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Full-length article Acta Pharmacologica Sinica 2008 February; 29 (2): 161-168 Modulation of synaptic GABAA receptor function by zolpidem in substantia nigra pars reticulata1 Li-li ZHANG2,3, Lei CHEN2, Yan XUE2, Wing-ho YUNG3,4 2Department of Physiology, Qingdao University, Qingdao 266071, China;
3Department of Physiology, The Chinese University of Hong Kong,
Shatin, Hong Kong
1 Project supported by the Research Grants
Council of Hong Kong (No CUHK 4175/02M to Dr Wing-ho YUNG) and the Foundation of Health
Department of Shandong Province (No 2005HW021 to Dr Lei CHEN).
Abstract
Aim: The substantia nigra pars reticulata (SNr) constitutes one of the output centers of the basal ganglia, and its abnormal
activity is believed to contribute to some basal ganglia motor disorders. Different lines of evidence revealed a major
contribution of GABAA receptor-mediated synaptic inhibition in controlling the activity of SNr. The benzodiazepine binding
site within the GABAA receptor is a modulation site of significant clinical interest. A high density of benzodiazepine binding
sites has been reported in the rat SNr. In the present study, we investigate the effects of activating benzodiazepine binding
sites in the SNr. Methods: Whole-cell patch-clamp recordings and motor behavior were applied.
Results: Superfusion of zolpidem, a benzodiazepine binding agonist, at 100 nmol/L significantly prolonged the decay time of
GABAA receptor-mediated postsynaptic currents. The prolongation on decay time induced by zolpidem was sensitive to the benzodiazepine
antagonist flumazenil, confirming the specificity on the benzodiazepine site. Zolpidem at 1 µmol/L exerted a stronger
prolongation on the decay time. A further experiment was performed on behaving rats. A unilateral microinjection of zolpidem into
the rat SNr caused a robust contralateral rotation, which was significantly different from that of control animals receiving the
vehicle injection. Conclusion: The present
in vitro and in vivo findings that zolpidem significantly potentiated GABA
currents and thus inhibited the activity of the SNr provide a rationale for further investigations into its potential in the
treatment of basal ganglia disorders.
Key words substantia nigra pars reticulata; benzodiaze-pine; zolpidem; GABAA receptors
Note: Please read the complete
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Introduction
The substantia nigra pars reticulata
(SNr) occupies one of the output centers of the basal ganglia circuit. It is well
known that the inhibitory neurotransmitter γ-aminobutyric
acid (GABA) is the major neurotransmitter used in the SNr,
which suggests that GABA-mediated neurotransmission in
this nucleus plays an important
function[1]. Anatomical and electrophysiological evidence has shown that the major
sources of GABAergic inputs in the SNr are the striatum,
globus pallidus, and local axon collaterals of GABAergic
output neurons[2_5].
Moderate to high densities of GABAA receptors were
expressed in the SNr[6,7], which mediate fast inhibitory
synaptic transmission. GABAA receptors are heteropentameric
structures assembled from various subunits, including
α1_6, β1_4, γ1_3, δ, ε, π, θ, and ρ1_3. The subunit combination of a
particular GABAA receptor plays a crucial role in
determining its pharmacological properties and physiological
functions. Most GABAA receptors contain at least both
α and β subunits, with 1 or more of the other subunits. There
are several binding sites within GABAA receptors that
interact with a diverse rage of
compounds[8]. The benzodiazepine binding site is one of the potent modulating sites, which leads
to anxiolytic, anticonvulsant, and sedative effects by
potentiating GABA currents. Zolpidem is an imidazopyridine agonist
with a high affinity on the benzodiazepine site containing the
α1 subunit. Early studies indicated that the highest level of
zolpidem binding sites occurred in the
SNr[9]. Quantitative autoradiography has shown that 6-hydroxydopamine lesion
significantly increased the binding of zolpidem in SNr, which
may reflect a compensatory
alteration[10,11]. The systemic administration of zolpidem produced an inhibition on the firing
of the SNr neurons[12]. The microinfusion of zolpidem and
other benzodiazepine agonists into the SNr produced
anticonvulsant effects on clonic and tonic-clonic
seizures[13,14]. Recently, a few clinic reports suggested that zolpidem
exerted a therapeutic effect on some groups of Parkinson's
patients[15_17]. However, the direct pharmacological effects
of zolpidem in the SNr are not known. In the present study,
whole-cell patch-clamp recordings and intranigral
microinjection were used to study the function of zolpidem in the rat
SNr.
Materials and methods
In vitro slice preparation Sprague-Dawley rats aged
12_14 d were used for the preparation of acute brain slices.
The animals were killed by decapitation. The brains were
then immediately removed and placed in ice-cold artificial
cerebrospinal fluid (ACSF) of the following composition (in
mmol/L): NaCl 125, KCl 2.0, MgSO4 1.2,
CaCl2 2.5, KH2PO4
1.2, glucose 11, and NaHCO3 26, which was continuously
bubbled with 95% O2 and 5%
CO2. Midbrain coronal slices (250 µm) containing the SNr were sectioned using a
vibrating microtome (Camden Instruments, Loughborough, UK)
as previously described[18]. Briefly, after equilibration for at
least 1 h, the slices were transferred to a small volume
chamber mounted on an upright microscope (Zeiss Axioskop,
Oberkochen, Germany) and superfused with ACSF at a rate of
1.5_2.0 mL/min maintained at a temperature of 34 °C.
Neuronal soma of the SNr neurons was directly visualized by a
combination of differential interference contrast optics and
contrast-enhanced infrared video microscopy.
Patch-clamp recording Whole-cell patch-clamp
recordings from the SNr neurons were obtained using a
patch-clamp amplifier (LM/PCA, List Medical, Darmstadt, Germany).
Whole-cell pipettes typically had a resistance of 3_4
MΩ when filled with an internal solution of the following
composition (in mmol/L): KCl 140, EGTA 1.0,
MgCl2 2.0, Na2ATP 2.0, Tris GTP 0.4, and HEPES 10; the pH was
adjusted to 7.25_7.30 with 1 mol/L KOH. The inclusion of
140 mmol/L KCl in the recording pipettes reversed the
polarity of GABAA receptor-mediated currents from outward to
inward. Monitoring through a camera, a pipette was placed
on the soma of a SNr neuron and whole-cell recording was
made. Normally, no series resistance compensation was
applied, but the cell was rejected if the series resistance
increased significantly (>20%) during recording.
(F)-2-Amino-5-phosphonopen-tanoic acid (AP5; 50 µmol/L) and
6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 20
µmol/L) were included to eliminate glutamate receptor-mediated synaptic
currents. Miniature postsynaptic currents (mPSC) were
isolated by the addition of 0.5 µmol/L tetrodotoxin (TTX) to the
ACSF. Inhibitory postsynaptic currents were recorded at a
holding potential of -70 mV. The current signal was filtered
at 3 kHz. Online or offline digitization (10 kHz) was made via
the Digidata-pClamp system (Axon Instruments, California,
USA). Computer files containing information of synaptic
currents were analyzed by the mini analysis program (version
6, Synaptosoft, Decatur, GA, USA), which automatically
generates various parameters, including the time of
occurrence, peak amplitude, and kinetics.
In vivo surgery Sprague-Dawley rats (250_280 g) were
used. The animals were individually housed in a
temperature regulated room and maintained on a 12 h:12 h light/dark
cycle. All rats had free access to food and water. On the day
of surgery, the rats were anesthetized with chloral hydrate
(400 mg/kg, intraperitoneally) and placed in a stereotaxic frame.
A guide cannula constructed from stainless steel (outer
diameter: 0.4 mm; inner diameter: 0.3 mm) was implanted into
the SNr (5.5 mm posterior, 2.3 mm lateral from the bregma,
8.0 mm ventral from the skull surface) on either side. The
cannulae were fixed to the skull with stainless steel screws
and dental acrylic. Stainless steel stylets were used to keep
the cannulae sealed.
Rotational test Following at least 3 d of recovery, the
rats were tested for motor/turning behavior. Drugs (0.2 µL)
were microinjected into the SNr in awake animals over a
2 min period. Injection cannulae were connected to a 1.0
μL microsyringe and a drug was injected. At the end of injection,
the cannula was left in the SNr for an additional 1 min before
removal and then replaced by a stylet. The net rotational
behavior was calculated for 30 min.
Histological controls After the test, the rats were
perfused with 10% formalin solution transcardially. Fifty
micrometer brain slices were cut to examine the sites of injection.
Only the data obtained from animals with correct placement
of the cannulae were used for the analysis.
Drugs and statistics Zolpidem and flumazenil were
purchased from Tocris (Avonmouth, UK). AP5, CNQX,
bicuculline, and TTX were obtained from Sigma (St Louis,
MO, USA). The data are expressed as mean±SEM. The
Kolmogorov-Smirnov test was used to compare 2
distributions of synaptic current inter-event intervals,
amplitudes, decay time, and rise time setting the threshold of
significance at a probability (P) of 0.05. Otherwise, paired or
unpaired Student's t-test was applied using a value of 0.05.
The net rotational behavior was analyzed by the
non-parametric one-way Kruskal-Wallis test followed by the
Mann_Whitney U-test.
Results
Identification of GABA and dopamine neurons
It is known that 2 types of neurons, GABA and dopamine neurons, exist
in the SNr. In the present study, the distinction between
dopamine and GABA neurons was based on their
electrophysiological
characteristics[19,20]. Briefly, dopaminergic
neurons displayed a low resting firing rate, slow
hyperpolarization after each action potential, and inward rectification in
response to hyperpolarizing current injection. In contrast,
GABAergic neurons were characterized by a relatively
high-frequency firing and absence of the inward rectification. The
neurons obtained in the present study were medium-sized
neurons, which exhibited the electrophysiological
characteristics of GABAergic neurons.
Effects of 100 nmol/L zolpidem on mPSC The mPSC
were found in all the SNr neurons, which were sensitive to
the GABAA receptor antagonist bicuculline (10 µmol/L). As
shown in Figure 1, superfusion of 100 nmol/L zolpidem
significantly prolonged the decay time, the time required for the
amplitude of the mPSC to decay to half its peak value,
without any change in the amplitude, rise time, and inter-event
intervals. In 6 cells recorded, 100 nmol/L zolpidem
significantly prolonged the decay time (control: 7.4±0.5 ms;
zolpidem: 10.3±0.3 ms, P<0.01). The prolongation on decay
time was only partially reversed after 20 min of washing. No
significant change was observed in amplitude (control:
64.7±5.8 pA; zolpidem: 70.5±7.6 pA,
P>0.05), rise time (control: 3.0±0.3 ms; zolpidem: 3.1±0.2 ms,
P>0.05) and frequency (control: 2.9±0.6 Hz; zolpidem: 3.0± Benzodiazepine antagonist blocked the
zolpidem-mediated prolongation of mPSC A further experiment was
performed to investigate the effects of the benzodiazepine
binding site antagonist flumazenil on the zolpidem-mediated
prolongation of the decay time. As shown in Figure 2, 10
µmol/L flumazenil alone did not induce any change on decay time
(control: 6.8±0.3 ms; flumazenil: 6.9±0.4 ms,
n=8, P>0.05), amplitude (control: 66.7±11.2 pA; flumazenil: 65.2±11.6 pA,
P>0.05), frequency (control: 4.1±0.7 Hz; flumazenil: 3.5±0.8 Hz,
P>0.05), and rise time (control: 2.9±0.2 ms; flumazenil: 3.1±0.3 ms,
P>0.05) of mPSC. However, in the presence of flumazenil, the
zolpidem-induced prolongation of the decay time could be completely prevented
(flumazenil+zolpidem: 7.1±0.4 ms, P>0.05 compared with
flumazenil alone). No significant difference was observed for
amplitude (flumazenil+zolpidem: 68.8±13.9 pA,
P>0.05), frequency (flumazenil+zolpidem: 3.2±0.7 Hz,
P>0.05), and rise time (flumazenil+zolpidem: 3.1±0.2 ms,
P>0.05) after flumazenil and zolpidem cosuperfusion.
Effects of 100 nmol/L zolpidem on spontaneous PSC
The effects of zolpidem on spontaneous PSC (sPSC) were tested.
As shown by the example in Figure 3A, 100 nmol/L zolpidem
prolonged the decay time and rise time of sPSC significantly.
In the 7 neurons studied, zolpidem prolonged the decay time
from 7.0±0.2 ms to 10.5±0.4 ms (P<0.01) and the rise time from
2.7±0.1 ms to 3.4±0.1 ms (P<0.01). There was no significant
effect on amplitude (control: 80.1±8.8 pA; zolpidem:77.0±8.0 pA, P>0.05) and frequency (control: 7.1±1.4 Hz;
zolpidem: 6.7±1.3 Hz, P>0.05). Figure 3B summarizes the
effects of 100 nmol/L zolpidem on sPSC. The increase on the
decay time of sPSC (49.9%±5.4%) was similar to that of mPSC
(40.7%±4.4%, P>0.05).
Effects of 1 µmol/L zolpidem on mPSC and sPSC
Further studies were performed to observe the effects of a higher
concentration of zolpidem on both mPSC and sPSC. In 6
neurons studied, 1 µmol/L zolpidem prolonged the decay
time of mPSC from 6.2±0.4 ms to 11.6±0.6 ms
(P<0.01) and amplitude from 65.5±5.9 pA to 77.1±7.2 pA
(P<0.05). There was no significant change in the rise time (control: 2.5±0.3
ms; zolpidem: 3.0±0.2 ms, P>0.05) and frequency (control:
3.8±0.7 Hz; zolpidem: 3.7±0.4 Hz,
P>0.05). The increase in the decay time induced by 1 µmol/L zolpidem was 87.8%±8.1%,
which was significantly stronger than that induced by the
concentration of 100 nmol/L (40.7%±4.4%,
P<0.05, Figure 4A).
In another 9 neurons studied, 1 µmol/L zolpidem
prolonged the decay time of sPSC from 6.9±0.3 ms to 11.3±0.5
ms (P<0.01) and the rise time from 2.5±0.1 ms to 3.0±0.1 ms
(P<0.01). There was no significant change in amplitude (control:
67.1±9.3 pA; zolpidem: 79.1±7.9 pA,
P> Effects of zolpidem on rotational behavior
To determine the modulation of zolpidem on motor behavior
in vivo, zolpidem was microinjected into the SNr. In 7 rats tested, a
unilateral microinjection of zolpidem (1 mmol/L, 0.2 µL)
induced a robust contralateral rotation (32.7±2.9 turns/30 min).
However, the vehicle microinjection only induced 0.7±0.3
turns/30 min contralateral rotation (n=6,
P<0.01 compared with zolpidem). In another 5 rats, a unilateral microinjection
of flumazenil (3 mmol/L, 0.2 µL) alone did not produce any
significant rotation (2.2±2.1 turns/30 min contralateral
rotation, P>0.05 compared with the control). However, the
presence of flumazenil could completely block the
contralateral rotation induced by the zolpidem microinjection (2.9±2.7
turns/30 min contralateral rotation, n=7,
P<0.05 compared with zolpidem alone). These data are summarized in Figure 5.
Discussion
It is well known that the subunit combination is critical in
determining the physiological functions and
pharmacological properties of the GABAA receptor in the
brain[8,21_23]. Early morphological studies, including
in situ hybridization, have shown that the
SNr expressed high levels of α1 subunits on the
GABAA receptor[7,24]. Zolpidem has high affinity for the
GABAA receptor containing α1
subunits[25,26]. Therefore, neurons with relatively high densities of
a1 subunits on the GABAA receptor usually exhibit high binding sites and
sensitivity for zolpidem[27,28]. In the present study, all neurons
recorded in the SNr exhibited sensitivity to 100 nmol/L
zolpidem, suggesting the functional presence of α1
subunits in the rat SNr.
Morphological evidence has revealed that the SNr
received GABAergic innervation from the striatum, globus
pallidus, and local axon collaterals. The action
potential-dependent inhibitory PSC of the SNr neurons mainly
originate from the axon collaterals because the striatal neurons
are quiescent. However, the action potential-dependent
pallidal GABAergic inputs are blocked under coronal
sectioning. To investigate the possible difference of the
GABAA receptor subunit composition arising from
striatonigral, pallidonigral, and nigronigral GABAergic
innervation, we further compared the effects of zolpidem on
mPSC and sPSC. The present results showed that zolpidem
exerted similar potency on the prolongation of the decay
time of mPSC and sPSC, suggesting that α1 subunit
expression may be similar in the SNr. However, it was
impossible to isolate the PSC arising from different sources and examine the
effects of zolpidem on them directly.
Much evidence has shown that the SNr is involved in
the control of several kinds of epileptic seizures. The firing
rate of SNr increased significantly at the beginning of
seizure[29]. The anticonvulsant drug gabapentin decreased the
firing rate of the SNr[30]. Furthermore, deep brain stimulation
of the SNr prevents seizures[31].
GABAergic transmission in the SNr is critical for seizure
control. Previous studies have shown that
GABAA receptor expression is reduced in the SNr of some epileptic
models[32]. However, a recent study revealed that the
GABAA receptor mediated inhibitory PSC, and
α subunit expression were not reduced in the SNr of gerbils with inherited
epilepsy[33]. Functional studies have shown that a microinjection of muscimol
into the SNr suppressed the electroshock model of
epilepsy[34], while bicuculline infusions are
proconvulsant[35]. The intranigral transplantation of GABA-producing cells have
been shown to exhibit significant anticonvulsant effects in
experimental epilepsy[36]. Recently, Gonzalez Ramirez
et al reported that benzodiazepine binding was enhanced in the
SNr in hyperthermia-induced seizure
rats[37]. Microinfusions of zolpidem had anticonvulsant effects on clonic and
tonic-clonic seizures[13]. The present findings prompted us to
hypothesize that the direct potentiation on GABA
transmission is the major mechanism of zolpidem-induced antiepileptic
effects in the SNr.
In conclusion, the present in vitro studies demonstrated
that zolpidem enhanced GABA transmission in the SNr by
activating the benzodiazepine site. Moreover, the finding
on the effects of zolpidem in the SNr may provide a rationale
for further investigations into its potential in the treatment
of some neurological diseases.
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