comparable in WT
and D2R/ mice, the similarity of the overflow amplitudes in WT and
D2R/ mice might be interpreted as a similarity of the DA release
per pulse in both genotypes.
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[in a new window]
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Figure 6.
DA overflow evoked in striatum of WT and D2R
/mice. DA overflow was evoked in the dorsal striatum by MFB
electrical stimulation consisting of four pulses at 100 Hz. In each
animal the evoked DA overflow was measured with the same electrode at
three different depths from the cortical surface (2.75, 3, and 3.25 mm). DA overflow was expressed in terms of change in dopamine
concentration by calibrating the electrode in vitro at
the end of each experiment. For each individual overflow two parameters
were measured: the half-life (i.e., the time for 50% decrease from the
maximum) and the maximal amplitude. The three pairs of values obtained
from the same animal were averaged. Data collected from several
experiments are given in Table 1.
|
|
Changes in striatal extracellular concentrations of DA in
response to cocaine and morphine administration in D2L null mice
The D2R gene encodes for two independent receptor isoforms, D2L
and D2S (Picetti et al., 1997). We have recently shown that deletion of
D2L in D2L/ mice profoundly modifies postsynaptic responses to DA
while it preserves autoreceptor-mediated functions (Usiello et al.,
2000). These results together with the observed suppression of
autoreceptor functions in D2R/ animals strongly suggest that the
D2S is the DA autoreceptor. Consequently, to provide insights into the
influence of D2L and D2S receptors on the DAergic response to drugs of
abuse, we analyzed cocaine and morphine-induced changes in
extracellular DA in D2L/ mice.
Similar DA concentrations were measured in the dialysates from WT
and D2L/ animals (WT: n = 13, 4.73 ± 0.6 pg/20 min; D2L /: n = 12, 3.96 ± 0.37 pg/20
µl) (genotype effect, F(1,23) = 1.12; p > 0.29). The injection of cocaine
significantly increased extracellular DA over time
(F(8,168) = 37.67; p < 0.0001) in a dose-dependent manner (dose × time interaction,
F(8,168) = 2.71; p < 0.007) (Fig. 7A). Importantly,
cocaine-induced increase in DA levels was identical in the two
genotypes (genotype effect, F(1,21) = 0.80; p > 0.38), regardless of the dose of cocaine
used (genotype × dose interaction,
F(1,21) = 0.63; p > 0.43) or time (genotype × time interaction,
F(5,105) = 0.87; p > 0.5).
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[in a new window]
|
Figure 7.
Cocaine and morphine-induced changes in
extracellular concentration of dopamine in WT and D2L/ mice.
A, The administration of cocaine (20 and 40 mg/kg, i.p)
and morphine (B) (9 and 18 mg/kg, s.c.) induced a
similar increase in dopamine in D2L/ and in WT animals. Dialysates
were collected in the striatum of freely moving animals every 20 min,
and data are expressed as mean ± SEM of changes from baseline.
|
|
Morphine administration in WT and D2L mutant mice elicited an increase
of the extracellular concentration of DA in the dorsal striatum
(F(8,104) = 4.05; p < 0.0003) in a dose-dependent manner (dose × time interaction,
F(8,104) = 3.88; p < 0.0004) (Fig. 7B). Similarly to what observed for cocaine
there was no significant difference in the response to morphine between
D2L mutant mice and WT littermates (genotype effect,
F(1,13) = 0.56; p > 0.46) and this regardless of the dose (genotype × dose
interaction, F(1,13) = 0.47;
p > 0.50) used and of time (genotype × time
interaction, F(5,65) = 0.14;
p > 0.97). Comparison of results in Figures 2 and 7
could be interpreted as the response to morphine, in the WT of D2R/
and D2L/ mice, is different. However, statistical analyses of the
values obtained in the two groups did not reveal any significant
difference. Furthermore, the only notable difference between means is
observed 80 min after morphine administration. The higher value in the
WT of the D2L experiment can be primarily accounted for by one animal
that had a very high response as also indicated by the very large error
bar at this time point.
These results indicate that a selective deletion of the D2L
receptor is not a sufficient condition for increasing the DAergic response to cocaine and morphine, suggesting a critical role of D2S
in regulating the magnitude of the response to these drugs.
| |
DISCUSSION |
DA plays a key role in the control of various physiological
functions. This control is achieved through the interaction with membrane receptors of the D1- or D2-like receptor families. Among these
families, members of the D2-like receptors bear an additional important
function related to the control of DAergic system homeostasis, the
autoreceptor function. The role of autoreceptors is critical, because
their activity indirectly regulates the function of all the other DA
receptors by modulating DA release. Presynaptic inhibition of DA
release is a physiological phenomenon by which extracellular DA
stimulates presynaptic autoreceptors to further inhibit DA release.
Since 1971 (Farnebo and Hamberger, 1971) this phenomenon has been
widely studied in vitro and in vivo (May and
Wightman, 1989; Starke et al., 1989; Suaud-Chagny et al., 1991;
Wiedemann et al., 1992). In particular, pharmacological as well as
anatomical studies have identified D2R and D3R as the potential
DA autoreceptors. However, lack of selective ligands able to
discriminate between D2 and D3 receptors has led to conflicting results
in the establishment of the D2-like receptor controlling the firing,
synthesis, and release of DA.
Here, we clearly show that expression of D2R is a necessary
condition for the maintenance of presynaptic inhibition. The deletion of D2 receptors in D2R mutant mice suppress the effects of the D2/D3
ligands, quinpirole and haloperidol, on DA release as studied by
microdialysis in freely moving animals. These results are further supported by in vivo voltammetry studies performed in the
dorsal striatum as well as in the AcbSh, a region where D3 receptors are highly expressed. Using this approach we show that in D2R/ mice
haloperidol effects on DA release evoked by MFB stimulation were
suppressed in both regions. Loss of DA-induced autoinhibition in the
dorsal striatum and AcbSh in D2R/ mice was also observed using
brief MFB stimulation mimicking physiological impulse flow.
Although D2R plays a crucial role in mediating the autoinhibition
observed in condition of high extracellular DA concentrations, our
results indicate that it plays a moderate role in controlling basal DA
release. Indeed, in D2R/ mice no significant changes were detected
in basal extracellular concentrations of DA, as measured by
microdialysis (present study; Dickinson et al., 1999) or in DA release
per pulse by voltammetry. In resting conditions (DA level 10 nM), it is very likely that D2R autoreceptors only exerts a
moderate tonic inhibition of DA release (Suaud-Chagny et al., 1991;
Dugast et al., 1997). In contrast, a maximal inhibitory autoreceptor
activity is observed when DA levels reach concentrations in the range
of 100 nM (Suaud-Chagny et al., 1991).
Previous pharmacological studies had implicated D3R as one of the DA
autoreceptors (Devoto et al., 1995; Gobert et al., 1995; Kreiss et al.,
1995; Lejeune and Millan, 1995), however results obtained in D3R KO
mice did not support these findings. In fact, neither DA synthesis nor
the firing rate of dopaminergic neurons is modified in the absence of
D3R (Koeltzow et al., 1998). Furthermore, putative selective D3R agents
were able to elicit similar effects in D3R-KO and WT mice (Koeltzow et
al., 1998). This suggests that the autoreceptor effects originally
attributed to the D3R in those studies where actually mediated by D2Rs.
Conversely, ablation of D2R expression leads to a total abrogation of
the inhibitory effects of DA on the firing of DAergic neurons in the
substantia nigra (Mercuri et al., 1997). In addition, analysis of
striatal synaptosomes preparations from D2R/ mice also suggested a
primary role of D2R in the control of DA release (L'Hirondel et al.,
1998). These observations together with the results presented in this article indicate that D2R is the major DA autoreceptor. Nevertheless, the study of Koeltzow et al. (1998) has shown that DA basal efflux is
significantly higher in D3R/ mice with respect to WT littermates. We did not observe such a difference between D2R/ mice and WT controls. This raises the interesting possibility that D3R is not
directly involved in the regulation of DA release from DAergic neurons,
a function that is served by D2R, but they could control basal DA
levels. It has indeed been postulated that D3R activity would mediate a
postsynaptic inhibitory feedback, which in its absence would increase
basal DA efflux (Koeltzow et al., 1998). These findings together with
ours may finally assign a role to D2R and D3R in regulating DA release.
It has been previously shown that D2R can modulate DA uptake (Meiergerd
et al., 1993; Cass and Gerhardt, 1994) and that DA uptake is decreased
in mice lacking D2 receptors (Dickinson et al., 1999). Here we observed
a trend to a lower DA half-life in D2R / mice compared with WT that
was not statistically significant. Because this parameter is almost
entirely governed by DA reuptake (Suaud-Chagny et al., 1995;
Benoit-Marand et al., 2000), at first glance, the present results seem
inconsistent with previous studies (Meiergerd et al., 1993; Cass and
Gerhardt, 1994; Dickinson et al., 1999). However, the DA overflow used
here to measure DA half-life was evoked by brief MFB stimulation, which
reached a maximal amplitude at <0.5 µM. In contrast,
Meiergerd et al. (1993) estimated the DA clearance rate from DA
overflows, evoked by local injection of high
K+ concentration, reaching a maximal
amplitude exceeding 25 µM. In both other studies (Cass
and Gerhardt, 1994; Dickinson et al., 1999), exogenous DA was locally
applied at a concentration of 200-400 µM, the resulting
DA overflow was measured at 0.3 mm from the injection pipette and
reached a maximal amplitude exceeding 1 µM. Altogether
these observations suggest that DA uptake is minimally regulated by D2
receptors in resting conditions, like in our experiments in which a not
statistically significant trend was found, but play a significant role
in case of high extracellular DA levels, like in previous published
reports, in which the DA transporters work closer to saturation and in
which D2 receptors are strongly stimulated.
The observation that D2R-mediated autoinhibition plays a major role in
controlling DA release in conditions of high extracellular DA levels
might explain the large influence of D2R on changes in extracellular DA
induced by drugs of abuse. Thus, the increase in DA induced by drug of
abuse is among the highest measurable and well above those induced by
physiological stimuli. Interestingly, our results show that DA increase
in response to morphine and cocaine is different in D2R/ mice and
is greater in response to cocaine than to morphine. This is very likely
attributable to the different mechanisms of action of the two drugs.
Cocaine increases DA by blocking the reuptake (Povlock and Schenk,
1997). Thus, in normal conditions the autoreceptor, which inhibits
firing and DA release, is the only remaining factor able to counteract cocaine effect. Indeed, in the absence of autoreceptors (i.e., D2R/
mice), an extremely high increase of DA is observed. In contrast,
morphine acts by increasing the firing of dopaminergic neurons (Johnson
and North, 1992). Consequently, loss of autoreceptors should lower the
threshold of morphine effect. However, the limiting factor in this case
is the activity of the DAT. Thus, when morphine is administered DA
increase should be, at least partially, compensated by DAT activity
even in the absence of the autoreceptors. Our results are in line with
this hypothesis. D2R/ mice do present a lower threshold response to
morphine than WT littermates. The difference between the two groups at
high morphine doses is still significant, but reduced in comparison to
the one observed with cocaine. Furthermore, a clear difference between
D2R/ and WT appears only late in time. This suggests that at the
beginning of the response to morphine DAT is the principal factor
limiting DA release and that inhibition of firing by autoreceptors
plays an essential role only when DA levels are high enough to
significantly stimulate D2 receptors.
Importantly, we show that the selective ablation of the D2L isoform of
the D2R does not modify the extracellular levels of DA in response to
cocaine and morphine. These results suggest that D2S receptors, which
are still expressed in D2L/ mice, play a crucial role in the
regulation of drug-induced changes in DA. Consequently, the large
enhancement of extracellular DA, induced by cocaine and morphine in
D2R/ mice, appears very likely to be caused by the deletion of the
D2S isoform of the D2 receptor. These are probably the most relevant
results shown in this study, because an increase in DA release has been
shown to be a key event mediating the addictive effect of drugs of
abuse. Therefore, we might speculate that a deregulation of D2
autoreceptor function, and in particular of the D2S isoform, might play
an important role in the pathophysiology of drug abuse as well as in
mediating vulnerability to drugs. This hypothesis is indirectly
supported by observations in animals spontaneously vulnerable to drug
abuse (Piazza et al., 1989; Piazza and Le Moal, 1996). These animals are characterized by an enhanced release of DA in response to addictive
drugs (Hooks et al., 1991; Rouge-Pont et al., 1993) as well as by a
lower number of D2R binding sites (Hooks et al., 1994) and lower
inhibition of DA discharge activity resulting from reduced
somatodendritic autoreceptor sensitivity (Marinelli and White,
2000).
In conclusion, D2Rs and in particular the D2S isoform are key elements
in regulating DA increase induced by drugs of abuse. The present
findings strengthen the hypothesis that deregulation of the expression
of these receptors, by increasing the DAergic response to drugs of
abuse, play a crucial role in the pathophysiology of addiction.
| |
FOOTNOTES |
Received Nov. 15, 2001; revised Feb. 7, 2002; accepted Feb. 8, 2002.
*
F.R.P., A.U., and M.B.M. have equally contributed to this work.
This work was supported by grants from Institut National de la
Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique, Hopitaux Universitaires de Strasbourg, Mission Interministérielle à la Lutte contre la Drogue et
la Toxicomanie, and Association pour la Recherche sue le Cancer
(E.B.), INSERM and Université de Bordeaux II (P.V.P.), and the
Mariano Scippacercola Foundation and FRM fellowships (A.U.). We are
grateful to V. Heidt, Muriel Petit, and Nelly Charrier for technical help.
Correspondence should be addressed to E. Borrelli, IGBMC, BP163, 67404 Illkirch Cedex C. U. de Strasbourg, France. E-mail: eb{at}igbmc.u-strasbg.fr.
| |
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TOP
ABSTRACT
INTRODUCTION
