Pharmacology, Biochemistry and Behavior 104 (2013) 113–118

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Pharmacology, Biochemistry and Behavior

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Physical exercise down-regulated locomotor side effects induced by haloperidol

treatment in Wistar rats
Pedro Porto Alegre Baptista a,⁎, Priscylla Nunes de Senna b, Mariana Fontoura Paim a, Lisiani Saur a,
Martina Blank c, Patricia do Nascimento b, Jocemar Ilha b, Mônica Ryff Moreira Vianna c,
Régis Gemerasca Mestriner a, d, Matilde Achaval b, Léder Leal Xavier a
a
Laboratório de Biologia Celular e Tecidual, Departamento de Ciências Morfofisiológicas, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
b
Laboratório de Histofisiologia Comparada, Departamento de Ciências Morfológicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
c
Laboratório de Biologia e Desenvolvimento do Sistema Nervoso, Departamento de Ciências Morfofisiológicas, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
d
Faculdade de Enfermagem, Nutrição e Fisioterapia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Extra-pyramidal symptoms (EPS) such as akinesia, dystonia, gait alteration and tremors are observed when dopa-
Received 30 August 2012 mine D2-receptors are blocked by pharmacological agents such as haloperidol. These alterations produce a
Received in revised form 30 November 2012 Parkinson disease-like state (PLS). Physical exercise has been proven to improve gait and locomotor symptoms in
Accepted 23 December 2012
Parkinson's disease; we sought to elucidate the effects of physical exercise on PLS induced by chronic administration
Available online 2 January 2013
of haloperidol in rats. We used 48 rats distributed into four groups: Control, Exercise, Haloperidol, and Hal+Exe. All
Keywords:
the animals received a daily injection of saline or haloperidol for 30 days, and the exercise groups underwent a daily
Exercise 30-minute exercise protocol for 20 days. The animals were subjected to the ink–paw test, bar test and open-field
Antipsychotics test throughout the training period. The haloperidol-induced akinesia increased throughout the days of injections,
Dopamine but exercise was shown to alleviate it. The assessment showed shortened stride length and increased stance width
Parkinsonism with the use of haloperidol, which were significantly alleviated by exercise. These results indicate that exercise could
Akinesia be an interesting approach towards reducing unwanted EPS caused by haloperidol.
Gait © 2013 Elsevier Inc. All rights reserved.

1. Introduction quality of PD patients (Herman et al., 2008) and in PD animal models

Extrapyramidal symptoms (EPS) are a collection of motor side-effects
that can arise with the use of dopamine D2-receptor blockers. Drugs of
this nature are widely used in the treatment of psychotic illnesses such
as schizophrenia and bipolarity (Inada et al., 2002). Haloperidol is an ex-
ample of a dopamine antagonist and, although it belongs to the first gen-
eration of antipsychotics drugs (APD), it is still the reference treatment for
schizophrenia (McCue et al., 2006). EPS presents a very specific set of
motor deficits such as tremors, akinesia, dystonia and gait alterations
(Lieberman et al., 2005; Miyamoto et al., 2005), which greatly resemble
the motor characteristics observed in Parkinson's Disease (PD) patients
and animal models (Amende et al., 2005; Guillot et al., 2008; Kurz et al.,
2007). For this reason, APD is said to cause Parkinsonism (Peluso et al.,
2012) or, as it will be referred to in this study, a Parkinson's-like state
(PLS).
Physical exercise is widely prescribed to PD patients in an attempt to
improve motor control and enhance life quality (Uitti, 2012). Treadmill
training, in particular, has been shown to greatly improve the gait
⁎ Corresponding author at: Departamento de Ciências Morfofisiológicas, Faculdade
de Biociências, PUCRS, Avenida Ipiranga, 6681, Prédio 12 Sala 144, CEP 90619-900,
Porto Alegre, RS, Brazil. Tel.: + 55 51 33203545.
E-mail address: pedropoa@gmail.com (P.P.A. Baptista).
(Pothakos et al., 2009). On the other hand, very little has been written
about gait alterations in PLS induced by APD, with some studies merely
mentioning the presence of a gait deficit in this state (Hansen et al.,
1997; Lieberman et al., 2005). Additionally, previous studies have
shown that physical exercise has some beneficial effects on EPS induced
by haloperidol in rats (Teixeira et al., 2011).
Given that APD induces PLS, generating important gait alterations that
are not completely understood, and that physical exercise has a beneficial
effect on EPS (Herman et al., 2008; Uitti, 2012), the main goals of this
study were to improve the knowledge about the motor gait deficit in-
duced by D2 blockers and to investigate the effects of physical exercise
in PLS induced by haloperidol.
2. Materials and methods
2.1. Animals
For this study, 48 male Wistar rats, three months old and weighing
200–300 g were obtained from the Institute of Basic Health Sciences
(ICBS) — UFRGS. They were maintained in a controlled environment
and housed in groups of five with food and water ad libitum, in a
12:12 h dark:light schedule. The animals were allocated into four groups
(twelve each): 1 — Saline and Sedentary (Control), 2 — Saline and

0091-3057/$ – see front matter © 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pbb.2012.12.020
114 P.P.A. Baptista et al. / Pharmacology, Biochemistry and Behavior 104 (2013) 113–118
Exercise (Exercise), 3 — Haloperidol and Sedentary (Haloperidol) and
4 — Haloperidol and Exercise (Hal+ Exe). All procedures were ap-
proved by our institution's ethics committee and were in accordance
with the National Institute of Health (USA). All efforts were made to re-
duce number and suffering of animals used.
2.2. Drug and exercise program
Saline solution (0.9% NaCl) or Haloperidol (0.3 mg/kg/day — Janssen-
Cilag Farmaceutica Ltda., Brazil) was administered intraperitoneally in a
single daily dose during 30 days. This dose was chosen based as previous
studies (Iwahashi et al., 1996; Kapur et al., 2003; Miyamoto et al., 2005;
Putzhammer et al., 2005) in which the plasmatic drug level was approx-
imately 1 nM. The first 4 days of drug injections, prior to initiating the ex-
ercise protocol, were used for treadmill habituation and to establish the
speed to be used in the study. The exercise protocol consisted of treadmill
walking for 30 min, 5 days a week for 4 consecutive weeks (a total of
20 days of exercise). All injections were applied 20–30 min before the
exercise session. The exercise load consisted of a low-intensity treadmill
walk at a speed of 4 m/min for 5 min, and then 6 m/min for the
remaining 25 min. This protocol was adapted from a previous study
using PD models (Yoon et al., 2007).
2.3. Behavioral tests and measurements
The animals were weighed in the pre-training (PT) period and at the
end of each week (1 week, 2 weeks, 3 weeks, and 4 weeks). The ink–
paw test and the open-field test were performed in PT and in 4 weeks.
The bar test was used in PT, 2 weeks and 4 weeks. All tests were
performed before the daily injection to avoid the acute effects of the drug.
For the ink–paw test, the hind paws of the animals were dyed with
non-toxic ink. Then, animals were individually placed on a catwalk with
the floor covered by white paper. As the animals walked on the appara-
tus, paw prints were left on the paper. A set of six consecutive steps
were analyzed using these parameters: 1 — Stride length (longitudinal
distance between consecutive prints); 2 — Stance width (latitudinal dis-
tance between consecutive left and right paw prints); 3 — Paw length
(distance between the print of the tip of the third toe and the ankle);
and 4 — Paw width (distance between the tip of the first toe and the
tip of the fifth toe) (Ilha et al., 2008) (Fig. 2).
In the bar test, akinesia was evaluated by placing both forelimbs on a
9 cm high horizontal bar and measuring the time taken by the animals
to remove both paws from the bar (Ohno et al., 2010; Vasconcelos et al.,
2003; Wu et al., 2009).
Fig. 1. A timeline of the experimental design. PT = pre-training, OF = open field test, W = weeks.
The open-field apparatus consisted of a 50 cm high, 60 cm× 40 cm
box made of plywood, with one glass side. The floor was divided by
drawn lines, composing 12 equal rectangles. Animals were individually
placed in a corner of the apparatus and their behavior was recorded for
3 min. All behavior measurements were automated using ANY-Maze
software (Version 4.70, Stoelting). The following parameters were ana-
lyzed: Lines crossed, total distance traveled, average speed, time mobile,
time immobile, time in the center and immobile episodes. Rearing data
was also analyzed. However, it is a rater-dependent variable.
A timeline with all experimental procedures can be seen in Fig. 1.
2.4. Statistics
To evaluate the ink–paw and open field tests, one-way ANOVA was
performed followed by Tukey's post hoc test to evaluate the differences
among the groups in the same period, while the differences in the same
group in different periods (PT and 4 weeks) were analyzed using a
t-paired test.
Repeated measures ANOVA followed by Tukey's post hoc test was
used to evaluate the bar test. All procedures were performed in the
SPSS 11.0 software (P b 0.05).
3. Results
3.1. Weight
In this study no significant change to the animals' weight was ob-
served (data not shown).
3.2. Ink–paw test
The ink–paw test demonstrated haloperidol induced gait alterations
that were alleviated by exercise. After 4 weeks of treatment the Haloper-
idol group showed a reduced stride length (F(3,46) =4.45, Pb 0.05) and
larger stance width (F(3,46) =11.14, Pb 0.001) when compared to all
groups. These effects were not seen in the Hal+Exe group (Fig. 3A and
B), hence, exercise alleviated gait alterations. However, the statistical
analysis showed that there was no significant change in paw length and
paw width in any of the groups (see Fig. 3C and D).
3.3. Bar test
The bar test showed a significant increase in akinesia associated with
haloperidol treatment, as represented by the time spent on the bar at the
different test intervals. The bar test results showed a significant effects in
 P.P.A. Baptista et al. / Pharmacology, Biochemistry and Behavior 104 (2013) 113–118 115

1- Stride length the 2 week (F(3,46) = 10.36, P b 0.001) and 4 week (F(3,46) = 15.70,
P b 0.001) measurements. In the Haloperidol group, PT was different
2- Stance width
from the 2 week and 4 week measurements (P b 0.05 and P b 0.001 re-
3-Paw length spectively), and the 2 week measurements differed from the 4 week
4-Paw width measurements (P b 0.05). The Hal + Exe group demonstrated a less
intense progression of akinesia, PT being statistically different only to
4 weeks (P b 0.05) (Fig. 4). These results show a down-regulation of
akinesia in animals treated with haloperidol and exercise.
When the groups were compared in the same period of treatment
(2 weeks or 4 weeks) a significant increase in the time spent on the
bar was observed in both haloperidol treated groups in comparison
with the Control (P b 0.001; P b 0.001 respectively) and Exercise groups
(P b 0.05; P b 0.05 respectively) (Fig. 4). The most important finding of
this test was that the increase in akinesia seen on the Haloperidol
group was attenuated by 4 weeks of physical exercise observed on the
Hal + Exe group (Fig. 4).

3.4. Open-field test

The open-field test showed a significant decrease in exploratory

Fig. 2. Schematic view of paw prints and measures. 1 — Stride length, 2 — Stance
width, 3 — Paw length, and 4 — Paw width.
behavior when PT and 4 week measurements were compared within
groups. It was observed a decrease in the number of lines crossed
(F(3,46) =0.52 P=0.66), total traveled distance (F(3,46) =0.63 P=0.59),
average speed (F(3,46) = 0.67 P = 0.57), mobile time (F(3,46) = 0.62
P = 0.60), and rearing (F(3,46) = 0.13 P = 0.93), and an increase in
the time immobile (F(3,46) = 0.60 P = 0.61) over the course of 4 weeks
and no alteration to time in center (data not shown). Intergroup anal-
ysis showed no differences in the same period (PT or 4 weeks)
(Fig. 5).

Fig. 3. Effects of haloperidol and exercise on gait in the ink–paw test. Where (A) a=Pb 0.01 when compared to all other groups; (B) a=Pb 0.001 when compared to all other groups;
(C) a=Pb 0.01 when compared to the Control and Hal+Exe groups, b=Pb 0.05 when compared to the Control and Hal+Exe groups; (D) a=Pb 0.01 when compared to the Exercise
and Hal+Exe groups (mean distance±SE).
116 P.P.A. Baptista et al. / Pharmacology, Biochemistry and Behavior 104 (2013) 113–118
Fig. 4. Effect of haloperidol and exercise on akinesia in the bar test. a=Pb 0.001 when
compared to the Control and Exercise groups, b=Pb 0.05 when compared to the Control
and Exercise groups, and c=Pb 0.05 when compared to all other groups. *Pb 0.05, and
***Pb 0.001 when compared to the groups indicated by the lines (mean time on bar±SE).
4. Discussion
Regarding the animals' weight, our findings are in accordance with a
previous study that showed that despite increased fat deposition, the
weight in male rats does not change with typical APD (Minet-Ringuet
et al., 2006). These results agree partially with what is known about
antipsychotic-induced weight gain (Bobes et al., 2003; Covell et al.,
2004; Lieberman et al., 2005). For example, a previous meta-analysis
has shown that atypical APD induced greater weight gain than
Fig. 5. Effects of haloperidol and exercise on bradykinesia in the open-field test. In all graphs *P b 0.05, **P b 0.01, and ***P b 0.001 when PT was compared with 4 weeks in all groups
(mean values ± SE).
haloperidol (Leucht et al., 2009). It is possible that the combination
of a typical APD, such as haloperidol, with the short treatment interval
used in our study was insufficient to induce significant changes in rat
body weight. The lack of weight changes observed could also be attrib-
uted to the use of male rats, since a previous study using rats showed
that APD affected females more rapidly than males (Pouzet et al., 2003).
Our study shows that haloperidol is responsible for reducing stride
length and increasing stance width, however these changes are alleviated
by associated exercise. Currently, haloperidol-induced gait alterations are
poorly understood. Comparison is traditionally made with PD-models be-
cause of the similarities between EPS/PLS and the symptoms of PD. In PD
animal models, the gait presents a faster stride frequency, a shorter stride
length, and smaller stance width (Amende et al., 2005; Guillot et al., 2008;
Kapur et al., 2003; Pothakos et al., 2009), conditions which are consistent
with findings in humans. The reduced stride length found in our study is
similar to the findings obtained using PD animal models (Amende et al.,
2005; Hansen et al., 1997; Kurz et al., 2007). This similarity between clas-
sical PD and haloperidol-induced PLS could be explained by nigrostriatal
dysfunction. A previous study has shown that measuring stride length is a
simple method of obtaining an index of motor disorders related to the
nigrostriatal system in mice (Fernagut et al., 2002).
A previous study showed that a single, acute, dose of haloperidol
was able to reduce the stride length of mice and that 24 h after the hal-
operidol administration the stride length returned to normal (Fernagut
et al., 2002). In our study, we observed that the shortening of the stride
length was present 24 h after haloperidol administration, but, in con-
trast to the previous study, our treatment was carried out chronically
for 30 days. Thus, this alteration is, perhaps, a side-effect produced by
the chronic use of haloperidol.
Furthermore, our findings showed an increase in stance width, which
usually indicates loss of balance (Cheng et al., 1997). Our study is, to the
 P.P.A. Baptista et al. / Pharmacology, Biochemistry and Behavior 104 (2013) 113–118
best of our knowledge, the first to demonstrate changes in this parameter
promoted by haloperidol use. Measurements of stance width are com-
monly evaluated in animal models of PD using different neurotoxic
agents, such as 6OHDA and MPTP (Amende et al., 2005; Guillot et al.,
2008; Metz et al., 2005; Pothakos et al., 2009). In these studies, reductions
in stance width are normally observed (Amende et al., 2005; Guillot et al.,
2008). These PD models are based on specific damaged dopaminergic
neurons in the substantia nigra (Amende et al., 2005; Metz et al.,
2005; Pothakos et al., 2009), whereas the use of haloperidol affects dif-
ferent neuronal populations (Huang et al., 2010). Moreover, haloperidol
is responsible for reduced dopamine binding, but it may also be respon-
sible for depolarization-blockage in other neuronal populations (Boye
and Rompré, 2000). Similarly, haloperidol has been shown to inhibit
the neuronal nitric oxide synthase (NOS) activity in vitro (Iwahashi et
al., 1996) and chronic haloperidol treatment resulted in decreased
striatal nitric-oxide (NO) levels in rats (Bishnoi et al., 2009); which au-
thors further relate to the onset of EPS. This reports could explain the
differences between typical APD-induced PLS and PD.
One of the most important findings of our study is that the stride
length and stance width of the Hal + Exe did not alter after the
4 week program, indicating that this approach could be interesting to
alleviate haloperidol-induced gait alterations. Previously, Putzhammer
et al. (2005) showed that impaired gait parameters can be normalized
by increasing treadmill velocities in patients treated with APD. Al-
though the effects of treadmill exercise on PLS are not fully established,
we know that both the synthesis and metabolism of DA have a close re-
lationship with physical exercise (Knab et al., 2009). It might contribute
to adjusting DA neurotransmission within an adequate range in re-
sponse to exercise velocity and intensity (Hattori et al., 1994).
We observed that use of haloperidol caused no paw length and paw
width alterations. Studies into drug-induced changes to paw length and
paw width are scarce, and it may be the case that paw placement pa-
rameters are mainly affected by more aggressive insults, such as large
or selective lesions to the nervous system and neuromuscular diseases
(Ilha et al., 2008; Metz et al., 2005). Along the 4 weeks of haloperidol
treatment an increase in the time to conclude the bar test (measure of
akinesia) was observed. The haloperidol dose used in our study – as pre-
viously described (Ohno et al., 2010) – and the interval between the last
dose and locomotor tests was unable to induce catalepsy.
In the Haloperidol group, the time on bar increases significantly be-
tween each time frame, suggesting a worsening of akinesia throughout
the treatment. However, physical exercise down-regulates the akinesia
of the animals treated for 4 weeks; this suggests that exercise soothes
chronic side-effect.
The locomotor effects of haloperidol are usually measured immedi-
ately after administration (Karl et al., 2006; Vasconcelos et al., 2003; Wu
et al., 2009). Our results for akinesia are similar to those reported using
same drug dose (Ohno et al., 2010). Typically, catalepsy is seen after
acute administration of typical APD (Vasconcelos et al., 2003; Wu et
al., 2009). Moreover, the half-life of haloperidol in rats is 4–6 times
faster than in humans, hence multiple doses are necessary to maintain
the same intensity of symptoms (Kapur et al., 2003). An evaluation of
microcatalepsy might also contribute to expanding our knowledge of
this subject and could be considered in similar future studies (Fowler
et al., 2001).
In the open-field test, we observed that motor exploratory behavior
was significantly reduced in all the groups. In our study the control
group, as well as all other groups, decreased exploration, so while
bradykinesia might have been present in any one of the groups, it was
probably overshadowed by the reduced exploratory behavior seen in
the other groups. Moreover, a previous study using the pole test, with
a similar dose of haloperidol, was found to be insufficient to promote
bradykinesia (Ohno et al., 2010).
When exploratory and anxiety parameters such as lines crossed,
total distance traveled, average speed and time mobile and rearings
from PT and 4 week sessions were compared within each experimental
117
group, a significant decrease in exploration was observed over time
(Fig. 5). The reduced exploratory behavior observed after 4 weeks could
be an indication of task apparatus habituation (Vianna et al., 2000).
Long-term habituation to novel stimuli is one of the most elementary
forms of nonassociative learning and has been shown to be long-lasting
even in its most elementary forms (Carew et al., 1972).
4.1. Conclusion
The main findings in our study are that chronic exposure to haloper-
idol induces substantial gait alterations and increased akinesia. These
changes in locomotor activity are attenuated by exercise. Thus, this
study further elucidates important aspects of the motor EPS/PLS in-
duced by haloperidol and some possible advantages of the application
of physical exercise to support psychiatric treatments.
Acknowledgments
This work was supported by Brazilian funding agencies (CNPq and
CAPES).
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