Neuroscience Letters 443 (2008) 204–208
Contents lists available at ScienceDirect
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Effects of levodopa on striatal monoamines in mice
with levodopa-induced hyperactivity
Anthony P. Nicholasa,b,∗, Kerstin Buckc, Boris Fergerc
aDepartment of Neurology, University of Alabama at Birmingham, USA
bThe Birmingham Veterans Administration Medical Center, Birmingham, AL, USA
cCNS Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
a r t i c l ei n f o
Received 21 May 2008
Received in revised form 15 July 2008
Accepted 15 July 2008
a b s t r a c t
The present study examines striatal monoamine changes in a murine model of levodopa-induced
dyskinesia (LID), a common side effect of Parkinson’s disease (PD) therapy. Mice previously exposed
to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and later made hyperactive with high-dose
(200mg/kg, i.p.) exogenous levodopa were compared to mice with normal motor behavior who received
raphy, dopamine (DA), serotonin (5HT), noradrenaline (NA) and their metabolites were then measured in
samples of striatum versus olfactory bulbs as controls. In the olfactory bulb, exogenous levodopa caused
increased DA levels and increased DA-, 5HT- and NA-turnover rates, but decreased 5HT and NA levels,
regardless of animal activity. These trends were also seen in the striatum, but animals with LID seemed
to have unique differences. Thus, in mice sacrificed at the height of their hyperactive LID behavior, stri-
atal DA and 5HT were significantly lower and DA- and 5HT-turnover rates were significantly higher than
control animals with normal motor behavior, regardless of levodopa exposure. In addition, the expected
increased NA-turnover rate seen in other specimens from animals exposed to levodopa was not seen in
the striatum of LID mice. The results of the present study demonstrate that there is a distinct profile
of striatal monoamines conducive to LID that must be considered when trying to explain the effects of
anti-LID drugs utilizing monoamine receptors.
© 2008 Elsevier Ireland Ltd. All rights reserved.
As a precursor molecule, exogenous levodopa can theoretically be
matic acid decarboxylase (AADC). This enzyme is found not only in
all neurons that produce catecholamines, including DA, and nora-
drenaline (NA), but also in those that produce indolamines such as
els decreased in a dose dependent manner . These experiments
and others [2,3,8,19] suggested that AADC in 5HT neurons, if over-
and that this would be done at the expense of 5HT production. In
NA producing cells, on the other hand, it was suspected that exoge-
nous levodopa would be converted to DA, but then this would be
to increase NA production. Indeed, when large doses of exogenous
∗Corresponding author at: SC 360G2, 1530 3rd Avenue South, Department of
Neurology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Tel.: +1 205 975 8509; fax: +1 205 934 6678.
E-mail address: firstname.lastname@example.org (A.P. Nicholas).
levodopa were given to normal rats, levels of brain NA increased,
but only transiently [9,26].
In Parkinson’s disease (PD), it is well known that catecholamine
neurons, such as those in the dopaminergic nigrostriatal path-
way, and noradrenergic neurons of the locus coeruleus are severely
degenerated [1,13]. Prior to the therapeutic use of levodopa, striatal
DA and NA in PD patients were found to be decreased by approxi-
mately 90% and 80%, respectively . As a result, it has long been
suspected that the efficacy of levodopa as one of the best pharma-
cological treatments for PD, depends upon surviving striatal 5HT
pathways containing AADC to convert a significant amount of the
exogenous levodopa into DA. However, prior to the use of levodopa
in PD, striatal 5HT levels were also found to be decreased by about
Due to the fact that striatal DA, NA and 5HT levels seem to be
affected both by the pathophysiological processes of PD and by
effect of debilitating, hyperactive involuntary movements referred
to as levodopa-induced dyskinesia (LID) is related to a combina-
tion of these monoamine changes . However, the influence of
exogenous levodopa on all striatal monoamines as it relates to the
0304-3940/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved.
A.P. Nicholas et al. / Neuroscience Letters 443 (2008) 204–208
emergence of this hyperactive side effect of PD treatment has not
yet been fully examined.
In a C57BL/6 mouse model of PD utilizing the neurotoxin 1-
methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [20,23], the
present study examines the influence of high dose levodopa given
with the peripheral AADC inhibitor carbidopa, on monoamine
production and metabolism in the striatum of hyperactive mice
previously exposed to MPTP, compared to mice with normal motor
behavior that either received high dose levodopa/carbidopa with-
out previous MPTP exposure or no treatment at all. Olfactory bulbs
as those present in the striatum and were shown in C57BL/6 mice
to result in similar MPTP-induced depletions of DA . The results
should determine if exogenous levodopa influences monoamine
if there is a unique monoamine profile in the striatum conducive to
LID behavior in particular.
Methods for preparing the mouse model of LID were performed
in accordance with NIH guidelines and described previously .
Briefly, 10–12-month-old male C57BL/6 mice (Charles River) were
divided into three groups, including (1) untreated normoactive
controls (n=4), (2) hyperactive animals previously given 30mg/kg
intraperitoneal injections of MPTP (Sigma, St. Louis, MO) in 5%
ethanol  for 10 consecutive days and later given intraperitoneal
injections of high dose levodopa (200mg/kg; Sigma, St. Louis, MO)
mixed with carbidopa (25mg/kg; Merck & Co., Inc., Whitehouse
Station, NJ) in normal saline, twice daily after 10–14 days of rest
(n=10), and (3) normoactive mice that also received high dose lev-
odopa, but were not previously exposed to MPTP (n=4). Motor
behaviors of MPTP-treated and non-treated animals were mea-
sured using an external cage rack Photobeam Activity System (PAS;
San Diego Instruments, San Diego, California). In contrast to con-
trol animals, only MPTP-exposed, levodopa-treated mice exhibited
hyperactive behavior, such as running, scratching, jumping, gnaw-
. In contrast to other LID animal models that also measured
movements subjectively using a blinded observer [8,16,24,29,32],
hyperactivity in these mice was determined solely using objective
measurements from the PAS apparatus. As with control animals,
mice with LID were sacrificed by decapitation 60min after the fifth
levodopa dose at the peak of hyperactivity and at the same time as
levodopa-treated control animals that were not hyperactive. The
striatum and olfactory bulbs of these mice were quickly removed,
frozen on dry ice and stored at −80◦C.
Prior to high-performance liquid chromatography (HPLC) anal-
ysis, all tissue samples were transferred separately to 15ml plastic
tubes and weighed. Ice-cooled perchloric acid (0.4M) was added to
the striatum (500?l), and olfactory bulbs (300?l) and the tissue
was homogenized for 10s using an ultrasonicator and centrifuged
for at least 20min at 3200×g at 4◦C. The supernatant was passed
through a 0.2?m filter (Minisart RC4, Sartorius AG, Germany) and
frozen again at −80◦C.
Using HPLC combined with electrochemical detection, the
lacetic acid (DOPAC) and homovanillic acid (HVA), 5HT and its
metabolite 5-hydroxyindoleacetic acid (5-HIAA) and NA and its
metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), under iso-
cratic conditions. The detector potential was set at +650mV using
a glassy carbon electrode and an ISAAC Ag/AgCl reference elec-
trode (Antec VT-03, Leyden, The Netherlands). Chromatographic
separation was performed using a reversed-phase column (Discov-
ery C18, 150mm×4.6mm i.d., 5?m particles, with pre-column,
Supelco, USA). The mobile phase included 1-octanesulfonic acid
sodium salt (0.32mM), Na2EDTA×2H2O (0.27mM), NaCl (8.0mM)
Fig. 1. Mean monoamine levels (±S.E.M.) in the olfactory bulb (A) and striatum
(B) of untreated control mice with normal motor behavior (Control), animals with
LID (LD-HYPER) and levodopa-treated control mice with normal motor behavior
(LD-Normal). P values of levodopa-treated groups vs. untreated group: ****<0.0001,
***<0.001, **<0.01, *<0.05; P values between levodopa-treated groups:####<0.0001,
and KH2PO4(50.0mM). After the pH was adjusted to 4.00 with
H3PO4, the mobile phase was then passed through a 0.22?m filter,
mixed with acetonitrile (95:5, v/v) and delivered at a flow rate of
pared among experimental groups using ANOVA and two-tailed
t-tests. Significance was defined as P<0.05.
The results showed that, compared to untreated animals and
regardless of animal activity and previous MPTP exposure, exoge-
nous levodopa tended to significantly increase DA and deplete 5HT
in normal acting animals that received levodopa but not MPTP,
proving that high striatal DA alone was not responsible for hyper-
activity. In LID mice, striatal DA was increased and 5HT and NA
decreased as compared to untreated controls, but only DA and 5HT
were statistically significantly decreased as compared to normal
gest that exogenous levodopa tends to increase DA at the expense
to levodopa exposure.
A.P. Nicholas et al. / Neuroscience Letters 443 (2008) 204–208
Fig. 2. Mean monoamine turnover rates (±S.E.M.) in the olfactory bulb (A) and
striatum (B) of untreated control mice with normal motor behavior (Control),
animals with LID (LD-HYPER) and levodopa-treated control mice with normal
motor behavior (LD-Normal). Dopamine turnover (DOPAC/DA); serotonin turnover
(5HIAA/5HT); noradrenaline turnover (MHPG/NA); P values for levodopa-treated
Exogenous levodopa was also shown to universally increase
DOPAC and HVA and decrease 5HIAA levels (Table 1), as well as
increase all monoamine turnover rates (Fig. 2), with a few impor-
tant exceptions. MHPG was not significantly different in olfactory
bulb or striatum between treatment groups, but HVA and 5HIAA
were significantly higher only in the striatum of LID animals as
compared to similarly levodopa-treated animals exhibiting nor-
mal motor behavior (Table 1). In the olfactory bulb, monoamine
turnover rates were not statistically significantly different between
hyperactive LID mice and similarly levodopa-treated animals
exhibiting normal motor behavior (Fig. 2A). In contrast, DA- and
5HT-turnover rates in the striatum of LID mice were highest, while
striatal NA-turnover was not significantly different from control
animals with normal motor behavior, whether they received lev-
odopa or not (Fig. 2B). Therefore, the expected increase in striatal
NA-turnover was not seen in mice with LID.
These findings are consistent with the hypothesis that when the
nigrostriatal system is damaged, as in PD or one of its animal mod-
els, relatively better intact 5HT terminal networks convert much of
the exogenous levodopa into DA, and this is done at the expense of
5HT production. It has already been shown that using our dosing
schedule of MPTP alone in C57BL/6 mice, striatal DA was depleted
by approximately 84% [23,31] and NA by 46% . However, the
results of the present study also show that previous damage of DA
pathways is not a prerequisite to causing decreases in 5HT, as con-
version of exogenous levodopa to DA at the expense of 5HT appears
to take place even in animals not exposed to MPTP. This can be
explained by the high likelihood that AADC in both DA and 5HT
neurons were saturated by excessive amounts of levodopa given in
these experiments, regardless of previous damage to DA pathways,
cence showed previously unseen DA immunoreactivity localized in
serotonergic fibers of the striatum and cell bodies of the midbrain
raphe nuclei only after rats were treated with exogenous levodopa
. In addition, using HPLC analysis, levodopa treatment in normal
rats resulted in significant loss of 5HT in many serotonergic and
dopaminergic regions of the brain, especially the striatum, while
striatal DA and DA-turnover  and enhancement of NA-turnover
in rat brain  were significantly higher. These findings are con-
sistent with the present study. Sprouting of serotonergic afferents
into the striatum was also seen after MPTP exposure in C57BL/6
mice , suggesting that striatal serotonergic hyperinnervation
may compensate for the lost function of dopaminergic neurons in
this model. In the present study, striatal 5HT levels were the low-
est in LID animals, suggesting an additional depleting effect of both
MPTP and levodopa. It was previously shown in C57BL/6 mice that
MPTP alone had no significant effect on striatal 5HT levels [15,31],
but the MPTP dosing schedules used in these prior experiments
differed from the present study.
sal increases in both DA and NA. Thus, levodopa first is converted to
in this location. DA would then be packaged in vesicles and should
be converted to NA in that location, since the NA-synthesizing
enzyme DBH is bound to the insides of vesicular membranes. How-
Monoamine metabolites in olfactory bulb and striatum in LID vs. control mice
Normoactive (n=4) no treatmentHyperactive (n=10) MPTP/carbidopa/levodopaNormoactive (n=4) carbidopa/levodopa
Olfactory bulb monoamine metabolites: mean ng/mg wet tissue weight (S.E.M.)
DOPAC 0.1455 (0.0072)
HVA 0.2604 (0.0188)
5HIAA 0.3677 (0.0099)
MHPG 0.5595 (0.0407)
Striatal monoamine metabolites: mean ng/mg wet tissue weight (S.E.M.)
HVA 0.6805 (0.0878)
5HIAA 0.6856 (0.0716)
MHPG 0.2393 (0.0137)
6.5243 (0.2871)***, #
0.6230 (0.0336)***, ##
***P<0.0001 vs. non-treated controls;##P<0.001,#P<0.01 hyperactive vs. normoactive carbidopa/levodopa treated groups.
A.P. Nicholas et al. / Neuroscience Letters 443 (2008) 204–208
levodopa treatment actually tended to universally decrease NA
levels rather than increase them, especially in the olfactory bulb,
and this effect was seen regardless of motor activity or previous
MPTP exposure. These results suggest that in animals treated with
levodopa, the cytosolic pool of DA in these noradrenergic terminals
is so high, that perhaps the increased production of synaptic vesi-
cles happens so rapidly that DBH incorporation into these vesicles
is lacking. This is consistent with previous studies in normal
rodents showing that exogenous levodopa increased primarily the
cytoplasmic pool of DA and that significant increases in vesicular
DA required previous catecholamine depletion . However, in the
present study, NA production in the striatum was not statistically
different between mice with normal motor behavior, whether
they previously received levodopa or not. Striatal NA levels were
lower only in hyperactive animals, confirming an MPTP-induced,
NA-depleting effect that was previously reported in C57BL/6 mice
Although there is a trend that levodopa treatment results
in increased NA-turnover, the present study demonstrates that
the MHPG/NA ratio also differs slightly, depending upon the site
examined. In the olfactory bulb, levodopa-induced NA-turnover
is universally increased, similar to both DA- and 5HT-turnover
rates. However, the expected increased turnover of NA in the stria-
tum is not seen in mice with LID, suggesting that in these mice
the small amounts of NA that are being produced are not being
recycled as quickly, perhaps resulting in abnormally sustained NA-
that highly selective alpha-2 noradrenergic blocking agents such as
idazoxan and fipamezole have been successfully used to counter-
act dyskinesia in the MPTP monkey model of LID [14,16,29] and
in human PD patients with these involuntary movements .
Although it is known that noradrenergic alpha-2 receptors are
plentiful in the striatum [17,21,27,30], the site of action resulting
in the anti-dyskinetic effect of idazoxan and fipamezole is still
Anti-dyskinetic effects utilizing serotonergic mechanisms have
also been shown with various drugs in animal models and humans
with LID, although most of these agents also bind to other
monoamine receptors as well . However, using more specific
5HT-receptor binding drugs, recent evidence suggests that in a 6-
hydroxydopamine rat model of PD, levodopa exposure results in
up-regulation of striatal 5HT-1B receptors  independent from
DA depletion and an anti-dyskinetic effect can be obtained with
5HT-1A  and -1B agonists [8,32], believed to be working at
auto-receptors on serotonergic neuronal cell bodies/dendrites and
terminals, respectively .
The results of the present study suggest that exogenous lev-
odopa can influence brain monoamine levels and metabolism
regardless of animal activity; however, there appears to be a
unique monoamine profile in the striatum of animals conducive
to developing LID behavior in particular. Other motor brain
areas in which monoamines are present should also be simi-
larly examined in future studies, as well as other animal models
of LID to see if these trends are consistent. In any case, the
present study suggests that in designing new monoaminergic
drugs to treat PD patients with LID, careful consideration should
be made regarding the choice of pharmacological profiles that
would optimally affect these altered DA, 5HT and NA brain
The authors would like to thank Dee Parsons for helping with
statistical calculations and the Alabama Parkinson Association, Inc.
and the University of Alabama at Birmingham Department of Neu-
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