EFFECTS OF NORADRENALINE AND SEROTONIN DEPLETIONS ON
THE NEURONAL ACTIVITY OF GLOBUS PALLIDUS AND SUBSTANTIA
NIGRA PARS RETICULATA IN EXPERIMENTAL PARKINSONISM
C. DELAVILLE,aS. NAVAILLESaAND A. BENAZZOUZa,b*
aUniversité Bordeaux Segalen, Centre National de la Recherche Sci-
entifique (CNRS UMR 5293), Neurodegenerative Diseases Institute,
146 rue Léo-Saignat, 33076 Bordeaux Cedex, France
bCentre Hospitalier Universitaire de Bordeaux, Place Amélie Raba-
Léon, 33000 Bordeaux, France
Abstract—Parkinson’s disease (PD) is characterized by a de-
generation of dopaminergic neurons and also by a degrada-
tion of noradrenergic neurons from the locus coeruleus and
serotonergic neurons from the dorsal raphe. However, the
effect of these depletions on the neuronal activity of basal
ganglia nuclei is still unknown. By using extracellular single-
unit recordings, we have addressed this question by testing
the effects of selective depletions of noradrenaline (NA) (with
ride (DSP-4)) and serotonin (5-HT) (with 4-chloro-L-phenylal-
anine (pCPA)) on the neuronal activity of globus pallidus (GP)
and substantia nigra pars reticulata (SNr) neurons in the
6-hydroxydopamine (6-OHDA) rat model of PD and sham-
lesioned rats. We showed that 6-OHDA–induced dopamine
(DA) depletion resulted in an increased number of GP and
SNr neurons discharging in a bursty and irregular manner,
confirming previous studies. These pattern changes were
region-dependently influenced by additional monoamine de-
pletion. Although the number of irregular and bursty neurons
in 6-OHDA rats tended to decrease in the GP after NA deple-
tion, it did not change after pCPA treatment in both GP and
SNr. Furthermore, a significant interaction between DA and
5-HT depletions was observed on the firing rate of SNr neu-
rons. By themselves, NA depletion did not change GP or SNr
neuronal activity, whereas 5-HT depletion decreased the fir-
ing rate and increased the proportion of bursty and irregular
neurons in both brain regions, suggesting that 5-HT, but not
NA, plays a major role in the modulation of both the firing rate
and patterns of GP and SNr neurons. Finally, our data sug-
gest that, in addition to the primary role of DA in the control
of basal ganglia activity, NA and 5-HT depletion also contrib-
ute to the dysregulation of the basal ganglia in PD by
changes to neuronal firing patterns. © 2011 IBRO. Published
by Elsevier Ltd. All rights reserved.
Key words: dopamine, noradrenaline, serotonin, globus pal-
lidus, substantia nigra pars reticulata, Parkinson’s disease.
Parkinson’s disease (PD) is a neurological disorder char-
acterized by motor and non-motor symptoms, attributed to
the progressive degeneration of dopamine (DA) neurons of
the substantia nigra pars compacta (SNc) (Ehringer and
Hornykiewicz, 1960). The loss of nigrostriatal DA neurons
is known to alter the dynamic activity of basal ganglia, a
group of subcortical structures involved in the control of
motor behavior, learning, associative/limbic, and sensori-
motor integration (Obeso et al., 2008). Other neurotrans-
mitter systems are also affected in PD, such as the nor-
adrenaline (NA) (Forno, 1996; Bertrand et al., 1997) and
serotonin (5-HT) systems (Kish, 2003; Kish et al., 2008).
The neurodegeneration of the locus cœruleus (LC) (In-
vernizzi et al., 2007), the principal source of NAergic pro-
jections in the brain (Chan-Palay and Asan, 1989; Chan-
Palay, 1991; Kish, 2003; Kish et al., 2008), is another
landmark of the disease that plays a role in motor and
non-motor symptoms (Donaldson et al., 1976; Rommel-
fanger et al., 2007; Delaville et al., 2011). The neurode-
generation of 5-HTergic neurons from the dorsal raphe
(DR) in animal models of PD and parkinsonian patients
(Kish, 2003; Kish et al., 2008) has been shown to partici-
pate in the emergence of non-motor symptoms such as
anxiety and “depressive-like” behavior (Temel et al., 2007;
Temel, 2010). Despite the focus on the influence of DA
loss on basal ganglia dysfunction, little is known about
5-HTergic and NAergic depletion effects on basal ganglia
neuronal activity in the parkinsonian brain.
It is well established that the neuronal activity of the
subthalamic nucleus (STN) neurons, a basal ganglia struc-
ture involved in the pathophysiology of PD, becomes irreg-
ular and bursty in the 6-hydroxydopamine (6-OHDA) rat
model of PD (Ni et al., 2001), in MPTP-treated monkeys
(Bergman et al., 1994) and in parkinsonian patients
(Hutchison et al., 1998; Benazzouz et al., 2002). This
pathological pattern of activity has also been reported in
the external globus pallidus (GP) and substantia nigra pars
reticulata (SNr) of PD patients (Hutchison et al., 1994,
1998; Sterio et al., 1994; Benazzouz et al., 2002). Similarly
in rats, DA depletion increased the proportion of bursty and
irregular neurons in the GP and SNr (Pan and Walters,
1988; Burbaud et al., 1995; Hassani et al., 1996; Ni et al.,
2000; Tai et al., 2003), although it did not change the
neuronal firing rate of these two nuclei (Murer et al., 1997;
Ni et al., 2000; Tai et al., 2003; Breit et al., 2007).
*Correspondence to: A. Benazzouz, Université Bordeaux Segalen,
Neurodegenerative Diseases Institute, Centre National de la Recher-
che Scientifique (CNRS UMR 5293), 146 Rue Léo-Saignat, 33076
Bordeaux Cedex, France. Tel: ?33 557 57 46 25; fax: ?33 556 90 14 21.
E-mail address: email@example.com (A. Benaz-
Abbreviations: DA, dopamine; DMI, desipramine; DR, dorsal raphe;
DSP-4, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride;
EDTA, ethylenediaminetetraacetic acid; GP, globus pallidus; LC, locus
cœruleus; MFB, medial forebrain bundle; NA, noradrenaline; pCPA,
4-chloro-L-phenylalanine; PD, Parkinson’s disease; PLSD, Fisher’s
protected least significant difference test; SNc, substantia nigra pars
compacta; SNr, substantia nigra pars reticulata; STN, subthalamic
nucleus; 6-OHDA, 6-hydroxydopamine.
Neuroscience 202 (2012) 424–433
0306-4522/12 $36.00 © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
Recently, we have shown that NA depletion alone or
combined with DA depletion in the rat also triggered the
emergence of an irregular and bursty pattern of activity in
the STN (Delaville et al., in press), in line with the inner-
vation of this basal ganglia nucleus by LC neurons (Boya-
jian and Leslie, 1987; Canteras et al., 1990; Parent and
Hazrati, 1995; Wang et al., 1996). Although few NA affer-
ents directly innervate GP and SNr neurons (Pifl et al.,
1991), these two structures are major targets of 5-HTergic
neurons (Pifl et al., 1991). Local 5-HT application in-
creased the firing rate of GP and SNr neurons (Rick et al.,
1995; Wang et al., 1996; Querejeta et al., 2005; Chen et
al., 2008; Zhang et al., 2010). We, therefore, hypothesize
that deficient NAergic or 5-HTergic neurotransmission
could directly or indirectly influence the electrical activity of
these two basal ganglia structures and further participate
in the pathological pattern of activity of basal ganglia nuclei
in the DA-depleted brain (Delaville et al., 2011).
The present study is aimed at investigating the effects
of NA and 5-HT depletions on the electrical activity of GP
and SNr neurons in the parkinsonian brain. Single-cell
electrophysiology recording in the GP and SNr has been
performed in 6-OHDA–lesioned or sham-lesioned rats that
have received either an N-(2-chloroethyl)-N-ethyl-2-bro-
mobenzylamine hydrochloride (DSP-4) or 4-chloro-L-phe-
nylalanine (pCPA) treatment to induce NA or 5-HT deple-
Adult male Sprague–Dawley rats, weighing 280–380 g were used.
They were housed five per cage under artificial conditions of light
(light/dark cycle, light on at 7:00 AM), temperature (24 °C), and
humidity (45%) with food and water available ad libitum. All animal
experiments were carried out in accordance with European Com-
munities Council Directive 2010/63/UE, and all efforts were made
to minimize the number of animals used and their suffering.
6-OHDA, DSP-4, pCPA, ascorbic acid, desipramine (DMI), and all
anesthesia drug were purchased from Sigma (Saint-Quentin
Monoamine depletion procedures
The present study was carried out on six groups of animals (see
Fig. 1). Each rat received either 6-OHDA (6-OHDA rats) or NaCl
0.9% (sham rats) into the right medial forebrain bundle (MFB).
Two weeks later, sham and 6-OHDA rats received DSP-4 (DSP-4
group and 6-OHDA/DSP-4 group respectively), pCPA (pCPA
group and 6-OHDA/pCPA group), or NaCl (sham group and
6-OHDA group). Animals exposed to DSP-4 or pCPA combined to
6-OHDA lesion did not develop any weight loss and had a good
jected into the MFB as previously described (Belujon et al., 2007).
After chloral hydrate anesthesia (400 mg/kg, i.p.; Sigma), rats
were placed in a stereotaxic frame (Kopf, Unimecanique, France).
Thirty minutes before the 6-OHDA injection, animals received an
i.p. injection of DMI (25 mg/kg, Sigma) to protect NA neurons. DMI
was dissolved in 0.9% NaCl and injected in a volume of 5 ml/kg
body weight. Each animal received a unilateral injection of 2.5 ?l
6-OHDA (Sigma, 5 mg/ml in sterile NaCl, 0.9%) with 0.1% ascor-
bic acid into the right MFB over a 5-min period using a 10-?l
Hamilton microsyringe. The coordinates were 2.8 mm posterior to
bregma (AP), 2 mm lateral to the midline (L), and 8.4 mm below
the skull (D) according to the brain atlas of Paxinos and Watson
(Paxinos and Watson, 1996).
6-OHDA was stereotaxically in-
sioning NAergic terminals of the LC, was dissolved in sterile NaCl
0.9% and used at a dose of 50 mg/kg according to the work of
Grzanna et al. (1989). This concentration has been shown to
DSP-4, a selective drug for le-
Fig. 1. Experimental design. At the beginning of the study, animals were injected with 6-OHDA (6-OHDA–lesioned rats) or saline (sham-lesioned rats)
into the right medial forebrain bundle (MFB). Two weeks later, each group was subdivided into three subgroups and the animals received an
intraperitoneal injection (i.p.) of DSP-4 or pCPA or NaCl. Six different groups resulted as follows: sham, DSP-4, pCPA, 6-OHDA, 6-OHDA/DSP-4, and
6-OHDA/pCPA. Each group was processed for electrophysiological recording in the GP and SNr (the number of neurons recorded is indicated for each
brain region in each group). After histological verification of the recorded sites (see Experimental procedures), rat brains were processed for
biochemical assessment of the extent of monoamine depletions, and only rats that displayed a percentage of depletion that fits with our inclusion
criterion for each monoamine were included in the statistical analysis (see the final number of rats per group). Saline 0.9% NaCl; pCPA,
4-chloro-L-phenylalanine; DSP-4, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride; 6-OHDA, 6-hydroxydopamine.
C. Delaville et al. / Neuroscience 202 (2012) 424–433425
induce about 80% bilateral depletion of endogenous NA in the
brain (Delaville et al., in press).
synthesis, was dissolved in sterile NaCl 0.9% and administered at
50 mg/kg during two successive days. This injection procedure,
previously developed in the laboratory (Delaville et al., in press),
has been shown to produce between 50% and 80% bilateral
depletion of 5-HT concentrations. This decrease in endogenous
5-HT is reversible 4 days after the last injection.
pCPA, a selective inhibitor of 5-HT
Extracellular single-unit recordings
Extracellular single-units recordings in the GP and SNr were
performed 1–2 weeks after the administration of DSP-4 and 2–3
days after the administration of pCPA as previously described
(Delaville et al., in press). Extracellular single-unit recordings were
made in rats anesthetized with urethane (1.2 g/kg i.p.) as previ-
ously reported (Ni et al., 2001). A single glass micropipette elec-
trode (impedance: 8–12 M?; aperture 0.5 ?m) was filled with 4%
Pontamine Sky Blue in 3 M NaCl and then lowered into the GP or
SNr according to the following stereotaxic coordinates (in mm: AP:
?0.9, L: ?3, D: 4.5–7.5 and AP: ?5.3, L: ?2.5, D: 6.5–9, for GP
and SNr, respectively; Paxinos and Watson, 1996). Both GP and
SNr neurons were recorded in each rat and were identified ac-
cording to their firing activity as previously reported (Ni et al.,
2000; Breit et al., 2007 for the GP/Benazzouz et al., 2000; Tai et
al., 2003 for the SNr). Extracellular neuronal activity was ampli-
fied, bandpass filtered (300–3000 Hz) using a preamplifier (Neu-
rolog, Digitimer, UK), and transferred via a Powerlab interface (AD
Instruments, Charlotte, NC, USA) to a computer equipped with
Chart 5 software (AD Instruments). Only neuronal activity with a
signal-to-noise ratio ?3:1 was recorded and used for further in-
vestigation. Basal firing of neurons was recorded for 20 min to
ascertain the stability of the discharge activity. At the end of each
session, the recording site was marked by an electrophoretic
injection (Iso DAM 80, WPI, Hertfordshire, UK) of Pontamine Sky
Blue after recording the last neuron of the last trajectory through
the micropipette at a negative current of 20 ?A for 7 min. The
location of the Pontamine Sky Blue dots was histologically verified
as previously reported (Belujon et al., 2007), and only brains with
clear blue dots in the GP and SNr were used for data analysis. A
reconstruction of each recording site for each trajectory under
microscope was carried out to consider only neurons recorded in
the target structure.
with a spike discriminator using a spike histogram program (AD
Instruments), and firing parameters (interspike interval: 5-ms bin)
were calculated using Neuroexplorer program (Alpha Omega,
Nazareth, Israel). Firing rates were expressed as the averaged
frequency of discharge calculated over the 20-min period of sta-
bilization, and the value for each group is the mean?SEM (Bur-
baud et al., 1995). Firing patterns were analyzed as previously
described (Labarre et al., 2008). Three patterns were determined:
a regular pattern, with a discharge density distribution of spike
train that follows a near-normal distribution; an irregular pattern,
which follows a Poisson distribution; and a bursty pattern, with a
discharge density histogram that follows two different distributions
(Kaneoke and Vitek, 1996). The number of cells discharging in
each pattern was expressed as a percentage of the total number
of neurons recorded.
The activity of each neuron was analyzed
Biochemical assessment of monoamine depletion
Selected animals for final analysis went through an additional
validation step regarding the extent of monoamines depletion.
This biochemical step was mandatory for the final inclusion of
animals in each group.
Tissue dosages of monoamines were performed by high-
performance liquid chromatography (HPLC) coupled with electro-
chemical detection, as previously described (De Deurwaerdere et
al., 1998; Navailles et al., 2010), to evaluate the extent and
selectivity of each monoamine depletion procedure (6-OHDA,
pCPA, and DSP-4) and their combination (6-OHDA?DSP-4 and
6-OHDA?pCPA). Tissue concentrations of DA were measured in
the anterior striatum and that of NA and 5-HT in the rostral part of
the frontal cortex, in line with the innervation density of the re-
spective monoamine terminals in each brain region (Steinbusch,
1981; Loughlin et al., 1982). At the end of electrophysiological
recordings, rats were decapitated, and their brains were removed
rapidly and frozen in cold isopentane. Both right and left portions
of the anterior striatum and the frontal cortex were dissected and
stored at ?80 °C until their use in biochemical assays. The tissues
were homogenized in 200 ?l of 0.1 N HClO4and centrifuged at
13,000 rpm for 30 min at 4 °C. Aliquots of the supernatants were
diluted in the mobile phase (½ for the cortex and ¼ for the
striatum) and injected into the HPLC column (Chromasyl C8,
150?4.6 mm, 5 ?m) protected by a Brownlee–Newgard precol-
umn (RP-8, 15?3.2 mm, 7 ?m). The mobile phase, delivered at
1.2 ml/min flow rate, was as follows (in mM): 60 NaH2PO4, 0.1
disodium EDTA, and 2-octane sulfonic acid plus 7% methanol,
adjusted to pH 3.9 with orthophosphoric acid and filtered through
a 0.22-?m Millipore filter. Detection of monoamines was per-
formed with a coulometric detector (Coulochem I, ESA, Knivsta,
Sweden) coupled to a dual-electrode analytic cell (model 5011).
The potential of the electrodes was set at ?350 and ?270 mV.
and each value is the mean?SEM. The percentage of monoamine
depletions in drug-treated animals was calculated with respect to
sham-lesioned animals. Each rat was included in its respective
group according to an inclusion criterion for each monoamine
depletion procedure: ?90% decrease in DA concentrations in the
lesioned-striatum, ?80% and ?50% reduction of NA and 5-HT
concentrations, respectively, in both sides of the frontal cortex.
Results are expressed in ng/mg of tissue,
Statistical analyses were done using SPSS (SPSS statistics 17.0,
New York, NY, USA). Biochemical and electrophysiological data
were studied by a two-way ANOVA (pretreatment?treatment) to
determine the ability of DSP-4 or pCPA (pretreatment) to modify
monoamine levels and firing rates induced by the 6-OHDA lesion
(treatment). Then, a one-way ANOVA (using group as the main
factor) was used to determine statistical differences between
groups. When significant (P?0.05), the ANOVA was followed by
the Fisher’s protected least significant difference test (PLSD) to
allow adequate multiple comparisons between groups. Changes
in the proportion of neuronal firing patterns between groups were
analyzed using a ?2test.
Effect of 6-OHDA, DSP-4, and pCPA on monoamine
tissue concentrations in the rat brain
Table 1 summarizes the tissue concentration values of DA
in the anterior striatum and NA and 5-HT in the frontal
cortex in the six experimental groups (see Fig. 1). The
6-OHDA, DSP-4, and pCPA administrations applied alone
or combined (6-OHDA/DSP-4 and 6-OHDA/pCPA) in-
duced a selective depletion of endogenous DA, NA, and
5-HT, respectively, without modifying other monoamines.
MFB decreased by almost 95% DA concentrations in the
6-OHDA injection into the right
C. Delaville et al. / Neuroscience 202 (2012) 424–433426
ipsilateral striatum compared with sham animals [P?
0.001, Fisher’s PLSD test after a significant one-way
ANOVA, F(5,45)?16.7, P?0.001]. DA levels in the non-
lesioned striatum were not significantly modified with re-
spect to sham rats [not significant (NS), Fisher’s PLSD
test]. DSP-4 or pCPA treatments by themselves did not
modify striatal DA concentrations in sham rats [NS, Fish-
er’s PLSD test]. In 6-OHDA-lesioned rats, pCPA and
DSP-4 did not change DA concentrations in the lesioned
striatum [two-way ANOVA, F(3,42)?0.14 and F(3,42)?0.12,
DSP-4 induced a dramatic decrease in NA concentrations
in both the right (?81%) and left (?87%) frontal cortex
[P?0.001, Fisher’s PLSD test after a significant one-way
ANOVA, F(5,49)?7.39 and F(5,47)?8.11, P?0.001, respec-
tively]. pCPA or 6-OHDA administration alone did not alter
NA tissue concentrations by themselves [NS, Fisher’s
PLSD test]. The statistical analysis did not reveal any
significant interaction between DSP-4 and 6-OHDA treat-
ment on NA concentrations [two-way ANOVA, F(3,46)?
0.63 and F(3,44)?0.24 for the right and left frontal cortices,
respectively; NS]. Indeed, the averaged (left and right) NA
depletion induced by DSP-4 was similar in the DSP-4
(?83.7%) and 6-OHDA/DSP-4 groups (?79.5%) [NS,
Fisher’s PLSD test].
The systemic administration of
duced a partial though substantial depletion of 5-HT con-
centrations in the right and left sides of the frontal cortex
(both about 71%) [P?0.001, Fisher’s PLSD test after a
significant one-way ANOVA, F(5,48)?7.46 and F(5,47)?6.1,
P?0.001, respectively]. DSP-4 or 6-OHDA administration
alone did not modify 5-HT levels [NS, Fisher’s PLSD test].
The statistical analysis did not reveal any significant in-
teraction between pCPA and 6-OHDA treatments on
5-HT concentrations [two-way ANOVA, F(3,45)?0.37 and
F(3,44)?0.61 for the right and left frontal cortices, respec-
tively, NS]. Indeed, the averaged (right and left) 5-HT
depletion induced by pCPA (?71.2%) was not significantly
different from that induced in the 6-OHDA/pCPA group
(?55%) [NS, Fisher’s PLSD test].
pCPA administration in-
Effects of NA and 5-HT depletions on GP and SNr
neuronal activity in 6-OHDA-lesioned rats
Effects of DSP-4 on GP and SNr neuronal activity.
NA depletion in 6-OHDA–lesioned rats did not modify the
spontaneous firing rate [two-way ANOVA, F(3,282)?10?4,
NS; Fig. 2A] of GP neurons (n?66). Neither the 6-OHDA
lesion (n?55) nor the DSP-4 administration (n?60) alone
changed the spontaneous firing rate of GP neurons com-
pared with sham animals (n?106) [one-way ANOVA,
F(3,285)?2.6, NS; Fig. 2A].
The firing pattern of GP neurons in 6-OHDA–lesioned
rats was not significantly modified by DSP-4 [NS, ?2?4.67,
df?2 for 6-OHDA/DSP-4 vs. 6-OHDA; Fig. 2B]. However,
NA depletion alone, without significant effect per se [NS,
?2?1.89, df?2, DSP-4 vs. sham rats; Fig. 2B], tended to
dampen the increase in the number of irregular (?4%) and
bursty neurons (?21%) induced by the 6-OHDA lesion
[P?0.01, ?2?11.42, df?2, 6-OHDA vs. sham rats; Fig.
2B]. Indeed, the number of irregular (36.4%) and bursty
(14.5%) neurons in the 6-OHDA group was reduced to
24.2% and 7.7%, respectively, in the presence of DSP-4.
Likewise, NA depletion in 6-OHDA–lesioned rats did
not modify the firing rate [two-way ANOVA, F(3,230)?0.004,
NS; Fig. 3A] or the firing pattern of SNr neurons (n?41)
[NS, ?2?0.47, df?2, 6-OHDA/DSP-4 vs. 6-OHDA; Fig.
3B]. The 6-OHDA lesion per se (n?61) decreased the
spontaneous nigral firing rate compared with sham ani-
mals (n?88) [P?0.01, Fisher’s PLSD test after a signifi-
cant one-way ANOVA, F(3,233)?4.79, P?0.01; Fig. 3A].
Furthermore, as described by Tai et al. (2003), the
6-OHDA lesion increased the proportion of SNr neurons
discharging with bursts or in an irregular manner [P?0.05,
?2?6.43, df?2, 6-OHDA vs. sham, Fig. 3B]. The DSP-4–
induced NA depletion alone (n?44) did not alter the firing
rate [NS, Fisher’s PLSD test; Fig. 3A] or the firing pattern
[NS, ?2?3.0, df?2, DSP-4 vs. sham rats; Fig. 3B] of SNr
Effect of pCPA on GP and SNr neuronal activity.
5-HT depletion did not significantly modify the firing rate of
GP neurons in 6-OHDA–lesioned rats (n?49) [two-way
ANOVA, F(3,249)?2.06, NS; Fig. 4A]. Overall, the firing rate
of GP neurons in the pCPA/6-OHDA group was not statis-
Table 1. Effect of the unilateral 6-OHDA lesion, the DSP-4, and pCPA administrations on tissue concentrations of DA in the anterior striatum, 5-HT,
and NA in the frontal cortex of the rat brain
TreatmentDA Anterior striatum NA Frontal cortex 5-HT Frontal cortex
LeftRight LeftRight LeftRight
Sham (n ? 13)
6-OHDA (n ? 8)
DSP-4 (n ? 8)
6-OHDA/DSP-4 (n ? 6)
pCPA (n ? 6)
6-OHDA/pCPA (n ? 6)
5738.2 ? 566.6
7340.8 ? 1339.7
6656.0 ? 942.0
6518.8 ? 935.2
6716.5 ? 993.9
7804.0 ? 722.1
5995.4 ? 577.7
307.9 ? 132.2***
7930.0 ? 1662.8
438.3 ? 148.9
6578.2 ? 1207.9
901.9 ? 526.0
147.2 ? 17.3
146.9 ? 14.2
19.5 ? 14.4***
40.9 ? 23.6££
153.1 ? 6.4
155.6 ? 18.6
151.7 ? 14.3
139.1 ? 15.4
29.3 ? 3.4***
18.3 ? 5.7££
114.8 ? 16.9
109.1 ? 13.6
160.3 ? 18.8
155.1 ? 20.9
227.5 ? 22.8
205.2 ? 26.0
46.7 ? 21.4***
77.4 ? 18.3£
166.3 ? 10.6
144.5 ? 14.2
138.5 ? 19.4
127.9 ? 11.3
47.3 ? 9.7***
57.8 ? 14.6££
Each value, expressed in ng/mg of tissue, represents the mean?SEM of 6 to 13 rats (see the number of rats for each group in parentheses).
***P ?0.001 versus the corresponding side of the sham group; £P ?0.05, ££P ?0.01 versus the corresponding side of the 6-OHDA group (Fisher’s
C. Delaville et al. / Neuroscience 202 (2012) 424–433427
tically different from that of the 6-OHDA group [NS, Fish-
er’s PLSD test after a significant one-way ANOVA,
F(3,252)?6.71, P?0.001; Fig. 4A). Although the spontane-
ous firing rate of pallidal neurons was not modified in
6-OHDA–lesioned rats (n?55) compared with sham-le-
sioned rats (n?106) [NS, Fisher’s PLSD test; Fig. 4A],
pCPA administration alone (n?44) induced a significant
decrease in GP neuronal firing rate [P?0.001 vs. the sham
group, Fisher’s PLSD test; Fig. 4A].
5-HT depletion did not alter the pattern of discharge of
GP neurons in 6-OHDA–lesioned rats [NS, ?2?0.08, df?2,
pCPA/6-OHDA vs. 6-OHDA; Fig. 4B]. Both 6-OHDA lesion
and pCPA depletion alone increased to a similar extent the
number of bursty (?4%) and irregular (?21% and ?16%,
respectively) GP neurons compared with sham rats
[P?0.01 and P?0.05, ?2?11.42 and 5.97, df ?2 for
6-OHDA and pCPA vs. sham, respectively; Fig. 4B], but
their individual effects were not cumulative in the pCPA/6-
Statistical analysis revealed a significant interaction of
pCPA administration on the firing rate of SNr neurons in
Fig. 2. Effect of DSP-4 administration on the spontaneous firing rate,
and the pattern of discharge of GP neurons in 6-OHDA–lesioned rats.
(A) Histograms represent the mean?SEM of the firing rate (expressed
in Hertz, Hz) of all GP neurons recorded in each experimental group
(see Fig. 1 for the number of cells). (B) Histograms represent the firing
pattern distribution of GP neurons discharging in a regular (white
portion), irregular (gray portion) manner, or with bursts (black portion).
The number of cells discharging in each pattern is expressed in
percentage of the overall population recorded and is indicated in the
corresponding portion. ** P?0.01 vs. sham group (?2test).
Fig. 3. Effect of DSP-4 administration on the spontaneous firing rate,
and the pattern of discharge of SNr neurons in 6-OHDA-lesioned rats.
(A) Histograms represent the mean?SEM of the firing rate (expressed
in Hertz, Hz) of all SNr neurons recorded in each experimental group
(see Fig. 1 for the number of cells). ** P?0.01 vs. sham group (Fisher’s
PLSD test). (B) Histograms represent the firing pattern distribution of
SNr neurons discharging in a regular (white portion), irregular (gray
portion) manner, or with bursts (black portion). The number of cells
discharging in each pattern is expressed in percentage of the overall
population recorded and is indicated in the corresponding portion.
* P?0.05, *** P?0.001 vs. sham group (?2test).
C. Delaville et al. / Neuroscience 202 (2012) 424–433 428
6-OHDA–lesioned rats [two-way ANOVA F(3,209)?7.99,
P?0.01; Fig. 5A]. Both the 6-OHDA lesion (n?61) and the
pCPA depletion alone (n?34) reduced nigral firing rate per
se [P?0.01 and P?0.001 vs. sham rats (n?88), respec-
tively; Fisher’s PLSD test after a significant one-way
ANOVA F(3,212)?6.17, P?0.001; Fig. 5A]. Nevertheless,
the effects of both treatments were not additive in the
pCPA/6-OHDA group (n?30) [NS, Fisher’s PLSD test,
pCPA/6-OHDA vs. 6-OHDA].
Statistical analysis did not reveal any significant differ-
ence in number of bursty and irregular neurons between the
6-OHDA/pCPA and the 6-OHDA group [NS, ?2?5.39, df ?2;
Fig. 5B]. However, both the 6-OHDA lesion [P?0.05,
?2?6.43, df ?2 vs. sham rats; Fig. 5B] and the 5-HT deple-
tion alone [P?0.01, ?2?12.4, df ?2 vs. sham rats; Fig. 5B]
increased the number of irregular (?25.5% and ?29.4%,
respectively) and bursty (?7.3% and ?14.7%, respectively)
nigral neurons. These effects tended to be cumulative when
Fig. 4. Effect of pCPA administration on the spontaneous firing rate,
and the pattern of discharge of GP neurons in 6-OHDA-lesioned
rats. (A) Histograms represent the mean?SEM of the firing rate
(expressed in Hertz, Hz) of all GP neurons recorded in each exper-
imental group (see Fig. 1 for the number of cells). *** P?0.001 vs.
sham group (Fisher’s PLSD test). (B) Histograms represent the
firing pattern distribution of GP neurons discharging in a regular
(white portion), irregular (gray portion) manner, or with bursts (black
portion). The number of cells discharging in each pattern is ex-
pressed in percentage of the overall population recorded and is
indicated in the corresponding portion. ** P?0.01, *** P?0.001 vs.
sham group (?2test).
Fig. 5. Effect of pCPA administration on the spontaneous firing rate,
and the pattern of discharge of SNr neurons in 6-OHDA-lesioned rats.
(A) Histograms represent the mean?SEM of the firing rate (expressed
in Hertz, Hz) of all SNr neurons recorded in each experimental group
(see Fig. 1 for the number of cells). ** P?0.01, *** P?0.001 vs. sham
group (Fisher’s PLSD test). (B) Histograms represent the firing pattern
distribution of SNr neurons discharging in a regular (white portion),
irregular (gray portion) manner, or with bursts (black portion). The
number of cells discharging in each pattern is expressed in percentage
of the overall population recorded and is indicated in the correspond-
ing portion. * P?0.05, ** P?0.01, *** P?0.001 vs. sham group (?2
C. Delaville et al. / Neuroscience 202 (2012) 424–433 429
both treatments were combined (?36.7% irregular and
?20% bursty neurons).
The present study shows that additional depletion of NA or
5-HT to dopamine depletion influences in a region-depen-
dent manner the electrophysiological properties of GP and
SNr neurons. Although NA depletion alone did not alter GP
and SNr neuronal activity, it dampened the pathological
increase in irregular and bursty pallidal neurons induced by
the DA depletion. 5-HT depletion alone induced similar
effects to the 6-OHDA lesion (except for a decreased firing
rate in the GP). The increased bursty pattern in the GP and
SNr and the decreased firing in the SNr induced by the
5-HT depletion were not cumulative with that induced by
the 6-OHDA lesion. These region-dependent effects on the
electrophysiological parameters examined may point to
specific mechanisms controlled by the three monoamines
that may participate in the dynamic regulation of basal
As expected from numerous data obtained in animal
models of PD and parkinsonian patients, the loss of DA
neurons induced changes in the pattern of activity of nu-
merous basal ganglia structures. As in the STN (Delaville
et al., in press), we observed an increase in the proportion
of neurons discharging in an irregular and bursty manner in
both the GP and SNr of rats with a 6-OHDA–induced DA
depletion, in line with previous studies performed in ro-
dents (Pan and Walters, 1988; Robledo and Feger, 1991;
Burbaud et al., 1995; Hassani et al., 1996; Murer et al.,
1997; Ni et al., 2000; Tai et al., 2003), MPTP-treated
monkeys (Filion and Tremblay, 1991; Bergman et al.,
1994) and parkinsonian patients (Hutchison et al., 1994;
Sterio et al., 1994). Although the firing pattern is consid-
ered as the most relevant pathological electrophysiological
parameter in PD, changes in the firing rate are more con-
trasted in the literature in line with the instability of this
parameter in animal models of PD. In our experimental
condition, the 6-OHDA lesion did not change the firing rate
of GP neurons. This result does not fit with the classical
model of basal ganglia circuitry, which postulates that GP
neurons should be hypoactive in the DA-depleted state
(Albin et al., 1989; DeLong, 1990). Among published data,
some authors have also shown changes in the firing pat-
tern without any change in the firing rate (Ni et al., 2000;
Magill et al., 2001; Breit et al., 2007), whereas others have
shown a slight but significant decrease in the mean dis-
charge rate of GP neurons associated with a change in the
firing pattern (Pan and Walters, 1988; Hassani et al.,
1996). In the SNr, our 6-OHDA lesioning procedure de-
creased the firing rate, in line with Wang et al. (2010),
whereas others reported an increase (Burbaud et al.,
1995) or no change (Murer et al., 1997; Tai et al., 2003).
Region-specific changes in GP and SNr neuronal ac-
tivity in rats with DA depletion were observed after addi-
tional NA or 5-HT depletion. Although the NA depletion did
not alter by itself any of the electrophysiological parameter
examined in the GP and SNr, it tended to decrease the
abnormal firing pattern induced by the 6-OHDA lesion in
the GP only. In parallel, the NA depletion has been previ-
ously shown to increase the number of irregular neurons
induced by the 6-OHDA lesion in the STN (Delaville et al.,
in press). These data suggest that the NA system may
participate in a region-dependent manner in the modula-
tion of the activity pattern of basal ganglia neurons while
not influencing the firing rate.
The firing pattern of pallidal neurons in 6-OHDA–le-
sioned rats is also sensitive to 5-HT modulation. DA and
5-HT depletion alone induced a similar increase in the
number of SNr neurons discharging with burst and/or ir-
regular patterns in the GP. In rats with both depletions, the
effects in the GP were not additive, suggesting that DA and
5-HT modulate this parameter through similar mechanisms
and in a region-specific manner in the GP, but not the SNr
nor STN (Delaville et al., in press). A 5-HT/DA interaction
was also observed in the decrease of the firing rate of SNr
neurons. Again, the lack of additional effect produced by
DA and 5-HT depletions together suggests a convergence
of these monoamines on the same circuit to regulate in a
region-specific manner the firing rate of SNr neurons. Neu-
roanatomical data available clearly indicate that DA-con-
taining neurons in the brain receive a prominent innerva-
tion of 5-HT neurons originating from the raphe nuclei of
the brainstem (Bedard et al., 2011; Parent et al., 2011;
Wallman et al., 2011). It is possible that the numerous
5-HT receptors expressed in basal ganglia structures may
confer this region-dependent influence over the parame-
ters examined (Di Giovanni et al., 2008, 2010; Navailles
and De Deurwaerdere, 2011).
According to the classical model of basal ganglia cir-
cuitry (Albin et al., 1989), GP and SNr neurons are directly
influenced by excitatory glutamatergic afferents from the
STN. In a recent study, we have shown that NA depletion
decreased the firing rate and increased the proportion of
bursty and irregular neurons in the STN (Delaville et al., in
press). Although these modifications of STN neuron activ-
ity are expected to be conveyed to their efferent structures,
the NA depletion did not modify either GP or SNr firing
activity. To our knowledge, few studies have focused on
NA modulation of these two nuclei. An in vitro study on GP
slices showed that the spontaneous neuronal activity was
unaffected by iontophoretic NA application (Perkins and
Stone, 1983) confirming the weak NAergic innervation and
very low density of NAergic receptors in the GP (Pifl et al.,
1991). In contrast to the GP, in vitro studies on SNr slices
have shown that NA increased the tonic firing of SNr
neurons (Berretta et al., 2000; Alachkar et al., 2006). The
present results, together with data obtained in the STN,
suggest that NA does not exert a tonic influence on GP and
SNr neurons, whereas NA tonically controls STN neuronal
activity (Delaville et al., in press). The absence of effect of
DSP-4–induced NA depletion on GP and SNr neuronal
activity may involve compensatory mechanisms through
other neurotransmitter systems innervating these nuclei,
which may dampen the direct influence of STN efferents.
Unlike the NA system, 5-HT plays a prominent role in
the regulation of GP and SNr neuronal activity. 5-HT de-
C. Delaville et al. / Neuroscience 202 (2012) 424–433 430
pletion induced a decrease in the firing rate paralleled by
an increase in the proportion of GP and SNr neurons
discharging with bursts and in an irregular manner,
whereas it did not modify the activity of STN neurons
(Delaville et al., in press). These effects could be because
of a direct deactivation of GP and SNr neurons in the
absence of 5-HT. GP neurons receive abundant 5-HT
afferents from the DR nucleus (DeVito et al., 1980; Lavoie
and Parent, 1990; Pifl et al., 1991; Charara and Parent,
1994), and electrical stimulation of the latter evoked an
increase in pallidal 5-HT extracellular levels measured by
microdialysis (McQuade and Sharp, 1997). Local applica-
tion of 5-HT increased the firing rate of GP neurons in vitro
(Chen et al., 2008) and in vivo (Querejeta et al., 2005;
Zhang et al., 2010). This modulation is more likely to occur
via an inhibition of GABA release from striatopallidal ter-
minals (Querejeta et al., 2005; Di Matteo et al., 2008).
5-HT exerts a tonic control on GP activity by suppressing
GABAergic inhibition through presynaptic 5-HT1Brecep-
tors. In addition to the firing rate change, we showed that
5-HT depletion increased the proportion of bursty and
irregular cells, suggesting that 5-HT can modulate the
firing pattern of GP neurons as well. This result is in good
agreement with the fact that local injection of 5-HT de-
creased the burst index of GP neurons (Kita et al., 2007).
SNr neurons receive the largest 5-HT innervation from the
DR nucleus compared with other brain regions (Miller et
al., 1975; Corvaja et al., 1993) and express the highest
density of 5-HT receptors. Microiontophoretic injection of
5-HT into the SNr produced mixed, although mostly inhib-
itory, effects (Collingridge and Davies, 1981; Dray, 1981;
Gongora-Alfaro et al., 1997). In spite of this evidence,
Lacey and coworkers have shown that 5-HT not only di-
rectly excites SNr neurons but also disinhibits them by
reducing GABA release from striatonigral terminals, acting
on presynaptic 5-HT1Breceptors (Rick et al., 1995; Stan-
ford and Lacey, 1996). Furthermore, 5-HT2Creceptor stim-
ulation excites SNr neurons in vivo (Di Giovanni et al.,
2001; Invernizzi et al., 2007). This effect was evident after
both systemic administration and local microiontophoretic
application of the 5-HT2Cagonists m-CPP and RO 60-
0175 (Di Giovanni et al., 2001; Invernizzi et al., 2007). It is,
therefore, possible that, in the absence of 5-HT after pCPA
injection in vivo, 5-HT2Cand 5-HT1Breceptors are not
activated resulting in an overall decrease in the firing rate
of SNr neurons.
The results of the present study provide evidence that the
5-HT system plays a major role in the modulation of both
the firing rate and patterns of GP and SNr neurons. Al-
though the influence of the NA system on these brain
regions is weak, it strongly modulates the activity of STN
neurons (Delaville et al., in press). These data show that,
in addition to the prominent influence of DA neurons on
basal ganglia activity, NA and 5-HT neurons also partici-
pate in the overall homeostasis of this network. Further-
more, we showed that the changes in GP and SNr neuro-
nal activity after DA depletion were region-specifically
modified by additional NA or 5-HT depletion suggesting
that, in the context of experimental parkinsonism, the mod-
ulatory role of these monoamines in GP and SNr is more
complex than expected and needs further investigation.
Acknowledgments—Claire Delaville was supported by a fellow-
ship from the “Ministère de l’Education Nationale, de la Recherche
et de la Technologie” (MENRT). The University Bordeaux Segalen
and the “Centre National de la Recherche Scientifique” (CNRS)
funded this study. We wish to thank Dr. Martin Guthrie for english
reading of the manuscript.
Alachkar A, Brotchie J, Jones OT (2006) Alpha2-adrenoceptor-medi-
ated modulation of the release of GABA and noradrenaline in the
rat substantia nigra pars reticulata. Neurosci Lett 395:138–142.
Albin RL, Young AB, Penney JB (1989) The functional anatomy of
basal ganglia disorders. Trends Neurosci 12:366–375.
Bedard C, Wallman MJ, Pourcher E, Gould PV, Parent A, Parent M
(2011) Serotonin and dopamine striatal innervation in Parkinson’s
disease and Huntington’s chorea. Parkinsonism Relat Disord
Belujon P, Bezard E, Taupignon A, Bioulac B, Benazzouz A (2007)
Noradrenergic modulation of subthalamic nucleus activity: behav-
ioral and electrophysiological evidence in intact and 6-hydroxydo-
pamine-lesioned rats. J Neurosci 27:9595–9606.
Benazzouz A, Breit S, Koudsie A, Pollak P, Krack P, Benabid AL
(2002) Intraoperative microrecordings of the subthalamic nucleus
in Parkinson’s disease. Mov Disord 17 Suppl 3:S145–S149.
Benazzouz A, Gao DM, Ni ZG, Piallat B, Bouali-Benazzouz R, Ben-
abid AL (2000) Effect of high-frequency stimulation of the subtha-
lamic nucleus on the neuronal activities of the substantia nigra pars
reticulata and ventrolateral nucleus of the thalamus in the rat.
Bergman H, Wichmann T, Karmon B, DeLong MR (1994) The primate
subthalamic nucleus. II. Neuronal activity in the MPTP model of
parkinsonism. J Neurophysiol 72:507–520.
Berretta N, Bernardi G, Mercuri NB (2000) Alpha(1)-adrenoceptor-
mediated excitation of substantia nigra pars reticulata neurons.
Bertrand E, Lechowicz W, Szpak GM, Dymecki J (1997) Qualitative
and quantitative analysis of locus coeruleus neurons in Parkinson’s
disease. Folia Neuropathol 35:80–86.
Boyajian CL, Leslie FM (1987) Pharmacological evidence for alpha-2
adrenoceptor heterogeneity: differential binding properties of
[3H]rauwolscine and [3H]idazoxan in rat brain. J Pharmacol Exp
Breit S, Bouali-Benazzouz R, Popa RC, Gasser T, Benabid AL, Benaz-
zouz A (2007) Effects of 6-hydroxydopamine-induced severe or
partial lesion of the nigrostriatal pathway on the neuronal activity of
pallido-subthalamic network in the rat. Exp Neurol 205:36–47.
Burbaud P, Gross C, Benazzouz A, Coussemacq M, Bioulac B (1995)
Reduction of apomorphine-induced rotational behaviour by sub-
thalamic lesion in 6-OHDA lesioned rats is associated with a nor-
malization of firing rate and discharge pattern of pars reticulata
neurons. Exp Brain Res 105:48–58.
Canteras NS, Shammah-Lagnado SJ, Silva BA, Ricardo JA (1990)
Afferent connections of the subthalamic nucleus: a combined ret-
rograde and anterograde horseradish peroxidase study in the rat.
Brain Res 513:43–59.
Chan-Palay V (1991) Locus coeruleus and norepinephrine in Parkin-
son’s disease. Jpn J Psychiatry Neurol 45:519–521.
Chan-Palay V, Asan E (1989) Alterations in catecholamine neurons of
the locus coeruleus in senile dementia of the Alzheimer type and in
C. Delaville et al. / Neuroscience 202 (2012) 424–433431
Parkinson’s disease with and without dementia and depression.
J Comp Neurol 287:373–392.
Charara A, Parent A (1994) Brainstem dopaminergic, cholinergic and
serotoninergic afferents to the pallidum in the squirrel monkey.
Brain Res 640:155–170.
Chen L, Yung KK, Chan YS, Yung WH (2008) 5-HT excites globus
pallidus neurons by multiple receptor mechanisms. Neuroscience
Collingridge GL, Davies J (1981) The influence of striatal stimulation
and putative neurotransmitters on identified neurones in the rat
substantia nigra. Brain Res 212:345–359.
Corvaja N, Doucet G, Bolam JP (1993) Ultrastructure and synaptic
targets of the raphe-nigral projection in the rat. Neuroscience
De Deurwaerdere P, Stinus L, Spampinato U (1998) Opposite change
of in vivo dopamine release in the rat nucleus accumbens and
striatum that follows electrical stimulation of dorsal raphe nucleus:
role of 5-HT3 receptors. J Neurosci 18:6528–6538.
Delaville C, Chetrit J, Abdallah K, Morin S, Cardoit L, De Deur-
waerdère P, Benazzouz A (in press) Emerging dysfunctions con-
sequent to combined monoaminergic depletions in Parkinsonism.
Neurobiol Dis, in press.
Delaville C, Deurwaerdère PD, Benazzouz A (2011) Noradrenaline
and Parkinson’s disease. Front Syst Neurosci 5:31.
DeLong MR (1990) Primate models of movement disorders of basal
ganglia origin. Trends Neurosci 13:281–285.
DeVito JL, Anderson ME, Walsh KE (1980) A horseradish peroxidase
study of afferent connections of the globus pallidus in Macaca
mulatta. Exp Brain Res 38:65–73.
Di Giovanni G, Di Matteo V, La Grutta V, Esposito E (2001) m-
chlorophenylpiperazine excites non-dopaminergic neurons in the
rat substantia nigra and ventral tegmental area by activating sero-
tonin-2C receptors. Neuroscience 103:111–116.
Di Giovanni G, Di Matteo V, Pierucci M, Esposito E (2008) Serotonin-
dopamine interaction: electrophysiological evidence. Prog Brain
Di Giovanni G, Esposito E, Di Matteo V (2010) Role of serotonin in
central dopamine dysfunction. CNS Neurosci Ther 16:179–194.
Di Matteo V, Pierucci M, Esposito E, Crescimanno G, Benigno A, Di
Giovanni G (2008) Serotonin modulation of the basal ganglia cir-
cuitry: therapeutic implication for Parkinson’s disease and other
motor disorders. Prog Brain Res 172:423–463.
Donaldson IM, Dolphin A, Jenner P, Marsden CD, Pycock C (1976)
The involvement of noradrenaline in motor activity as shown by
rotational behaviour after unilateral lesions of the locus coeruleus.
Dray A (1981) Serotonin in the basal ganglia: functions and interac-
tions with other neuronal pathways. J Physiol (Paris) 77:393–403.
Ehringer H, Hornykiewicz O (1960) Distribution of noradrenaline and
dopamine (3-hydroxytyramine) in the human brain and their be-
havior in diseases of the extrapyramidal system [in German]. Klin
Filion M, Tremblay L (1991) Abnormal spontaneous activity of globus
pallidus neurons in monkeys with MPTP-induced parkinsonism.
Brain Res 547:142–151.
Forno LS (1996) Neuropathology of Parkinson’s disease. J Neuro-
pathol Exp Neurol 55:259–272.
Gongora-Alfaro JL, Hernandez-Lopez S, Flores-Hernandez J, Galar-
raga E (1997) Firing frequency modulation of substantia nigra
reticulata neurons by 5-hydroxytryptamine. Neurosci Res 29:
Grzanna R, Berger U, Fritschy JM, Geffard M (1989) Acute action of
DSP-4 on central norepinephrine axons: biochemical and immu-
nohistochemical evidence for differential effects. J Histochem Cy-
Hassani OK, Mouroux M, Féger J (1996) Increased subthalamic neu-
ronal activity after nigral dopaminergic lesion independent of dis-
inhibition via the globus pallidus. Neuroscience 72:105–115.
Hutchison WD, Allan RJ, Opitz H, Levy R, Dostrovsky JO, Lang AE,
Lozano AM (1998) Neurophysiological identification of the subtha-
lamic nucleus in surgery for Parkinson’s disease. Ann Neurol
Hutchison WD, Lozano AM, Davis KD, Saint-Cyr JA, Lang AE,
Dostrovsky JO (1994) Differential neuronal activity in segments of
globus pallidus in Parkinson’s disease patients. Neuroreport 5:
Invernizzi RW, Pierucci M, Calcagno E, Di Giovanni G, Di Matteo V,
Benigno A, Esposito E (2007) Selective activation of 5-HT(2C)
receptors stimulates GABA-ergic function in the rat substantia
nigra pars reticulata: a combined in vivo electrophysiological and
neurochemical study. Neuroscience 144:1523–1535.
Kaneoke Y, Vitek JL (1996) Burst and oscillation as disparate neuronal
properties. J Neurosci Methods 68:211–223.
Kish SJ (2003) Biochemistry of Parkinson’s disease: is a brain sero-
tonergic deficiency a characteristic of idiopathic Parkinson’s dis-
ease? Adv Neurol 91:39–49.
Kish SJ, Tong J, Hornykiewicz O, Rajput A, Chang LJ, Guttman M,
Furukawa Y (2008) Preferential loss of serotonin markers in cau-
date versus putamen in Parkinson’s disease. Brain 131:120–131.
Kita H, Chiken S, Tachibana Y, Nambu A (2007) Serotonin modulates
pallidal neuronal activity in the awake monkey. J Neurosci 27:
Labarre D, Meissner W, Boraud T (2008) Measure of the regularity of
events in stochastic point processes, application to neuron activity
analysis. 33rd IEEE International Conference on Acoustics,
Speech and Signal Processing, Las Vegas, NV. pp 489–492.
Lavoie B, Parent A (1990) Immunohistochemical study of the sero-
toninergic innervation of the basal ganglia in the squirrel monkey.
J Comp Neurol 299:1–16.
Loughlin SE, Foote SL, Fallon JH (1982) Locus coeruleus projections
to cortex: topography, morphology and collateralization. Brain Res
Magill PJ, Bolam JP, Bevan MD (2001) Dopamine regulates the im-
pact of the cerebral cortex on the subthalamic nucleus-globus
pallidus network. Neuroscience 106:313–330.
McQuade R, Sharp T (1997) Functional mapping of dorsal and median
raphe 5-hydroxytryptamine pathways in forebrain of the rat using
microdialysis. J Neurochem 69:791–796.
Miller JJ, Richardson TL, Fibiger HC, McLennan H (1975) Anatomical
and electrophysiological identification of a projection from the mes-
encephalic raphe to the caudate-putamen in the rat. Brain Res
Murer MG, Riquelme LA, Tseng KY, Pazo JH (1997) Substantia nigra
pars reticulata single unit activity in normal and 60HDA-lesioned
rats: effects of intrastriatal apomorphine and subthalamic lesions.
Navailles S, Benazzouz A, Bioulac B, Gross C, De Deurwaerdère P
(2010) High-frequency stimulation of the subthalamic nucleus and
L-3,4-dihydroxyphenylalanine inhibit in vivo serotonin release in
the prefrontal cortex and hippocampus in a rat model of Parkin-
son’s disease. J Neurosci 30:2356–2364.
Navailles S, De Deurwaerdere P (2011) Presynaptic control of sero-
tonin on striatal dopamine function. Psychopharmacology (Berl)
Ni Z, Bouali-Benazzouz R, Gao D, Benabid AL, Benazzouz A (2000)
Changes in the firing pattern of globus pallidus neurons after the
degeneration of nigrostriatal pathway are mediated by the subtha-
lamic nucleus in the rat. Eur J Neurosci 12:4338–4344.
Ni ZG, Bouali-Benazzouz R, Gao DM, Benabid AL, Benazzouz A
(2001) Time-course of changes in firing rates and firing patterns of
subthalamic nucleus neuronal activity after 6-OHDA-induced do-
pamine depletion in rats. Brain Res 899:142–147.
Obeso JA, Rodríguez-Oroz MC, Benitez-Temino B, Blesa FJ, Guridi J,
Marin C, Rodriguez M (2008) Functional organization of the basal
ganglia: therapeutic implications for Parkinson’s disease. Mov Dis-
ord 23 Suppl 3:S548–S559.
C. Delaville et al. / Neuroscience 202 (2012) 424–433432
Pan HS, Walters JR (1988) Unilateral lesion of the nigrostriatal path- Download full-text
way decreases the firing rate and alters the firing pattern of globus
pallidus neurons in the rat. Synapse 2:650–656.
Parent A, Hazrati LN (1995) Functional anatomy of the basal ganglia.
II. The place of subthalamic nucleus and external pallidum in basal
ganglia circuitry. Brain Res Brain Res Rev 20:128–154.
Parent M, Wallman MJ, Gagnon D, Parent A (2011) Serotonin inner-
vation of basal ganglia in monkeys and humans. J Chem Neuro-
Paxinos G, Watson C 1996). The rat brain in stereotatic coordinates.
San Diego: Academic Press.
Perkins MN, Stone TW (1983) Neuronal responses to 5-hydroxytryp-
tamine and dorsal raphe stimulation within the globus pallidus of
the rat. Exp Neurol 79:118–129.
Pifl C, Schingnitz G, Hornykiewicz O (1991) Effect of 1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine on the regional distribution of
brain monoamines in the rhesus monkey. Neuroscience 44:591–
Querejeta E, Oviedo-Chávez A, Araujo-Alvarez JM, Quiñones-Cárde-
nas AR, Delgado A (2005) In vivo effects of local activation and
blockade of 5-HT1B receptors on globus pallidus neuronal spiking.
Brain Res 1043:186–194.
Rick CE, Stanford IM, Lacey MG (1995) Excitation of rat substantia
nigra pars reticulata neurons by 5-hydroxytryptamine in vitro: evi-
dence for a direct action mediated by 5-hydroxytryptamine2C re-
ceptors. Neuroscience 69:903–913.
Robledo P, Feger J (1991) Acute monoaminergic depletion in the rat
potentiates the excitatory effect of the subthalamic nucleus in the
substantia nigra pars reticulata but not in the pallidal complex.
J Neural Transm Gen Sect 86:115–126.
Rommelfanger KS, Edwards GL, Freeman KG, Liles LC, Miller GW,
Weinshenker D (2007) Norepinephrine loss produces more pro-
found motor deficits than MPTP treatment in mice. Proc Natl Acad
Sci U S A 104:13804–13809.
Stanford IM, Lacey MG (1996) Differential actions of serotonin, medi-
ated by 5-HT1B and 5-HT2C receptors, on GABA-mediated syn-
aptic input to rat substantia nigra pars reticulata neurons in vitro.
J Neurosci 16:7566–7573.
Steinbusch HW (1981) Distribution of serotonin-immunoreactivity in
the central nervous system of the rat-cell bodies and terminals.
Sterio D, Beric ´ A, Dogali M, Fazzini E, Alfaro G, Devinsky O (1994)
Neurophysiological properties of pallidal neurons in Parkinson’s
disease. Ann Neurol 35:586–591.
Tai CH, Boraud T, Bezard E, Bioulac B, Gross C, Benazzouz A (2003)
Electrophysiological and metabolic evidence that high-frequency
stimulation of the subthalamic nucleus bridles neuronal activity in
the subthalamic nucleus and the substantia nigra reticulata.
FASEB J 17:1820–1830.
Temel Y (2010) Limbic effects of high-frequency stimulation of the
subthalamic nucleus. Vitam Horm 82:47–63.
Temel Y, Boothman LJ, Blokland A, Magill PJ, Steinbusch HW, Visser-
Vandewalle V, Sharp T (2007) Inhibition of 5-HT neuron activity
and induction of depressive-like behavior by high-frequency stim-
ulation of the subthalamic nucleus. Proc Natl Acad Sci U S A
Wallman MJ, Gagnon D, Parent M (2011) Serotonin innervation of
human basal ganglia. Eur J Neurosci 33:1519–1532.
Wang R, Macmillan LB, Fremeau RT Jr., Magnuson MA, Lindner J,
Limbird LE (1996) Expression of alpha 2-adrenergic receptor sub-
types in the mouse brain: evaluation of spatial and temporal infor-
mation imparted by 3 kb of 5’ regulatory sequence for the alpha 2A
AR-receptor gene in transgenic animals. Neuroscience 74:199–
Wang Y, Zhang QJ, Liu J, Ali U, Gui ZH, Hui YP, Chen L, Wang T
(2010) Changes in firing rate and pattern of GABAergic neurons in
subregions of the substantia nigra pars reticulata in rat models of
Parkinson’s disease. Brain Res 1324:54–63.
Zhang SJ, Wang H, Xue Y, Yung WH, Chen L (2010) Behavioral and
electrophysiological effects of 5-HT in globus pallidus of 6-hydroxy-
dopamine lesioned rats. J Neurosci Res 88:1549–1556.
(Accepted 10 November 2011)
(Available online 25 November 2011)
C. Delaville et al. / Neuroscience 202 (2012) 424–433433