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The Journal of Neuroscience, August 1, 1999, 19(15):6629-6636
Presynaptic Regulation of Glutamate Release in the Ventral
Tegmental Area During Morphine Withdrawal
Olivier J.
Manzoni and
John T.
Williams
Vollum Institute, Oregon Health Sciences University, Portland,
Oregon 97201
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ABSTRACT |
The regulation of glutamate (Glu) release from the excitatory input
to dopamine cells in the ventral tegmental area (VTA) during acute
withdrawal from morphine was studied in slices from animals treated for
6-7 d with morphine. EPSCs were inhibited by opioid agonists
acting at µ-subtype receptors but not by selective  - or
 -subtype agonists. The opioid inhibition was reduced by 65% with
the potassium channel blocker 4-aminopyridine (4-AP; 100 µM) and a 12-lipoxygenase inhibitor, baicalein (5 µM), suggesting that opioids acted via a transduction
pathway involving activation of a voltage-dependent potassium
conductance by lipoxygenase metabolites as has been shown in the
periaqueductal gray (Vaughan et al., 1997 ). During withdrawal,
neither the potency nor the efficacy of
D-Ala-Met-enkephalin-Gly-ol (DAMGO) were changed; however, the blockade of µ-opioid inhibition by both 4-AP and baicalein was
reduced. In addition, the potency of baclofen to depress EPSCs by
GABA-B receptors and the effects of the GABA-uptake inhibitor NO-711
(10 µM) were increased in withdrawn rats. Finally, group 2 (but not group 4 or 1) metabotropic glutamate receptor-mediated presynaptic inhibition was also enhanced in morphine-withdrawn rats.
These results suggest that one of the consequences of withdrawal from
chronic morphine is an enhanced presynaptic inhibition of the
excitatory inputs to the dopamine cells of the VTA. Inhibition of
glutamate release during acute withdrawal would add to the inhibition
of dopamine cells that is mediated by an augmented release of GABA
(Bonci and Williams, 1997).
Key words:
ventral tegmental area; opioid; glutamate; GABA; metabotropic receptors; morphine withdrawal
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INTRODUCTION |
The VTA is a component of the
endogenous reward circuit that is thought to be activated by many drugs
of abuse, including opioids (Bozarth and Wise, 1981). Rats will lever
press for microinjection of opioids into the VTA, suggesting that the
VTA is one site involved in the reinforcing properties of opioids
(Devine and Wise, 1994). Pharmacological evidence suggests that the
terminals of afferent fibers from the nucleus accumbens and ventral
pallidum mediate GABA-B IPSPs, whereas GABA release from
interneurons acts via GABA-A receptors (Johnson and North, 1992a,b;
Johnson et al., 1992a; see also Paladini et al., 1998). Opioids cause
an acute inhibition of both GABA-A and GABA-B IPSPs (Johnson and North, 1992a), and withdrawal from morphine affects the regulation of synaptic
transmission at both synapses by a cAMP-dependent mechanism (Bonci and
Williams, 1996, 1997).
Excitatory synaptic input mediated by glutamate is a key component of
the regulation of dopamine cell excitability and is known to play an
important role in the actions of many drugs of abuse (Kalivas and
Stewart, 1991; Kalivas, 1993). The glutamate afferents arise from three
primary sources: the medial prefrontal cortex, the pedunculopontine
region, and the subthalamic nucleus (Fallon and Loughlin, 1995). One
role of the glutamatergic innervation to the VTA is to mediate a switch
from pacemaker-like firing in dopamine cells to burst-firing pattern
(Gariano and Groves, 1988; Svensson and Tung, 1989; Johnson et al.,
1992b; Murase et al., 1993; Zhang et al., 1994). Presynaptic regulation
of glutamate release from these excitatory synapses by opioids has not
been investigated and could be important in shaping the pattern of activity of dopamine cells.
The goal of the present study was to determine the acute actions of
opioids on glutamate-mediated transmission in the VTA and then identify
adaptive changes in excitatory synaptic transmission during acute
withdrawal from chronic opioid treatment. The results show that opioids
acutely inhibit glutamate release and that during withdrawal the
transduction pathway mediating this inhibition is not the same as in
control. The results also show an increased sensitivity to presynaptic
inhibition by both glutamate (autoreceptors) and GABA (heteroreceptors)
metabotropic receptors, suggesting that glutamate release would be
depressed during acute opioid withdrawal. Because the pattern of
dopamine cell activity in the VTA is dependent on excitatory glutamate
drive, the present data form a cellular basis for the decreased
activity of dopamine cells observed during acute withdrawal from
morphine in vivo (Diana et al., 1995).
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MATERIALS AND METHODS |
Chronic morphine treatment was done using time-released morphine
pellets (75 mg of morphine per pellet obtained from National Institute
on Drug Abuse). The pellets were implanted subcutaneously in
anesthetized rats (ketamine-xylazine), one on the first day and two on
days 3 and 5. Experiments were performed on days 6 or 7. This protocol
has been shown to produce strong opioid dependence (Chieng and
Christie, 1995). Whole-cell recordings of membrane current were made
from dopamine neurons in horizontal slices of rat midbrain (holding
potential,  70 mV). This method has been described previously
(Williams et al., 1984). In brief, rats (Wistar, 160-220 gm) were
anesthetized with halothane and killed. The midbrain was sliced (200 µm) in the horizontal plane using a vibratome at 4°C and maintained
in physiological saline (morphine-free). Slices (up to three)
containing the VTA were stored before being placed in the recording
chamber and superfused (2 ml/min) with warmed (35°C) Krebs'
solution-bicarbonate buffer containing the following (in
mM): NaCl 126, KCl 2.5, NaH2PO4
1.2, MgCl2 1.2, CaCl2 2.4, glucose 11, NaHCO3 21.4 saturated with 95% O2 and 5% CO2. All experiments were done after washing slices with
morphine-free solution for a minimum of 1 hr and as long as 6 hr. These
slices from morphine-treated animals were termed opioid-withdrawn. The superfusion medium contained picrotoxin (100 µM) and
strychnine (1 µM) to block GABA-A and glycine-mediated
synaptic currents, respectively. There was no effect of this solution
on the holding current of the dopamine cells. All drugs were added at
the final concentration to the superfusion medium.
Cells were visualized using an upright microscope with infrared
illumination, and recordings were made with whole-cell electrodes containing the following (mM): KCl 128, NaCl 20, MgCl21, EGTA 1, CaCl2 0.3, Mg-ATP 2, GTP 0.3, and cAMP 0.2 buffered with HEPES 10, pH 7.3. Electrode resistance was
2-4 M , acceptable access resistance was <15 M, and the holding
potential was 70 mV. An Axopatch-200A (Axon Instruments, Foster City,
CA) was used to record the data, which were filtered at 1 kHz,
digitized at 5 kHz on a DigiData 1200 interface (Axon Instruments) and
collected on a personal computer using ACQUIS-1 software (Bio-Logic) or pClamp6. To evoke synaptic currents, stimuli (100-300 µsec duration) were delivered at 0.033 Hz through bipolar tungsten electrodes placed
near (30-100 µm) the cell body. Two stimuli were applied at an
interval of 50 msec (Manabe et al., 1993), and the paired-pulse ratio
was calculated by dividing the amplitude of the EPSC evoked by the
second stimulus by the amplitude of the first EPSC evoked by the first
stimulus. A change in the paired-pulse ratio is thought to result from
the alteration in transmitter release caused by a presynaptic mechanism
(Manabe et al., 1993). Evoked EPSC amplitudes were measured by
averaging a 2 msec window around the peak and subtracting the average
value obtained during a 5 msec window immediately before the stimulus.
Spontaneous miniature EPSCs (mEPSCs) were recorded in the presence of
tetrodotoxin (TTX; 300 nM) using pClamp 6.0 (Axon
Instruments; 120 sweeps for each condition, 1 sec/sweep). The internal
solution contained Cs gluconate instead of KCl. mEPSC amplitude and
interinterval time were measured using Axograph 3.6. For this analysis,
a template of mEPSCs having the width and time course of a typical
synaptic event (a double exponential: f(t) = exp(t/rise) exp(t/decay), where
rise = 0.5 msec and decay = 3 msec), was slid along the data
trace one point at a time. At each position, this template is optimally
scaled and offset to fit the data, and a detection criterion is
calculated. The detection criterion is the template scaling factor
divided by the goodness-of-fit at each position. An event is detected
when this criterion exceeds a threshold and reaches a sharp maximum.
The limit of detection was 5 pA.
The fitting of concentration-response curves were calculated according
to y = {ymax ymin/1 + (x/EC50)n} + ymin (where 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. Statistical
analyses were done with the Mann-Whitney U test, the
Kolmogorov-Smirnov, or the Spearman Rank Correlation tests using
Statview (Abacus Concepts, Calabasas, CA); p < 0.05 was taken as indicating statistical significance (**p < 0.05; ***p < 0.01). Drugs used were
8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX) from Research
Biochemicals (Natick,
MA);(2S,1'S,2'S)-2-(2'-carboxycyclopropyl)glycine (L-CCGI), L-2-amino-4phosphono-butyrate
(L-AP-4),
(S)-4-carboxy-3-hydroxyphenylglycine (4C3HPG),
6-Nitro-7-sulfamoybenzo-[f]quinoxaline-2,3-dione disodium (NBQX),
(S)-3,5-dihydroxyphenylglycine
[(S)-DHPG] from Tocris Neuramin; TTX, picrotoxin,
strychnine, [Met]5enkephalin, forskolin, DAMGO, U69593,
[D-Pen]2
[D-Pen]5enkephalin, 4-AP from Sigma (St.
Louis, MO); baicalein from BIOMOL">Biomol (Plymouth Meeting, PA); dendrotoxin
from Calbiochem (La Jolla, CA) and Alomone Laboratories (Jerusalem,
Israel); and CGP 56999A was generously provided by Dr. A. Sutter at
Novartis Pharma.
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RESULTS |
Acute inhibition by µ-opioids
Whole-cell recordings were made from dopamine cells that were
identified by their prominent hyperpolarization-induced inward current
(Johnson and North, 1992b). Electrically evoked glutamate EPSCs were
completely blocked by NBQX (5 µM). In all experiments other synaptic currents were blocked with receptor antagonists (see
Materials and Methods). Slices from both control and morphine-treated animals were prepared and maintained in morphine-free solution.
In control slices, the opioid agonists [Met]5enkephalin
(ME; 10 µM) and DAMGO (10 µM) had no effect
on the holding current but depressed the amplitude of the evoked EPSCs
by ~50% (Fig. 1). The inhibition
caused by ME (10 µM) was completely blocked by naloxone
(1 µM; n = 3) and the selective
µ-receptor antagonist CTAP (1 µM; n = 9; Fig. 1). Thus µ-opioid receptors were responsible for the
inhibition. This suggestion was further supported by the observation
that neither the selective agonist [D-Pen]2
[D-Pen]5enkephalin (DPDPE; 1 µM) nor the
selective agonist U69593 (1 µM) affected EPSCs (Fig.
1C).
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Figure 1.
Inhibition of glutamate EPSCs by opioids is
mediated by activation of µ-opioid receptors. A,
Top, Superimposed current traces showing the effect of
ME (10 µM) in control (left) and in the
presence of CTAP (1 µM; right). The plot
below shows the entire experiment, plotting the amplitude of the EPSC
as a function of time. In this and other plots, the bars
indicate the period during which the superfusion solution contained the
indicated drug. B, Summarized results demonstrating the
inhibition of evoked EPSCs by ME (10 µM;
n = 6). In this and other plots, the amplitude of
the evoked EPSC was normalized for each cell using the mean amplitude
recorded during the first 10 min and plotted as a function of time.
C, Summary of the experiments showing the inhibition of
the EPSC by ME (10 µM; 49 ± 9%;
n = 6), DAMGO (10 µM; 51 ± 9%;
n = 4), DPDPE (1 µM; 7 ± 6%;
n = 7), U69593 (1 µM; 4 ± 14%;
n = 7), and ME (10 µM) plus CTAP (1 µM) (6 ± 5%; n = 9).
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This inhibition was thought to result from presynaptic inhibition of
glutamate release based on two observations. First ME caused a shift in
the paired-pulse ratio toward facilitation (mean inhibition, 55 ± 3%; mean increase in paired-pulse ratio, 146 ± 8%;
n = 32) and, although there was considerable variation
from cell to cell, the shift in the paired-pulse ratio was related to
the amount of inhibition (Fig. 2). The
second method used to determine the site of opioid action was by
measuring the effect of opioids on the frequency of spontaneous mEPSCs.
The µ-opioid agonist, DAMGO (10 µM) decreased the
frequency of spontaneous mEPSCs, from 2.8 ± 0.2 Hz in control to
1.6 ± 0.2 Hz (Mann-Whitney U test, p = 0.0031; n = 9; Fig.
3C) and caused a significant
shift of the cumulative frequency distribution to the right (Fig.
3B). The decrease in frequency caused by DAMGO was
completely reversed by naloxone (1 µM, Fig.
3B). During the inhibition caused by DAMGO neither the mean
amplitude of the mEPSCs (12.3 ± 2.7 pA and 12.5 ± 3;
Mann-Whitney U test, p = 0.69; Fig. 3), nor
the cumulative amplitude distribution were modified
(Kolmogorov-Smirnov test, p < 0.9999). Taken together
there results indicate that µ-subtype opioid receptors located on
presynaptic glutamate terminals inhibit EPSCs to the dopamine cells of
the VTA.
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Figure 2.
Inhibition of the EPSC by ME (10 µM)
is accompanied by a change in the paired-pulse ratio toward
facilitation. Top, Three superimposed current traces
illustrating the effect of ME on EPSCs induced using a paired-pulse
protocol. The inhibition of the first EPSC (S1) by ME is
larger than the second (S2). The inset shows the second
EPSC (S2) after normalizing the amplitude of the EPSCs
evoked by the first stimulus. This illustration indicates a shift
toward facilitation. Bottom is a plot of the inhibition
induced by ME against the paired-pulse ratio for 32 cells. The
line is constructed from a linear regression analysis
and indicates that the variables correlated significantly ( = 0.62; p = 0.0004, Spearman rank correlation). The
open circle indicates the average inhibition and shift
in paired-pulse ratio for all these cells (change in paired-pulse
ratio = 146 ± 8%; ME-induced inhibition = 55 ± 3%).
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Figure 3.
DAMGO (10 µM) inhibits the frequency
but not the amplitude of mEPSCs. A, Raw traces
illustrating mEPSCs and the effect of DAMGO and DAMGO plus naloxone.
B, The interevent interval distribution curve was
significantly shifted to the right by DAMGO and reversed in presence of
naloxone (Kolmogorov-Smirnov test, p < 0.0001).
C, The effect of DAMGO on the average frequency
(left, Mann-Whitney U test,
p = 0.0031) and amplitude (right,
Mann-Whitney U test, p = 0.69).
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Opioid inhibition during withdrawal from chronic morphine
Neither the sensitivity (EC50 = 0.08 µM) nor the maximal effect of DAMGO were changed during
withdrawal from morphine (Fig. 4A). Based on recent
reports indicating that the transduction mechanism for opioid
inhibition of transmitter release was dramatically altered during
opioid withdrawal (nucleus accumbens, Chieng and Williams, 1998;
periaqueductal gray (PAG), Ingram et al., 1998) the mechanism of opioid
inhibition of glutamate release was investigated in the VTA.
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Figure 4.
The sensitivity of the EPSC to inhibition by DAMGO
was not changed, however, the blockade of the opioid inhibition by 4-AP
and baicalein was reduced during opioid withdrawal. A,
Concentration- response curves showing the inhibition by DAMGO in
untreated (solid circles) and withdrawn (open
circles) slices. B, An illustration of the
effect of 4-AP on the EPSC and the resulting reduction in the
inhibition caused by ME. Left, Three superimposed traces
showing the inhibition caused by ME. Right, The same
cells after superfusion with 4-AP (100 µM). The amplitude
of the EPSC is larger, and the inhibition caused by ME is reduced. The
bar graph below summarizes the results obtained with 4-AP and baicalein
on the inhibition caused by ME and baclofen. The inhibition caused by
ME was significantly reduced by both 4-AP and baicalein, whereas the
inhibition caused by baclofen was not changed. C
summarizes results using withdrawn slices showing that the blockade of
the ME-induced inhibition caused by 4-AP and baicalein was
significantly reduced. In addition, the ME-induced inhibition was not
significantly decreased in the presence of the kinase inhibitor
staurosporine (STAU; 1 µM; 20 min) or
staurosporine plus 4-AP.
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Given the well known effect of chronic morphine treatment to upregulate
adenylyl cyclase activity (Sharma et al., 1975; Terwilliger et al.,
1991), the role of the cAMP cascade at this excitatory synapse in the
VTA was first examined. The amplitude of EPSCs was increased by the
adenylyl cyclase activator forskolin. However, the augmentation was not
different in morphine-withdrawn and control slices (control, 143 ± 13%, n = 15; withdrawn, 140 ± 10%,
n = 11). The transduction mechanism was further
investigated with the use of the nonselective kinase inhibitor
staurosporine (STAU). The opioid inhibition was not affected by STAU (1 µM; 20 min; Fig. 4C) in both control and
withdrawn slices. Another consequence of the activation of adenylyl
cyclase is an increase in extracellular adenosine that has been shown
to inhibit GABA IPSCs in the VTA (Bonci and Williams, 1996) and nucleus
accumbens (Chieng and Williams, 1998) and glutamatergic EPSCs in the
hippocampus (Manzoni et al., 1995; Brundege et al., 1997). At this
glutamate synapse in the VTA, however, blockade of A1 adenosine
receptors with DPCPX (200 nM, 20 min) neither augmented
basal synaptic transmission (109 ± 7% change in untreated,
n = 13; 100 ± 6% change in withdrawn, n = 9), nor increased the effect of forskolin in slices
from untreated or withdrawn animals (untreated 137 ± 11%,
n = 7; withdrawn 135 ± 20%, n = 5). Thus, there was no detectable upregulation of the adenylyl
cyclase-protein kinase A cascade caused by morphine withdrawal at this
glutamate synapse in the VTA. This result differs from the increase in
GABA-A IPSPs in withdrawn slices mediated by an upregulation of the
cAMP-dependent cascade in the VTA (Bonci and Williams, 1997), nucleus
accumbens (Chieng and Williams, 1998), PAG (Ingram et al., 1998), and
dorsal raphe (Jolas et al., 1998).
It was recently reported that opioids inhibit GABA release via a
transduction pathway involving the activation of a voltage-dependent potassium conductance by lipoxygenase metabolites in the brainstem PAG
(Vaughan et al., 1997). This mechanism of opioid inhibition was tested
in the VTA. In untreated rats, the ME-induced inhibition of evoked
EPSCs was significantly reduced by the voltage-dependent potassium
channel blocker 4-AP (100 µM; Fig. 4B).
In withdrawn slices, however, the inhibition caused by ME was not
significantly changed by 4-AP (Fig. 4C). Preincubation of
the slices with the 12-lipoxygenase inhibitor baicalein reduced the
ME-mediated EPSC depression in control but not in morphine-withdrawn
slices (Fig. 4). Interestingly, the effects of 4-AP and baicalein were
selective for the µ-opioid receptor inhibition because GABA-B
receptor-mediated inhibition by baclofen was insensitive to both
compounds (Fig. 4). These results suggest that during morphine
withdrawal there is a change in the transduction pathway that normally
mediates presynaptic inhibition. Because the degree of inhibition
mediated by the 4-AP-baicalein-sensitive pathway was reduced, and the
inhibition caused by opioids was not changed, it appears that in
withdrawn slices there has been an upregulation of another mechanism
that mediates presynaptic inhibition.
Augmented presynaptic inhibition by GABA-B receptors
In slices from untreated rats, baclofen decreased the amplitude of
evoked EPSCs (see Fig. 6) and reduced the mean frequency of spontaneous
mEPSCs (from 2.8 ± 0.2 to 1.3 ± 0.2 Hz;
n = 9; Mann-Whitney U test,
p = 0.0012; Fig. 5) and
shifted the interevent interval distribution curve significantly to the
right (Kolmogorov-Smirnov test, p < 0.001). Despite
having a powerful postsynaptic action, baclofen did not have a
significant effect on the average amplitude mEPSCs (untreated,
12.3 ± 2.7 pA, n = 13; withdrawn, 8.9 ± 2.2 pA, n = 9, Mann-Whitney U test,
p = 0.39) or the cumulative amplitude distribution of
mEPSCs (Kolmogorov-Smirnov test, p = 0.35). Thus, in
addition to the activation of potassium currents in dopamine cells,
GABA-B receptors also inhibit glutamate EPSCs by a presynaptic mechanism. The effects of baclofen were always reversed by the GABA-B
antagonist CGP 56999A (1 µM).
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Figure 5.
Presynaptic inhibition of spontaneous mEPSCs by
baclofen. A, Raw current traces illustrating the
inhibition of mEPSCs by baclofen and the reversal of that inhibition by
CGP 56999A. B, Plots of the average amplitude
(left) and frequency (right) of mEPSCs in
control (con, solid bars), in baclofen
(B; 10 µM), and in CGP56999A
(CGP; open bars). Baclofen (10 µM) caused inhibition of the frequency of mEPSCs (from
2.8 ± 0.2 to 1.3 ± 0.3 Hz; Mann-Whitney
U test, p = 0.0012) without
significantly reducing the average amplitude (control, 12.3 ± 2.7 pA; withdrawn 8.9 ± 2.2; Mann-Whitney U test,
p = 0.39).
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As a control experiment, concentration-response curves to baclofen
were constructed measuring the inhibition of electrically evoked EPSCs
in withdrawn and untreated slices. In withdrawn slices, the sensitivity
but not the maximal effect of baclofen was increased (Fig.
6A). The
EC50 for baclofen was 2.1 ± 0.8 µM in
control and 0.5 ± 0.3 µM in withdrawn slices (9-13
experiments). This unexpected increase in the sensitivity to baclofen
may suggest that withdrawal from morphine has altered inhibition by
receptors unrelated to opioids.
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Figure 6.
Presynaptic inhibition by GABA-B receptors was
increased in withdrawn slices. A,
Concentration-response curves to baclofen in untreated and
morphine-withdrawn slices showing that the sensitivity but not the
maximal effect of baclofen was increased. The EC50 for the
GABA-B agonist was 2.1 ± 0.8 µM in untreated slices
and 0.5 ± 0.3 µM in morphine-withdrawn slices.
B, The GABA-uptake blocker NO-711 (10 µM)
slightly reduced the amplitude of evoked EPSCs in slices from untreated
animals (16.8 ± 5%) but significantly inhibited EPSCs in
morphine-withdrawn slices (48 ± 7%; Mann-Whitney
U test, p = 0.005). The
NO-711-induced inhibition was reversed by CGP 56999A (1 µM). C, Plot of the amplitude of the EPSC
amplitude (left axis) and paired-pulse ratio
(right axis) showing that the depression of evoked EPSCs
in the presence of NO-711 was accompanied by a shift in the
paired-pulse ratio toward facilitation.
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The increased sensitivity to GABA-B-mediated inhibition was further
examined using endogenous GABA. It has been shown in slices of
hippocampus that under conditions where there was an increase in GABA
release, the spatial range of over which GABA acts was increased
(Isaacson et al., 1993). Because it has been shown that GABA-A IPSPs in
the VTA were augmented during morphine withdrawal (Bonci and Williams,
1997), it was possible that the increased GABA-A IPSCs could overwhelm
normal uptake mechanisms to increase the extracellular concentration of
GABA and result in the activation of GABA-B receptors on
glutamate-releasing terminals. The GABA-B antagonist CGP 56999A had no
effect by itself in control or withdrawn slices (untreated, 108 ± 6%, n = 11; withdrawn, 109 ± 3%,
n = 8). The role of endogenous GABA was examined
further using the GABA-uptake blocker NO-711 (Suzdak et al., 1992).
Inhibition of GABA reuptake was expected to increase the likelihood to
detect GABA at glutamate-releasing terminals. Although NO-711 (10 µM) had little effect on the amplitude of EPSCs in
control slices, it caused an inhibition of EPSCs in withdrawn slices
(Fig. 6), the inhibition was accompanied by an increase in the
paired-pulse ratio (Fig. 6) and was completely blocked by CGP 56999A (1 µM). Thus, in withdrawn slices after blockade of GABA
reuptake, endogenous GABA activated GABA-B receptors to presynaptically
inhibit glutamate release. This result supports previous work
indicating an increase in GABA release during opioid withdrawal,
however also indicates that normal GABA reuptake processes are capable
of limiting the diffusion of GABA even in withdrawn slices.
Augmented presynaptic inhibition by metabotropic
glutamate receptors
To further examine the changes in presynaptic regulation of
glutamate release induced by chronic morphine treatment, the inhibition of glutamate release by metabotropic glutamate receptors (mGluRs) was
examined. Several mGluRs have been cloned and classified into three
families: group 1 consists of mGluR1 and mGluR5 both positively coupled
to phospholipase C, whereas group 2 receptors (mGluR2/3) and group 3 mGluRs (mGluR4/6/7/8) are negatively coupled to adenylyl cyclase
(Nakanishi, 1992). Activation of all mGluRs have been shown to decrease
transmitter release at many sites in the brain (Nakanishi, 1992),
including the VTA (Bonci et al., 1997; Wigmore and Lacey, 1998).
In agreement with previous reports (Bonci et al., 1997; Wigmore and
Lacey, 1998), application of selective agonists (Conn and Pin, 1997) of
group 2 [(S)-4C3HPG, 50 µM] or group
3 mGluRs (L-AP-4, 10 µM) caused an inhibition
of the evoked EPSC that was accompanied by an increase in the
paired-pulse ratio. The group 2 agonist (S)-4C3HPG
(50 µM) caused a 17 ± 3.5% inhibition of the EPSC
(n = 9) and a 122 ± 4% change in the
paired-pulse ratio. The group 3 agonist L-AP-4 (10 µM) caused a 46 ± 11% inhibition of the evoked
EPSC (n = 5) and a 197 ± 20% change in the
paired-pulse ratio (see also Fig. 7,
legend).
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Figure 7.
Increased mGluR inhibition in morphine-withdrawn
slices. A, Evoked EPSCs were inhibited by the selective
group 2 mGluR agonists (S)-4C3HPG (50 µM) and LCCG1 (1 µM). The inhibition was
significantly larger in withdrawn slices compared with untreated
controls. The (S)-4C3HPG inhibition was 17 ± 4% in untreated slices and 50 ± 4% in withdrawn slices
(Mann-Whitney U test, p = 0.018). A
change in the paired-pulse ratio from 122 ± 4% in control to
146 ± 13% in withdrawn slices suggests that the increase in
sensitivity resulted from a presynaptic action. The LCCG1 inhibition
was 28 ± 4.6% in naive slices and 40 ± 3.5% in
morphine-withdrawn slices (Mann-Whitney U test,
p = 0.048). B, There was no effect
of morphine withdrawal on group 1 (specifically activated by
(S)-DHPG, 100 µM) or group 3 (selectively activated by L-AP-4) mGluRs.
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During morphine withdrawal, the inhibition of EPSCs induced by the
selective activation of group 2 mGluRs by either
(S)-4C3HPG (50 µM) or LCCG1 (1 µM) was enhanced (Fig. 7A). In contrast, the inhibition caused by the group 1 and 3 mGluR-specific agonists (S)-DHPG (100 µM) and
L-AP-4 (10 µM) was identical in both groups (Fig. 7B). Thus, withdrawal from chronic morphine caused a
selective increase of presynaptic inhibition induced by group 2 mGluRs.
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DISCUSSION |
The results show that opioids acting on µ-opioid receptors
inhibit glutamate EPSCs in dopamine cells in the VTA. In control animals, this inhibition is mediated by a mechanism that was sensitive to blockade of a voltage-dependent potassium conductance by 4-AP and to
baicalein, an agent that blocks the metabolism of arachidonic acid by
the lipoxygenase pathway. During acute withdrawal from chronic morphine
treatment there was a fundamental change in the presynaptic regulation
of the glutamate release at this synapse. First, the transduction
pathway responsible for the opioid receptor-mediated inhibition was
less sensitive to agents that disrupt the normal inhibition (4-AP and
baicalein). Second, there was an enhancement of the presynaptic
inhibition mediated by GABA and glutamate metabotropic receptors. This
increased sensitivity would serve to limit glutamate release onto
dopamine cells and decrease their excitability.
Mechanism of µ-opioid inhibition
The mechanism of presynaptic inhibition caused by opioids has been
the subject of considerable effort that, until recently, has revolved
around two effectors, activation of an inwardly rectifying potassium
conductance and inhibition of voltage-dependent calcium conductance (Di
Chiara and North, 1992). A third mechanism involving the activation of
a voltage-dependent potassium conductance has been shown to inhibit
glutamate EPSCs at hippocampal mossy fibers (Simmons and Chavkin,
1996). In the PAG, arachidonic acid metabolites have been shown to be
responsible for the activation of this voltage-dependent potassium
conductance and the resulting inhibition of GABA-A IPSCs (Vaughan et
al., 1997). Although µ-opioid receptors on glutamate terminals in the
PAG were not coupled to this pathway (Vaughan et al., 1997), the
present results suggest that this mechanism may be extended to
excitatory synapses in the VTA.
In the PAG, the opioid-induced inhibition was blocked by dendrotoxin, a
more selective potassium channel blocker than 4-AP (Vaughan et al.,
1997). In the present study, inconsistent results were obtained with
dendrotoxin, using a similar protocol and dendrotoxin purchased
from two commercial sources. In eight cells, the ME-induced inhibition
was tested first in dendrotoxin (100 nM) and then in 4-AP
(100 µM). In three cells, both dendrotoxin and 4-AP
caused a similar blockade of the ME-induced inhibition, however when all the results were averaged there was no significant effect of
dendrotoxin in the same group of cells in which the ME inhibition was
significantly decreased by 4-AP [control, 45 ± 6%; dendrotoxin (100 nM), 41 ± 8%; 4-AP (100 µM),
18 ± 3.5%). In all experiments, dendrotoxin caused an obvious
increase in the rate of spontaneous EPSCs, suggesting that it was
somewhat effective. These results may suggest that dendrotoxin blocked
a subset of channels that were insensitive to inhibition by ME. The
effects of 4-AP and baicalein were not, however, totally nonselective
because the GABA-B-mediated inhibition was not blocked by either 4-AP
or baicalein. Selectivity of these compounds may also be suggested by
the observation that the blockade of opioid action was significantly
reduced during withdrawal. A similar reduction in sensitivity to these
compounds was observed in the PAG in withdrawn slices (Ingram et al.,
1998).
Transduction mechanisms change during withdrawal
Chronic use of opioids results in tolerance to and dependence on
the drug (Johnson and Fleming, 1989). Withdrawal results from adaptive
changes in response to chronic drug abuse, such as an upregulation of
the cAMP-dependent cascade (Sharma et al., 1975; Terwilliger et al.,
1991). Withdrawal from chronic morphine treatment has been shown to
augment µ-opioid receptor-mediated inhibition of GABA IPSCs in the
nucleus accumbens (Chieng and Williams, 1998) and in the PAG (Ingram et
al., 1998). In withdrawn slices of nucleus accumbens, the maximal
inhibition caused by µ-opioid receptor activation was increased
(Chieng and Williams, 1998). Similarly, in the PAG the sensitivity to
µ-opioid receptor agonists was increased (Ingram et al., 1998). In
both those studies the increased opioid action was dependent on the
activity of adenylyl cyclase. In each study, after inhibition of
cAMP-dependent kinase activity (with staurosporine or H89), the
increased effect of opioids was reduced to control values. Those
results indicated that the upregulated cAMP cascade during withdrawal
not only increased transmitter release but was itself sensitive to
inhibition by opioids. In the present study, there was no indication
that the cAMP-dependent pathway had an effect on glutamate release
during withdrawal.
There was however a clear change in the transduction mechanism
responsible for the opioid inhibition of transmitter release. In
withdrawn slices, opioids mediated an inhibition of transmitter release
by a mechanism that was not sensitive to 4-AP and baicalein, indicating
that there was an upregulation of an alternate, and as yet
unidentified, mechanism. The increased sensitivity to mGluR- and
GABA-B-receptor-mediated inhibition at this synapse may suggest that a
common transduction pathway mediates inhibition for all three receptors
during acute morphine withdrawal. The present work further indicates
that the mechanisms responsible for presynaptic inhibition are not
static and can vary with the experimental conditions and after chronic
drug treatment.
Increased sensitivity of presynaptic GABA and glutamate
metabotropic receptors
Withdrawal from chronic morphine enhanced the potency of GABA-B
and mGluR agonists to inhibit glutamate release. Similarly, an
augmented inhibition of NMDA-mediated EPSCs by mGluR agonists after
chronic morphine treatment has been reported in the nucleus accumbens
(Martin et al., 1999). It is interesting to note that mGluRs have
sequence similarities with GABA-B receptors (Kaupmann et al., 1997)
that may result in common coupling mechanisms, thus equivalent changes
induced by withdrawal. Drugs acting at GABA-B receptor have been
proposed as possible pharmacotherapeutic agents in drug addiction
(Roberts et al., 1996; Roberts and Andrews, 1997). Likewise, inhibitory
mGluRs have been described at the excitatory terminals to midbrain
dopamine cells (Bonci et al., 1997; Wigmore and Lacey, 1998), and
recent evidence indicates a role for mGluRs in morphine and nicotine
withdrawal syndromes (Fundytus and Coderre, 1997a,b; Helton et al.,
1997) as well as the sensitization to amphetamine (Kim and Vezina,
1998). We show here that the presynaptic inhibition induced by group 2 (but not group 3) mGluRs was enhanced in VTA slices prepared from
morphine-withdrawn rats. This observation is in agreement with a report
describing that a selective group 2 mGluR agonist attenuates the
severity of precipitated morphine withdrawal syndromes in rats
(Fundytus and Coderre, 1997a,b). The present report supports the
hypothesis that presynaptic GABA-B and mGluR receptors or the signal
transduction pathway mediated by these receptors may be affected in
similar ways by drugs of abuse.
Increased extracellular GABA during opiate withdrawal
GABA-B-mediated heterosynaptic depression regulates excitatory
transmission in the hippocampus, and transmitter uptake has been shown
to control the spatial range of synaptically released GABA (Isaacson et
al., 1993). The hypothesis that withdrawal from chronic morphine
augments GABA tone at glutamate synapses in the VTA was explored. There
was no GABA tone as determined by the effect of the GABA-B antagonist
CGP 56999A in either control or withdrawn slices, suggesting that
reuptake of GABA was sufficient to limit the extent of GABA diffusion.
After blockade of GABA reuptake, with NO-711, the EPSC was
significantly inhibited in withdrawn slices, and this inhibition was
reversed by the GABA-B antagonist CGP 56999A. Thus, in withdrawn
slices, NO711 mediated an inhibition resulting from the activation of
GABA-B receptors. Two mechanisms could account for this observation.
First, enhanced GABA release during withdrawal (Bonci and Williams,
1997) could mediate this heterosynaptic effect. Second, the increased
sensitivity of GABA-B receptors to reduce glutamate transmission in
withdrawn slices found in the present study could account for this
result. The physiological significance of either mechanism is the same, an increase in GABA-mediated inhibition of glutamate release.
In summary, withdrawal from chronic morphine was found to modify
excitatory terminals to dopamine cells in two ways that may be linked.
First, the mechanism of µ-opioid inhibition was altered and second,
the actions of agonists of metabotropic receptors to both glutamate and
GABA were enhanced. The augmented presynaptic inhibition by GABA and
glutamate metabotropic receptors will ultimately reduce glutamate
release and therefore decrease dopamine cell firing. The decrease in
glutamate release, along with the increased probability of GABA release
from interneurons would not only reduce the excitability of dopamine
neurons but also limit the occurrence of burst firing. These results
provide a cellular basis for the profound decrease of mesolimbic
dopaminergic neuronal activity observed in vivo in
morphine-withdrawn rats (Diana et al., 1995).
| |
FOOTNOTES |
Received April 6, 1999; accepted May 12, 1999.
This research was supported by Institut National de la Santé et
de la Recherche Médicale, Fondation Simone et Cino Del Ducca, the
National Institute on Drug Abuse (NIDA)/INVEST program, and NIDA Grant
DA 08163. We thank Drs. J. Brundege, J. Bockaert, P. Chavis, and S. Ingram for critical reading of this manuscript and Dr. A. Sutter at
Novartis Pharma (Switzerland) for generously providing CGP 56999A.
Correspondence should be addressed to J. T. Williams, Vollum
Institute, Oregon Health Sciences University L-474, 3181 Southwest Sam
Jackson Park Road, Portland, OR 97201.
| |
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ABSTRACT
INTRODUCTION
Compound via MeSH
