Behavioral Neuroscience

2010, Vol. 124, No. 2, 305310

2010 American Psychological Association

0735-7044/10/$12.00 DOI: 10.1037/a0018931

Electro-Acupuncture Stimulation Acts on the Basal Ganglia Output Pathway

to Ameliorate Motor Impairment in Parkinsonian Model Rats
Jun Jia, Bo Li, Zuo-Li Sun, Fen Yu, Xuan Wang, and Xiao-Min Wang
Capital Medical University
The role of electro-acupuncture (EA) stimulation on motor symptoms in Parkinsons disease (PD) has not
been well studied. In a rat hemiparkinsonian model induced by unilateral transection of the medial
forebrain bundle (MFB), EA stimulation improved motor impairment in a frequency-dependent manner.
Whereas EA stimulation at a low frequency (2 Hz) had no effect, EA stimulation at a high frequency (100
Hz) significantly improved motor coordination. However, neither low nor high EA stimulation could
significantly enhance dopamine levels in the striatum. EA stimulation at 100 Hz normalized the MFB
lesion-induced increase in midbrain GABA content, but it had no effect on GABA content in the globus
pallidus. These results suggest that high-frequency EA stimulation improves motor impairment in
MFB-lesioned rats by increasing GABAergic inhibition in the output structure of the basal ganglia.
Keywords: electro-acupuncture, DA, GABA, Rota-Rod treadmill, Parkinsons disease

in GABA neuron activity in the substantia nigra pars reticulata

(SNr) (Zhou, Matta, & Zhou, 2008). Firing intensity and patterns
are often altered in the SNr GABAergic output pathways in the
parkinsonian brain (Hutchison et al., 2004). Inactivation of SNr in
a primate model of PD has been shown to ameliorate parkinsonian
motor symptoms, further demonstrating the importance of SNr in
motor control (Wichmann, Kliem, & DeLong, 2001).
Previous work has demonstrated that high-frequency electroacupuncture (EA) stimulation significantly reduced abnormal rotational behavior and enhanced the survival of degenerating dopaminergic neurons following medial forebrain bundle (MFB)
axotomy (Liang et al., 2003). These effects might be attributable to
enhanced synthesis and release of neurotrophic factors (Liang et
al., 2002, 2003) and alleviation of inflammatory reactions in the
SN (Liu et al., 2004). Furthermore, EA stimulation reversed the
lesion-mediated decrease of Substance P content in the ventral
midbrain (Jia et al., 2009). These studies suggested that EA stimulation may result in changes in neuronal activity in the basal
ganglia (Zangen & Hyodo, 2002).
Therefore, the present study was conducted to evaluate the
effects of different frequencies of EA stimulation (0, 2, or 100 Hz)
on motor behavior and dopamine content in the striatum in MFBtransected rats. Changes in GABA content in the midbrain and the
globus pallidus (GP) were also measured to assess the modulatory
effect of EA stimulation on neuronal activity in the basal ganglia.

Acupuncture is a popular alternative therapy in patients with

Parkinsons disease (PD) and might provide some benefit in the
clinical setting (Rabinstein & Shulman, 2003). A survey of PD
patients demonstrated that patients who received acupuncture reported improvement of their symptoms (Shulman et al., 2002). In
addition, acupuncture is very safe and well tolerated, and it has no
known interactions with medications (Eng, Lyons, Greene, &
Pahwa, 2006).
PD is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars
compacta (SNc). The behavioral deficits of PD, including resting
tremor, rigidity, and bradykinesia, are expressed when striatal
dopamine (DA) depletion exceeds 60 80% (Bernheimer, Birkmayer, Hornykiewicz, Jellinger, & Seitelberger, 1973). It has
followed from these observations that the best course of therapy
might be to increase the DA content of the striatum. However,
increasing evidence suggests that a poor relationship exists between the dopamine content of the striatum and the improvement
of motor symptoms during treatment (Gash et al., 1996; Tseng,
Baetge, Zurn, & Aebischer, 1997). On the other hand, parkinsonian movement disorders are often associated with abnormalities

Jun Jia, Bo Li, Zuo-Li Sun, Fen Yu, Xuan Wang, and Xiao-Min Wang,
Department of Physiology, Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing,
Peoples Republic of China.
This study was supported by the National Basic Research Program of
China (2006CB500700), the National Natural Science Foundation of China
(30472245), Key Project of the Beijing Natural Science Foundation and the
Beijing Education Committee (kz200510025014), the Talent Training Plan
of Beijing (20081d 0501800206), and the Capital Medical University fund
(107420).
Correspondence concerning this article should be addressed to Xiao-Min
Wang, Department of Physiology, Capital Medical University, 10 Xi Tou
Tiao, You An Men Wai, Beijing 100069, PR China. E-mail: xmwang@ccmu
.edu.cn

Method
Animal Care and MFB Axotomy
Adult male Wistar rats weighing 200 230 g were obtained from
the laboratory animal center, Capital Medical University, and
housed in a standard 12-hr light dark cycle with ad libitum access
to food and water. The rats were anesthetized with chloral hydrate
(350 mg/kg ip) and then positioned in a stereotaxic apparatus
(David Kopf Instruments, Tujunga, CA) with the mouth bar set at
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3.3 mm. MFB lesions were performed using a retractable

Scouten wire knife as described previously (Tseng et al., 1997).
The experimental procedures were approved by the Committee on
Animal Care and Usage, Capital Medical University, and all
efforts were made to minimize animal suffering.

EA Stimulation
Rats were randomly divided into five groups: the sham group,
the MFB-lesioned group, and the MFB-lesioned group followed by
0-, 2-, and 100-Hz EA stimulation. The EA stimulation was
administered on Day 2 following MFB lesioning as described
previously (Liang et al., 2003). Two stainless steel needles 0.25
mm in diameter and 5 mm in length were inserted obliquely at the
acupuncture point Dazhui (Du 14, just below the spinous process
of the vertebra prominens) and horizontally at the Baihui point (Du
21, at the midpoint of the line connecting the two ears). For the
0-Hz group, the needles were placed into the acupoints, but no
electrical stimulation was administered. Bidirectional square wave
electrical pulses (0.2-ms duration, 2 Hz and 100 Hz), designated as
EA, were given for a total of 30 min each day, 6 days per week.
The duration of EA treatment was limited to 4 weeks. The intensity
of the stimulation was increased stepwise from 1 to 2 mA and then
to 3 mA, with each step lasting 10 min. EA was administered to
awake, unrestrained animals while in their cages.

Rota-Rod Test
The motor coordination of rats was evaluated on Rota-Rod
treadmills (Stoelting Company, Wood Dale, IL). The apparatus
consisted of a base platform and a rotating rod with a diameter of
6 cm and a nonslippery surface. The accelerating speed of the
Rota-Rod was set to increase from 6 rpm/min to 40 rpm/min
within 2 min. The rats were placed on the treadmill, and the timers
were set with acceleration programmed to automatically stop when
the rat fell off. The maximal cutoff time was set to 600 s. Rats were
tested on the Rota-Rod at 7, 14, 21, and 28 days following MFB
lesioning.

Tissue Collection and Processing

Five rats from each group were randomly selected 28 days after
MFB transection. After decapitation, the brain was quickly removed. The ventral midbrain (the section of the SN, bregma from
4.8 to 6.3 mm) and GP were dissected, rapidly frozen on dry
ice, and stored at 80C.

High-Performance Liquid Chromatography (HPLC)

Concentrations of DA were quantified by a modified method of
HPLC combined with electrochemical detection (HPLC-ECD) as
described elsewhere (Kotake, Heffner, Vosmer, & Seiden, 1985).
The concentrations of GABA were determined using HPLC with
laser-induced fluorescence detection. On the day of assay, tissue
samples were weighed and then homogenized in 150 l of 0.1 mM
acetic acid as described previously (Carlson, Behrstock, Tobin, &
Salamone, 2003). Briefly, samples or standards were derivatized
with the same volume of the o-phthaldialdehyde reagent solution
(P0532 of Sigma Chemical, St. Louis, MO). The resulting mixture
was automatically injected by a refrigerated autoinjector into a

symmetry shield-C18 reverse-phase column (150 3.8 mm, 5 m

particle size; Waters Corporation, Milford, MA). The mobile phase
consisted of 50 mM sodium acetate (pH was adjusted to 6.8 using
acetic acid), methanol, and tetrahydrofuran. The flow rate was 1.0
ml/min, maintained with two Shimadzu LC (Agilent, Santa Clara,
CA) pumps. Putative GABA peaks were identified by comparing
retention times of GABA standard (SigmaAldrich) to retention
times of the sample peak. The concentrations were estimated by
rationing peak areas of GABA and its external standard (Agilent
Chemstation analytical software). The running time for each determination was 40 min.

Statistical Analysis
Data were expressed as means SEM. Statistical significance
was assessed using one-way analysis of variance followed by the
NewmanKeuls post hoc test of difference between groups. A
value of p .05 was considered statistically significant.

Results
EA Stimulation Improves Motor Coordination
The Rota-Rod treadmill test was performed following EA stimulation of all experimental rats to investigate the effects of different frequencies of EA stimulation on motor coordination, The
MFB-lesioned rats demonstrated a decreased treadmill occupancy
time compared with the sham group under all conditions (see
Figure 1A). From Week 2, the rats receiving 100-Hz EA stimulation demonstrated significantly increased treadmill occupancy
time compared with MFB-lesioned rats ( p .05). These improvements in motor coordination were retained for the duration of the
high-frequency EA treatment. These data demonstrate that 100-Hz
EA stimulation can enhance motor coordination in MFBtransected rats.

EA Stimulation Did Not Increase DA Content

in the Striatum
Wire knife lesions of the MFB dramatically decreased the DA
content in the ipsilateral striatum in hemiparkinsonian rats compared
with the sham group ( p .01). In contrast, MFB lesions did not result
in significant changes in DA levels on the contralateral side (see
Figure 1B). The HPLC-ECD analysis data demonstrate that neither
low- nor high-frequency EA stimulation could enhance the DA level
in the ipsilateral striatum. These results suggest that the improvement
in motor coordination is not fully dependent on the restoration of the
striatal DA content, as seen in our EA-treated hemiparkinsonian rats.

Effect of EA on GABA Content in the GP

and the Midbrain
To investigate the effects of MFB lesioning and EA treatment
on the output structures of the basal ganglia, we examined the
GABA content in the GP and the ventral midbrain area. Our data
show that the GABA content of the ipsilateral GP was higher in
MFB-lesioned rats than in sham groups, but no changes were
observed on the contralateral side (see Figure 2A). This result is
consistent with previous reports that ipsilateral DA lesions induce

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307

through a mechanism that involves the potentiation of GABAergic

inhibition in the basal ganglia output structure (SNr).
Previous studies have confirmed that a slower rate of degeneration and progression of motor impairment occurs following MFB
axotomy (Brecknell, Dunnett, & Fawcett, 1995; Knusel et al.,
1992). In this model, 100-Hz EA stimulation (but not 2 Hz or 0
Hz) significantly improves motor coordination as manifested by
performance on the Rota-Rod test. However, the mechanisms
underlying this improvement are not fully understood.
The striatum is the primary projection target of SNc dopaminergic neurons. Movement disorders can result when striatal DA
depletion exceeds 70%. The restoration of DA levels in the striatum is thought to be critical for treatment of PD. However, many
studies have demonstrated motor improvement without restoration
of striatal DA content. For example, intracerebral injection of glial

Figure 1. (A) Effects of electro-acupuncture (EA) stimulation on motor

coordination of rats measured by the Rota-Rod treadmill test. The time
spent on the treadmill among the five groups was recorded at the end of 1,
2, 3, and 4 weeks post-transection. Values are represented as means
SEM; n 715; p .05, p .01 versus the medial forebrain bundle
(MFB)-lesioned group. (B) Effect of EA stimulation on striatum dopamine
(DA) content of MFB-transected rats 28 days after MFB transection. The
striatum dopamine content was measured by high-performance liquid
chromatography with electrochemical detection. The results are given as
means SEM; n 6 10; p .01 versus sham lesioned side.

a marked increase in the GABA levels in the output nuclei (the GPi
and the SNr) of the basal ganglia (Windels, Carcenac, Poupard, &
Savasta, 2005). No significant differences in the GABA content
were detected between rats with the MFB lesion and hemiparkinsonian rats receiving EA stimulation of any frequency. In contrast
to the results from the GP, 100-Hz EA stimulation normalized
midbrain GABA from the increased levels observed in MFBlesioned rats. This effect was not seen in hemiparkinsonian rats
subjected to 0- or 2-Hz EA stimulation (see Figure 2B).

Discussion
The present study demonstrates that high-frequency EA stimulation can improve the motor coordination of MFB-lesioned rats

Figure 2. Effect of electro-acupuncture (EA) stimulation on (A) globus

pallidus (GP) and (B) ventral midbrain GABA content in medial forebrain
bundle (MFB)-transected rats. The GABA content was measured by highperformance liquid chromatography. The histograms represent the mean
content on the unlesioned side and the lesioned side of MFB-lesioned rats.
The values are expressed as percentages SEM of the sham values; n
5; p .05 versus sham rats and # p .05 versus MFB rats.

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cell-derived neurotrophic factor (GDNF) has significantly improved parkinsonian behavioral symptoms but does not affect DA
levels in the caudate nucleus or putamen of 1-Methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys (Gash et al.,
1996). Moreover, continuous release of low levels of GDNF near
the SN has also been reported to protect nigral dopaminergic
neurons from MFB axotomy-induced degeneration and to significantly improve apomorphine-induced rotational behavior. However, GDNF infusion did not prevent the loss of DA in the striatum
(Tseng et al., 1997). Our previous experiments (Jia et al., 2009;
Liang et al., 2003) and present study demonstrate that 100-Hz EA
stimulation can significantly improve movement disorders in
MFB-lesioned rats without affecting DA levels in the striatum
(Liang et al., 2003). Analysis of the DA content in the striatum
shows that there is no significant difference between the MFBlesioned group and the groups treated with 2-Hz or 100-Hz EA.
However, rats treated with high-frequency EA stimulation showed
a slightly higher striatal DA content than those treated with lowfrequency EA stimulation. These effects of 100-Hz EA stimulation
might be attributable to enhanced synthesis and release of neurotrophic factors (Liang et al., 2002, 2003) and alleviation of inflammatory reactions in the SN (Liu et al., 2004). L-dopa-induced
rotational behavior has suggested that DA levels in the striatum are
only elevated for a short time, whereas DA levels in the SN remain
elevated until the behavioral effects of L-dopa have subsided. This
suggests that elevated DA levels in the SN maintain circling
behavior when striatal DA levels have begun to decline (Robertson
& Robertson, 1989). Morphological evidence also revealed that
EA at 100 Hz protected axotomized dopaminergic neurons from
degeneration in the SN (Jia et al., 2009). Therefore, a SN-based
mechanism potentially involved in the improvement of motor
disorders should be investigated.
SNc dopaminergic neurons release DA not only via axonal
terminals that affect neurotransmission within the striatum but also
via dendrites, some of which densely protrude into the SNr
(Nieoullon, Cheramy, & Glowinski, 1977). This anatomical arrangement makes it possible for dendritically released DA to
interact with SNr neurons, thus affecting the activity of this key
output structure of the basal ganglia (Windels & Kiyatkin, 2006b).
In MFB-lesioned rats, we found that high-frequency EA stimulation prevented the degeneration of both dopaminergic cell bodies
in the SNc and dopaminergic neurons that arborize in the SNr (Jia
et al., 2009). These data indicate that high-frequency EA stimulation may induce an increase in DA release within the SNr, which
may result in significant alterations in the output pathways of SNr
neurons. However, it remains unclear how increased dendritic DA
release might affect SNr GABAergic projection neurons
(Gonzalez-Hernandez & Rodriguez, 2000).
The SNr is usually considered a major output nucleus of the
basal ganglia, and striato-nigral GABAergic projections are primary inputs to SNr neurons. However, D1 DA receptors were
identified on GABA (Yung et al., 1995) and glutamate terminals
(Rosales et al., 1997) synapsing on SNr neurons. Therefore, the
effects of DA on SNr neurons may be indirect, resulting from
presynaptic modulation of GABA or glutamate (GLU) inputs, the
two opposing forces regulating the activity of these cells. Windels
and Kiyatkin (2006a) have studied the effects of iontophoretic DA
and amphetamine on SNr neurons in awake, unrestrained rats.
Their results showed that the activity state of GABAergic SNr

neurons may be modulated by dendritic release of DA through

activation of D1 DA receptors on the terminals of striato-nigral
efferents. It has also been suggested that increased somatodendritic
DA release can decrease the activity of SNr neurons by increasing
GABA input. On the other hand, in vitro work also suggests that
DA may affect SNr activity via modulation of glutamatergic inputs
(Wittmann, Marino, & Conn, 2002). Somatodendritically released
DA may play an additional role in regulating GLU release from
subthalamic terminals in the SN (Hatzipetros & Yamamoto, 2006).
It indicated that somatodendritically released DA in the SN provides negative feedback control on overstimulated or phasic GLU
release from subthalamic nucleus (STN) terminals within the SN
by activation of D2 dopamine heteroreceptors. Moreover, lesion or
high-frequency stimulation of the STN reduces most of the motor
impairments associated with PD (Parkin et al., 2001; Benazzouz et
al., 2000). This effect is presumably mediated by a reduction in the
activity of the subthalamo-nigral pathway.
Although previous studies have indicated that GAD67 mRNA
levels are increased in the GP after dopaminergic neuronal degeneration (Billings & Marshall, 2004; Soghomonian & Chesselet,
1992), this increase in GAD67 mRNA is believed to be secondary
to activation of excitatory subthalamo-pallidal projections. In this
study, we found that EA stimulation has no effect on the increased
GABA content in GP in MFB-lesioned rats. This suggests that EA
stimulation does not entirely modulate the activity of GP neurons,
which is affected by the two processes of degeneration of dopaminergic neurons: activation of STN inputs to GP neurons and the
removal of nigro-pallidal DA transmission (Billings & Marshall,
2004; Soghomonian & Chesselet, 1992).
The GABA content in the midbrain also increased in hemiparkinsonian rats, which is consistent with other reports (Boulet et al.,
2006). Some of this nigral GABA may result from an increase in
GP neuronal activity from GABAergic pallido-nigral projections
to the SNr (Celada, Paladini, & Tepper, 1999). In anesthetized
hemiparkinsonian rats, GP lesions abolish the increase in SNr
GABA levels induced by STN high-frequency stimulation (Windels et al., 2005). However, SNr inhibition may also result from
activation of the intranigral axon collateral network of GABAergic
SNr cells (Mailly, Charpier, Menetrey, & Deniau, 2003). According to the classical model, direct striatonigral GABAergic pathway activation inhibits the tonically active GABAergic neurons of
the SNr, abolishing target nucleus inhibition in premotor structures
in the thalamus and brainstem (Chevalier & Deniau, 1990). Thus,
the inhibition of SNr neurons may be important in mediating
movement hyperactivity. Here, we show that high-frequency EA
stimulation decreases the content of GABA in the midbrain of
MFB-lesioned rats. This implies that EA results in increased
somatodendritic DA release, resulting in inhibition of the activity
of SNr neurons. In keeping with this, high-frequency EA stimulation was found to antagonize the MFB lesion-induced increases
in GAD67 mRNA levels in the midbrain (Jia et al., 2009). Previous
studies (Guridi et al., 1996; Salin, Manrique, Forni, &
Kerkerian-Le Goff, 2002) have shown that STN high-frequency
stimulation or subthalamotomy reverses the DA lesion-mediated
increase in GAD67 mRNA levels in SNr neurons. The observed
reduction of GAD67 mRNA levels in the midbrain indicates that
EA stimulation may reduce inhibitory excitatory efferent activity
from the output pathways of the basal ganglia. Therefore, EA

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treatment may affect GABA transmission to target brain regions,

especially to SNr neurons in the basal ganglia output structure.
Rats receiving 0-Hz EA stimulation exhibited no improvement
in motor coordination. This observation indicates that electrical
stimulation, and not just needle placement, is necessary for the
positive effects of EA therapy. In addition, low-frequency stimulation (2 Hz) showed no significant change compared with the
MFB-lesioned group. This suggests that different frequencies of
EA stimulation may affect different brain regions or that certain
basal ganglia structures may be less sensitive to the low-frequency
stimulation.
Electrostimulation at the Dazhui (Du 14) and Baihui (Du 21)
acupoints produces a neuroprotective effect on dopaminergic neurons in the SN. Park et al. (2003) also demonstrated that acupuncture at the Yanglingquan (GB 34) and Taichong (LR 3) acupoints
reduces the degeneration of dopaminergic neurons. However, acupuncture at nonacupoint or nondirectly related acupoints does not
halt the degeneration of dopaminergic neurons (Kim et al., 2005).
These results provide evidence for the existence of acupoint specificity. This is consistent with evidence from fMRI studies (Zhang
et al., 2004), although additional research is necessary to further
corroborate this phenomenon.
The GDNF-induced changes in DA levels seen in rhesus monkeys were limited to the SN, ventral tegmental area, and GP.
MPTP-induced depletion of DA in the caudate nucleus and putamen was not reversed by GDNF administration (Gash et al., 1996).
These results suggest that the SN, ventral tegmental area, and GP
all play important roles in regulating motor functions. In contrast,
it has also been reported that after lesioning with
6-hydroxydopamine, DA released per pulse from residual terminals in the striatal slices is increased relative to the control, which
may serve a compensatory function to maintain dopaminergic
control over striatal function. However, future studies are needed
to determine whether EA stimulation induces changes in DA
regulation (release and uptake) or DA receptors in the striatum that
contribute to the recovery of movement functions.

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Received September 15, 2009

Revision received November 30, 2009
Accepted January 15, 2010