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The Journal of Neuroscience, October 1, 1998, 18(19):7996-8002
Decreased Presynaptic Sensitivity to Adenosine after Cocaine
Withdrawal
Olivier
Manzoni1, 2,
Didier
Pujalte1,
John
Williams2, and
Joël
Bockaert1
1 Centre National de la Recherche Scientifique,
Unité Propre de Recherches 9023, 34094 Montpellier Cedex
05, France, and 2 Vollum Institute, Oregon Health Sciences
University, Portland, Oregon 97201.
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ABSTRACT |
The nucleus accumbens (NAc) is a site mediating the rewarding
properties of drugs of abuse, such as cocaine, amphetamine, opiates,
nicotine, and alcohol (Wise and Bozarth, 1987 ; Koob, 1992; Samson and
Harris, 1992; Woolverton and Johnson, 1992; Self and Nestler, 1995;
Pontieri et al., 1996). Acute cocaine has been shown to decrease
excitatory synaptic transmission mediated by the cortical afferents to
the NAc (Nicola et al., 1996), but the effects of long-term cocaine
treatment and withdrawal have not been explored. Here, we report that
long-term (1 week) withdrawal from chronic cocaine reduced the potency
of adenosine to presynaptically inhibit glutamate (Glu) release by
activating adenosine A1 receptors. Adenosine A1 receptors were not
desensitized, because the potency of the metabolically stable adenosine
analog N6-cyclopentyl-adenosine was unchanged after
chronic cocaine withdrawal. When adenosine transporters were blocked,
the potency of adenosine to inhibit Glu release from naive and
cocaine-withdrawn NAc slices was similar. These results suggest that
one of the long-term consequences of cocaine withdrawal is an augmented
uptake of adenosine. This long-lasting change expressed at the
presynaptic excitatory inputs to the medium spiny output neurons in the
NAc may help identify new therapeutic targets for the treatment of drug
abuse.
Key words:
nucleus accumbens; chronic cocaine; adenosine; transporter; withdrawal; drug abuse
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INTRODUCTION |
The nucleus accumbens (NAc) is
essential to the reinforcing properties of cocaine and all other
addictive drugs (Hyman, 1996; Koob, 1996). The vast majority of cells
in the NAc are GABAergic medium spiny neurons that have a very negative
resting membrane potential in brain slices in vivo as
in vitro. In addition, medium spiny neurons of the NAc are
interconnected by a dense network of recurrent collaterals and
therefore depend on glutamatergic excitatory afferents to generate
action potentials (Smith and Bolam, 1990; Pennartz et al., 1994). Acute
and chronic treatment with psychostimulants affect both dopamine
(DA) levels (Kalivas and Duffy, 1990; Self and Nestler, 1995)
and glutamatergic transmission (Nie et al., 1994; Pierce et al., 1996)
in the NAc. Slice experiments (Pennartz et al., 1990) have shown that
excitatory cortical afferents to the NAc express long-term potentiation
(Pennartz et al., 1993; Kombian and Malenka, 1994). Psychostimulants,
such as cocaine and amphetamine, decrease excitatory synaptic
transmission to the NAc via the activation of dopamine D1-like
receptors (Nicola et al., 1996). DA receptor inhibition of glutamate
(Glu) release could be mediated by either direct presynaptic D1
receptors activation (Nicola et al., 1996) or postsynaptic interaction
between dopamine D1 and NMDA receptors, causing the release of
adenosine that then acts on presynaptic adenosine A1 receptors (Harvey
and Lacey, 1997). Finally, presynaptic metabotropic Glu receptors are
also able to inhibit Glu release to the NAc (Manzoni et al., 1997). The
purpose of this study was to identify the adaptive changes in the
regulation of transmitter release at the excitatory afferents to the
NAc during withdrawal from chronic cocaine treatment.
Because a role for adenosine in the long-term changes of synaptic
transmission in response to chronic cocaine has been described in the
ventral tegmental area (Bonci and Williams, 1996) and there is evidence
for complex interactions between DA and adenosine receptors (Ferre et
al., 1997; Harvey and Lacey, 1997), we focused on adenosine-mediated
presynaptic regulation of excitatory transmission. Presynaptic A1
receptors have a strong inhibitory action on Glu release from
prefrontal cortex afferents (Uchimura and North, 1991; Harvey and
Lacey, 1997).
In this report, it is shown that withdrawal from chronic cocaine
reduces the apparent presynaptic sensitivity to adenosine. When
adenosine transporters were blocked, the potency of adenosine to
inhibit Glu release was identical in NAc slices from naive and
cocaine-withdrawn rats. It is concluded that cocaine withdrawal augments the uptake of adenosine.
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MATERIALS AND METHODS |
Parasagittal NAc and hippocampal slices (400 µm thick) were
prepared as described previously (Manzoni and Bockaert, 1995; Manzoni
et al., 1997) from 4- to 7-week-old male Sprague Dawley rats. The
artificial CSF used for all experiments contained (in mM): 126 NaCl, 2.5 KCl, 1.2 MgCl2, 2.4 CaCl2, 18 NaHCO3, 1.2 NaH2PO4, and 11 glucose, and was
equilibrated with 95% O2-5% CO2. Picrotoxin (100 µM) was present in all experiments to block
GABAA synaptic responses. Animals were given once daily
intraperitoneal injections of saline or cocaine (20 mg/kg) for 2 weeks.
The animals were tested 1 d or 1 week after the last cocaine
injection. All experiments were done in the absence of cocaine such
that slices from cocaine-treated animals were termed
cocaine-withdrawn.
To evoke synaptic potentials, stimuli (100 µsec duration) were
delivered at 0.033 Hz via bipolar stainless steel electrodes placed at
the prefrontal-accumbens border (Manzoni et al., 1997). Recordings
were made in the rostromedial dorsal accumbens close to the anterior
commissure. Whole-cell recordings (Blanton et al., 1989) were made with
patch pipettes containing (in mM): 122.5 Cs gluconate, 17.5 CsCl, 10 HEPES, 0.2 EGTA, 8 NaCl, 2 MgATP, 0.2 cAMP, and 0.3 Na3GTP, pH 7.2, 290-300 mOsm. Paired-pulse facilitation (PPF) was elicited by stimulating the input twice with a 50 msec interval. An Axopatch-1D (Axon Instruments) was used to record the
data, which were filtered at 2 kHz, digitized at 5 kHz on a DigiData
1200 interface (Axon Instruments), and collected on a personal computer
using ACQUIS-1 software (Bio-Logic). For field potential recordings,
both the field EPSP (fEPSP) slope (calculated with a least
square method) and fEPSP amplitude were measured. In whole-cell
recordings, EPSC amplitudes were measured by averaging a 5 msec window
around the peak and subtracting the average value obtained during a 5 msec window immediately before the stimulus. During miniature EPSC
(mEPSC) recordings, 1 µM tetrodotoxin was added to
the CSF. The mEPSCs were detected off-line using software that selected
putative mEPSCs according to both their fast rise time and slower decay
time (Manzoni et al., 1997). The fitting curves were calculated
according to y = {ymax  ymin/1 + (x/EC50)n} + ymin (in which ymax = response in the absence of agonist, ymin = response remaining in presence of maximal agonist concentration, x = concentration, EC50 = concentration of
agonist producing 50% of the maximal response, and n = slope) with Kaleidagraph software (Abelbeck Software). All values are
given as mean ± SEM and are normalized to their relative
baseline. Statistical analysis were done with the Mann-Whitney
U test using Statview-Student (Abacus Concepts,
Calabasas, CA). p < 0.05 indicated statistical
significance. Drugs used are as follows: 8-cyclopentyl-theophylline
(8-CPT), 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX),
N6-cyclopentyl-adenosine (N6CPA), and RO
20-1724 from Research Biochemicals (Natick, MA);
L-CCGI, L-AP-4, and (S)-4C3HPG from
Tocris Neuramin; tetrodotoxin, DA, cocaine,
S-(4-nitrobenzyl)-6-thioinosine (NBTI), and dipyridamole (DIPY) from
Sigma (St. Louis, MO).
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RESULTS |
The initial experiments used extracellular field potential
recordings to measure the effects of adenosine on synaptic responses evoked by stimulating prefrontal cortex fibers (Nicola et al., 1996;
Manzoni et al., 1997). Activation of A1 adenosine receptors cause
inhibition at many central synapses (Dunwiddie, 1985; Uchimura and
North, 1991; Manzoni et al., 1994; Harvey and Lacey, 1997). We observed
that fEPSPs, in the core of the NAc, were strongly inhibited by
bath-applied adenosine (data not shown). Adenosine (50 µM) reduced the fEPSP to 46.9 ± 9.3% of its basal
value. This depression was completely blocked by the A1 antagonists
8-CPT (40 µM) and DPCPX (200 nM); 50 µM adenosine reduced the fEPSP to 96.2 ± 3.1% and
112.2 ± 5.1% of control in the presence of 8-CPT or DPCPX,
respectively (p < 0.005; Mann-Whitney
U test, when comparing the inhibitory actions of 50 µM adenosine in the presence or absence of 8-CPT or
DPCPX; n = 3 and 5, respectively).
Whole-cell patch-clamp experiments indicated that this inhibition was
mediated by presynaptic A1 receptors. First, the adenosine-induced depression always caused an increase in the PPF (a presynaptic form of
short-term plasticity). Adenosine (50 µM) reduced the evoked EPSCs to 45 ± 11% of control and increased PPF to
170 ± 44% of control (n = 5), confirming
previous reports (Uchimura and North, 1991; Harvey and Lacey,
1997). Second, adenosine strongly inhibited the frequency of
spontaneous mEPSCs without changing their amplitude (Fig.
1C).
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Figure 1.
Reduction of A1 adenosine presynaptic inhibition
in the NAc of rats withdrawn from cocaine. A, Thirty
micromolar adenosine reduced the fEPSP to 50 ± 7%
(n = 7) of its basal value in naive rats
(top traces). In rats withdrawn from cocaine for 1 d (bottom traces), 30 µM adenosine reduced
the fEPSP to 82 ± 7% of its basal value. Traces represent
averages of 10 consecutive EPSPs. B, Withdrawal from
cocaine reduced the potency of adenosine to inhibit Glu release. The
EC50 values for adenosine was 32 ± 4 µM
(n = 9) in control rats, 70 ± 9 µM (n = 9) after 1 d withdrawal,
and 166 ± 3 µM (n = 8) after
8 d withdrawal. Each point is expressed as the percentage of
control responses in the absence of agonist, and the error bars
represent SEM. C, Cocaine withdrawal reduced the
inhibitory effects of adenosine of spontaneous Glu release. In control
rats (filled circles), the mEPSCs frequency was
reduced to 35.9 ± 5.8% of its baseline value
(n = 7), whereas the mEPSCs amplitude remained
unchanged (94.7 ± 4.7% of control). Withdrawal from cocaine did
not modify the average basal mEPSCs frequency (control rats, 5.6 ± 1.2 Hz; n = 9; cocaine-withdrawn rats, 4.8 ± 0.5 Hz; n = 9; p = 0.93;
Mann-Whitney U test) but clearly reduced the amount of
inhibition induced by 50 µM adenosine (open
circles); the maximal inhibition of the mEPSCs frequency was
68.7 ± 7.1% (n = 8), with no change in
mEPSCs amplitude.
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Rats were given once daily intraperitoneal injections of saline or
cocaine (20 mg/kg) for 2 weeks. Experiments were done 1 d or 1 week after the last cocaine injection. In slices prepared from naive
rats, adenosine (30 µM; 5 min) caused a depression of
synaptic transmission of ~50%, whereas in rats withdrawn from cocaine for 1 or 8 d this concentration of adenosine was without effect (Fig. 1A). Dose-response curves for adenosine
were shifted to the right in animals withdrawn from cocaine compared
with control, with no change in the maximal adenosine-induced
inhibition (Fig. 1B). Thus, withdrawing rats from
chronic cocaine injection had dramatic consequences on A1 presynaptic
inhibition of evoked Glu release in the NAc.
Cocaine withdrawal also affected the A1 inhibition of spontaneous Glu
release. In naive rats, the frequency of the mEPSCs was reversibly
depressed by adenosine (50 µM), an effect that was
reduced in rats withdrawn from cocaine (Fig. 1C). Withdrawal from cocaine did not modify the average basal mEPSC frequency (control
rats, 5.6 ± 1.2 Hz; n = 9; cocaine-withdrawn
rats, 4.8 ± 0.5 Hz; n = 9; p = 0.93; Mann-Whitney U test). Thus, chronic cocaine treatment
resulted in a long-term reduction in the potency of adenosine to
presynaptically inhibit transmitter release.
To distinguish between presynaptic changes attributable to a genuine
desensitization of presynaptic A1 receptors and modifications independent of A1 receptors, the effect of the selective and
metabolically stable adenosine A1 agonist N6CPA was examined. In
contrast to what was observed with adenosine, the dose-response curve
for N6CPA was the same in control and cocaine-withdrawn slices (Fig. 2A). This indicates
that a decrease in the sensitivity of adenosine A1 receptors was not
responsible for the long-term changes induced by cocaine
withdrawal.
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Figure 2.
The potency of the selective and
metabolically stable adenosine A1 agonist N6CPA was the same in control
and cocaine-withdrawn slices (1 d withdrawal). A, The
EC50 values for N6CPA were 43 ± 9 nM in
slices prepared from naive rats and 47 ± 16 µM in
slices from withdrawn rats (n = 5 and 7, respectively). B, The presynaptic effects of adenosine
were not diminished in the hippocampus. Both NAc and hippocampus slices
were prepared from the same animals. At the Schaffer collateral-CA1
pyramidal cells synapse of cocaine-withdrawn rats, adenosine-induced
presynaptic inhibition of Glu release was similar to what was observed
in naive rats; the EC50 values were 68 ± 4 µM (n = 5) and 53 ± 4 µM (n = 5), respectively.
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To test whether the presynaptic effects of adenosine were diminished in
other brain regions, hippocampal slices were prepared from the same
rats used for the NAc slice experiments. As shown in Figure
2B, at the Schaffer collateral-CA1 pyramidal cells
synapse, adenosine-induced presynaptic inhibition of Glu release was
normal in rats withdrawn from cocaine, suggesting that this effect is indeed specific to the NAc.
To further investigate the consequences of cocaine withdrawal in the
NAc, the effects of activation of dopamine D1 and metabotropic Glu
receptors (mGluRs) were examined (Nicola et al., 1996; Manzoni et al.,
1997). The inhibition of fEPSP caused by cocaine (30 µM; 10 min) and DA (100 µM; 10 min) was not different in
slices from control and cocaine-withdrawn rats (Table
1). In addition, the inhibition caused by
presynaptic mGluRs was not changed after chronic cocaine treatment.
Neither the inhibition induced by the selective group 3 mGluR agonist
L-AP-4 nor by the selective group 2 mGluR agonists
L-CCG1 and (S)-4C3HPG was modified after withdrawal (Table
1). Together, these observations excluded a general decrease of
presynaptic inhibition as a possible explanation for the effect of
cocaine withdrawal.
Acute withdrawal from cocaine and morphine lead to an upregulation in
the cAMP-dependent cascade in several areas of the brain (Nestler and
Aghajanian, 1997). Biochemical studies (Terwilliger et al., 1991; Self
and Nestler, 1995; but see Mayfield et al., 1992) have indicated an
overall upregulation of the cAMP-dependent cascade in the NAc in
response to chronic cocaine treatment. The role of the cAMP cascade
during cocaine withdrawal was examine by application of the adenylate
cyclase (AC) activator forskolin (FSK) (10 µM; 20 min)
(Seamon and Daly, 1986). FSK caused a potentiation of fEPSPs in control
rats (Fig. 3A) that was not
changed in rats withdrawn from cocaine (Fig. 3A). The
inactive FSK analog dideoxy-FSK (10 µM; 10 min) was
without effect (data not shown), indicating that the effects of FSK
were attributable to AC activation. The FSK-induced enhancement was
potentiated when slices were preincubated in the presence of the
adenosine A1 antagonist DPCPX (200 nM), indicating that the
metabolism of cAMP is one important source of extracellular adenosine
in NAc slice, as reported previously in the hippocampus (Dunwiddie and
Hoffer, 1980; Brundege et al., 1997; Dunwiddie et al., 1997). The
DPCPX-induced potentiation was similar in naive and withdrawn rats
(Fig. 3B). Thus, withdrawal from chronic cocaine did not
cause an upregulation of AC at the excitatory synapses to the NAc.
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Figure 3.
Withdrawal from cocaine did not cause an
upregulation of the AC at the excitatory terminal to the NAc.
A, The AC activator FSK caused a similar augmentation of
the EPSC in naive (filled circles;
n = 8) and cocaine-withdrawn (1 d withdrawal)
(open squares; n = 9) slices.
B, The FSK-induced enhancement was potentiated by the
adenosine A1 antagonist DPCPX to a similar extend in naive
(filled circles; n = 5) and
cocaine-withdrawn (open squares; n = 5) slices.
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The levels of endogenous adenosine depend on the activity of
adenosine-forming and adenosine-degrading enzymes (Brundege and Dunwiddie, 1997). In addition, adenosine uptake is an important mechanism that controls the extracellular levels of adenosine in the
brain (Dunwiddie and Hoffer, 1980; Dunwiddie, 1985; Dunwiddie and Diao,
1994; Brundege and Dunwiddie, 1997; Brundege et al., 1997; Dunwiddie et
al., 1997). Adenosine levels were estimated by measuring the increases
of the EPSCs amplitude caused by the A1 antagonists 8-CPT and DPCPX.
When uptake mechanisms were fully active, the effects of A1 antagonists
were small, indicating rather low tonic extracellular levels of
adenosine in both naive and cocaine-withdrawn rats (Fig.
4A). The source of this
basal level of adenosine was examined using the cAMP-dependent
phosphodiesterase inhibitor RO 20-1724 (Beavo and Reifsnyder, 1990).
As shown in Figure 4A, RO 20-1724 caused an increase
of the fEPSP to an extent similar to what was observed with the A1
antagonist in both naive and cocaine-withdrawn slices. In addition,
preincubation with DPCPX totally occluded the RO 20-1724
enhancement (Fig. 4A). The results support the
hypothesis that the metabolism of cAMP is one primary source of
extracellular adenosine in the NAc.
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Figure 4.
Endogenous adenosine levels are regulated by
metabolism and reuptake. A, The A1 antagonists
moderately increased the fEPSP, showing low endogenous extracellular
levels of adenosine in both naive and cocaine-withdrawn rats. The
cAMP-dependent phosphodiesterase inhibitor RO 20-1724 caused an
increase of the fEPSP similar to what was observed with the A1
antagonists in both naive and cocaine-withdrawn slices (1 d
withdrawal). Preincubation with DPCPX totally occluded the RO 20-1724
enhancement. B, The adenosine uptake inhibitors DIPY and
NBTI depress the fEPSP by increasing the extracellular adenosine
concentration; in both naive (n = 8) and
cocaine-withdrawn (n = 6) rats, the uptake
inhibitors caused a strong inhibition of the fEPSP that was totally
antagonized by DPCPX.
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In hippocampal slices, the adenosine uptake inhibitors DIPY and NBTI
have been shown to depress the fEPSP by increasing the extracellular
adenosine concentration (Dunwiddie and Hoffer, 1980; Dunwiddie and
Diao, 1994). Accordingly, in both naive and cocaine-withdrawn rats,
this combination of uptake inhibitors caused a strong inhibition of
excitatory synaptic transmission that was be totally antagonized by the
adenosine A1 antagonist DPCPX (Fig. 4B). Thus,
adenosine uptake is essential to control low extracellular levels of
adenosine in the NAc, as has been found in the hippocampus (Dunwiddie
and Hoffer, 1980; Dunwiddie and Diao, 1994).
The possibility that chronic cocaine treatment could result in an
upregulation of adenosine uptake was tested in experiments with
reuptake inhibitors (Dunwiddie and Diao, 1994). Treatment with the
uptake blockers NBTI and DIPY caused a large depression of the fEPSP
(Fig. 4B). Under these conditions, accumulation of endogenous adenosine reduced the fEPSP to the point that a precise measure of the effects of exogenously applied adenosine was not possible. To reduce levels of endogenous adenosine, slices were preincubated with RO 20-1724 (200 µM) to block adenosine
production from cAMP metabolism. This greatly reduced the inhibition
induced by the uptake blockers (Fig.
5A). This observation confirms
that phosphodiesterase-mediated degradation of cAMP is a major source of extracellular adenosine in the NAc.
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Figure 5.
Role of uptake in regulating adenosine levels in
cocaine-withdrawn rats. A, Phosphodiesterase-mediated
degradation of cAMP is an important source of extracellular adenosine
in the NAc. The inhibition induced by the uptake blockers NBTI plus
DIPY (n = 6) was greatly reduced when slices were
preincubated with RO 20-1724 (200 µM;
n = 6) to block adenosine production from cAMP
metabolism. B, When adenosine uptake was blocked by a
mixture of NBTI plus DIPY and endogenous adenosine formation was
reduced with RO 20-1724, the potency of adenosine to inhibit
excitatory synaptic transmission was similar in naive and chronic
cocaine rats after 1 d of withdrawal. The EC50 values
were 2.1 ± 5.5 µM (n = 5) and
4.8 ± 0.4 µM (n = 6) for naive
and cocaine-withdrawn slices, respectively.
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By reducing the endogenous concentration of adenosine, the sensitivity
of A1 receptors to exogenously applied adenosine could be determined.
As shown in Figure 5B, with adenosine uptake blocked, the
potency of adenosine to inhibit excitatory synaptic transmission was
similar in slices from naive and cocaine-withdrawn rats (Fig. 5B). Thus, inhibition of adenosine reuptake reversed the
"cocaine-withdrawn phenotype".
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DISCUSSION |
This report suggests that cocaine withdrawal augments adenosine
uptake to decrease the potency of adenosine-mediated inhibition of Glu
release. This result predicts that the enhanced adenosine uptake will
ultimately increase Glu release to increase the excitability of medium
spiny neurons. In fact, increased Glu release has been observed in the
NAc of cocaine-sensitized rats (Pierce et al., 1996), and the
mechanisms described in the present report may contribute to the
adaptive responses to chronic cocaine. Modulation of the excitatory
inputs of the NAc is significant, because medium spiny neurons are
essentially quiescent and their activity is dependent on glutamatergic
excitation (Pennartz et al., 1994).
Presynaptic inhibition by adenosine A1 receptors is widespread in the
CNS (Dunwiddie, 1985; Brundege and Dunwiddie, 1997). In addition
to the known effects of adenosine on PPF (Harvey and Lacey, 1997), this
report shows that adenosine strongly decreases the frequency of mEPSCs,
reinforcing the idea that A1 receptors mediate strong presynaptic
depression of Glu release from excitatory afferents in the NAc.
In addition to A1 receptors, D1 dopamine receptors and group 2/3 mGluRs
are known to inhibit Glu release at presynaptic sites in the NAc
(Nicola et al., 1996; Manzoni et al., 1997). The apparent diminution of
A1 inhibition may be explained by a general decrease of presynaptic
inhibition in response to chronic cocaine, based on a decrease in
Gi and Go in the NAc (Terwilliger et al.,
1991). However, chronic cocaine did not change the inhibitory effects of D1 dopamine, group 2/3 mGluRs receptors, or metabolically stable adenosine receptor agonists. Thus, a change in presynaptic receptor coupling to inhibition is unlikely.
One important aspect of this study is that the cocaine-induced
alteration of the adenosine uptake was present for at least 8 d
after withdrawal. The fact that presynaptic inhibition by adenosine was
not modified in the hippocampus suggests that this effect of chronic
cocaine selectively affected the NAc, a structure thought to be
involved in drug abuse behaviors. Further regional specificity is
suggested by the observation that an upregulation of adenosine tone in
response to chronic cocaine was found in the ventral tegmental area
(Bonci and Williams, 1996). Using a similar approach, such an increase
was not detected in the present study. This result indicates marked
regional specificity of the cocaine-induced adaptations of the
adenosine systems.
This study also contrasts with reports suggesting an overall
upregulation of the cAMP-dependent cascade in the NAc in response to
chronic cocaine treatment (Terwilliger et al., 1991; Self and Nestler,
1995; for review, see Nestler et al., 1996; Nestler and Aghajanian,
1997; Self et al., 1998). Although the cAMP pathway does affect
synaptic release at this excitatory glutamatergic synapse to medium
spiny neurons in the NAc (Fig. 3), the regulation of this pathway
through the cAMP cascade was not affected during withdrawal from
chronic cocaine treatment. This observation is consistent with
biochemical studies showing that neither basal nor DA-stimulated AC
activity was affected by chronic cocaine in the NAc (Mayfield et al.,
1992).
The main source of adenosine in the NAc is the degradation of cAMP by a
RO 20-1724-sensitive cAMP-dependent phosphodiesterase, which is not
changed during cocaine withdrawal. This seems to be a specific feature
of the NAc, because phosphodiesterase inhibitors have little effect on
the extracellular levels of adenosine in the hippocampal slices
preparation (S. Masino and T. Dunwiddie, personal
communication). Inhibition of cAMP-dependent phosphodiesterase considerably reduced the extracellular accumulation of adenosine induced by the uptake blockers. Thus, the accurate measurement of the
sensitivity to exogenous adenosine was enabled. In these conditions, we
found that the potency of adenosine to inhibit excitatory transmission
was identical in naive and cocaine-withdrawn rats. The simplest
interpretation of the results is that withdrawal from cocaine caused
the upregulation of adenosine transporters in the NAc. Biochemical
experiments have shown an upregulation of adenosine transporter-binding
sites in the striatum in opiate-tolerant mice (Kaplan and Leite-Morris,
1997). Together with the present report, this suggests that adenosine
transporters might be a common target for drug of abuse-induced
neuronal plasticity. The cloning of several nucleoside-adenosine
transporters (Pajor and Wright, 1992; Huang et al., 1994; Griffiths et
al., 1997a,b; Ritzel et al., 1997; Yao et al., 1997) may help
determine the molecular mechanisms underlying the susceptibility of NAc
adenosine transporters to cocaine-induced modifications.
Although the initial effects of acute cocaine are attributable to the
blockade of monoamine transporters leading to an increase in
extracellular DA (presumably followed by activation of dopamine receptors), part of the long-term consequences of withdrawal from chronic cocaine might be on neuromodulators unrelated to the primary targets of cocaine. This concept is consistent with previous reports showing upregulated adenosine metabolism in response to chronic cocaine
in the ventral tegmental area (Bonci and Williams, 1996). Moreover,
dopamine D1 receptor-mediated presynaptic inhibition of excitatory
transmission in the NAc seems to be, in part, attributable to the
D1-dependent release of adenosine from medium spiny neurons (Harvey and
Lacey, 1997; Nicola and Malenka, 1997), suggesting complex cross talk
between adenosine A1 and dopamine D1 receptors (for review, see Ferre
et al., 1997).
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FOOTNOTES |
Received May 15, 1998; revised July 8, 1998; accepted July 14, 1998.
This research was supported by grants from the Centre National de la
Recherche Scientifique, Institut National de la Santé et de la
Recherche Médicale, Communauté Economique
Européenne Biotech and Biomed, the Bayer Company,
Fondation Simone et Cino Del Ducca, the National Institute on Drug
Abuse-INVEST program, and National Institute on Drug Abuse
Grant DA04523. The authors would like to thank M. Passama for the
artwork, Jean-Marie Michel for writing the mEPSCs acquisition and
analysis software, and Drs. M. Kavanaugh and J. Brundege for critical
reading of this manuscript.
Correspondence should be addressed to Dr. Olivier Manzoni, Oregon
Health Sciences University L-474, 3181 S.W. Sam Jackson Park Road,
Portland, Oregon 97201.
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Top
Abstract
Introduction
Compound via MeSH
