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

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Pharmacology, Biochemistry and Behavior

j ou rn a I homepag e: www. e I sevi er. com/locate/ph a rm bi och em beh

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 e, Patrícia do Nascimento b' Jocemar Ilha b, Mônica Ryff Moreira Vianna e,
Régis Gemerasca Mestriner a. d , Matilde Achaval b, Léder Leal Xavier ª
ª Laboratório de Biologia Celular e Tecidual, Departamento de Ciências Morfojisiológicas, Pontijicia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
h Laboratório de Histojisiologia Comparada, Departamento de Ciências Morfológicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
e Laboratório de Biologia e Desenvolvimento do Sistema Nervoso, Departamento de Ciências Morfojisiológicas, Pontificia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
d Faculdade de Enfermagem, NuOição e Fisioterapia, Pontificia Universidade Católica do Rio Grande do Sul. Porto Alegre, RS, Brazil

ARTICLE INFO ABSTRACT

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 exerdse has been proven to improve gait and locomotor symptoms in
Accepted 23 December 2012
Parkinson's disease; we sought to eluddate the effects of physical exerdse on PLS induced by chronic administration
Available online 2 January 2013
of haloperidol in rats. We used 48 rats distributed into four groups: Contrai, Exercise, Haloperidol, and Hal + Exe. Ali
Keywords: the animais received a daily injection of saline or haloperidol for 30 days, and the exercise groups underwent a daily
Exercise 30-minute exerdse protocol for 20 days. Toe animais were subjected to the ink-paw test, bar test and open-field
Antipsychotics test throughout the training period. Toe haloperidol-induced akinesia increased throughout the days of injections,
Dopamine but exercise was shown to alleviate it. Toe assessment showed shortened stride length and increased stance width
Parkinsonism with the use ofhaloperidol, which were significantly alleviated by exercise. These results indicate that exercise could
Akinesia be an interesting approach towards redudng unwanted EPS caused by haloperidol.
Gait © 2013 Elsevier Inc. Ali rights reserved.

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

Extrapyramidal symptoms (EPS) are a collection of motor side-effects
that can alise 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 ((nada et ai., 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 ai., 2006). EPS presents a very specific set of
motor deficits such as tremors, akinesia, dystonia and gait alterations
(Lieberman et ai., 2005; Miyamoto et ai., 2005), which greatly resemble
the motor characteristics observed in Parkinson's Disease (PD) patients
and animal models (Amende et ai., 2005; Guillot et ai., 2008; Kurz et ai.,
2007). For this reason, APD is said to cause Parkinsonism (Peluso et ai.,
2012) or, as it will be referred to in this study, a Parkinson's-like state
(PIS).
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 lpiranga, 6681, Prédio 12 Sala 144, CEP 90619-900,
Porto Alegre, RS, Brazil. Tel.: + 55 51 33203545.
E-mail address: pedropoa@gmail.com (P.PA. Baptista).
(Pothakos et ai., 2009). On the other hand, very little has been written
about gait alterations in PIS induced by APD, with some studies merely
mentioning the presence of a gait deficit in this state (Hansen et ai.,
1997; Lieberman et ai., 2005). Additionally, previous studies have
shown that physical exercise has some beneficial effects on EPS induced
by haloperidol in rats (Teixeira et ai., 2011).
Given that APD induces PIS, generating important gait alterations that
are not completely understood, and that physical exercise has a beneficial
effect on EPS (Herman et ai., 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 PIS induced by haloperidol.
2. Materiais and methods
2.1. Animais
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 animais were allocated into four groups
(twelve each): 1 - Saline and Sedentary (Control), 2 - Saline and

0091-3057 /$ - see front matter © 2013 Elsevier lnc. Ali rights reserved.
http://dx.doi.org/10.10I 6/j.pbb.2012.12.020
114 P.PA. Baptista eta/. / Pharmacology, Biochemistry and Behavior 104 (2013) 113-118
Exercise (Exercise), 3 - Haloperidol and Sedentary (Haloperidol) and
4 - Haloperidol and Exercise ( Hal + Exe). Ali procedures were ap­
proved by our institution's ethics committee and were in accordance
with the National lnstitute ofHealth (USA). Ali efforts were made to re­
duce number and suffering of animais used.
2.2. Drug and exercise program
Saline solution (0.9% NaCI) 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 ai., 1996; Kapur et ai., 2003; Miyamoto et ai., 2005;
Putzhammer et ai., 2005) in which the plasmatic drug levei was approx­
imately 1 nM. The first 4 days ofdrug injections, prior to initiating the ex­
ercise protocol, were used for treadmill habituation and to establish the
speed to be used in the study. Toe exercise protocol consisted oftreadmill
walking for 30 min, 5 days a week for 4 consecutive weeks (a total of
20 days of exercise). Ali injections were applied 20-30 min before the
exercise session. Toe 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 ai., 2007).
2.3. Behaviora/ tests and measurements
Toe animais were weighed in the pre-training (PT) period and at the
end of each week (1 week, 2 weeks, 3 weeks, and 4 weeks). Toe ink­
paw test and the open-field test were performed in PT and in 4 weeks.
Toe bar test was used in PT, 2 weeks and 4 weeks. Ali 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 animais were dyed with
non-toxic ink. Then, animais were individually placed on a catwalk with
the floor covered by white paper. As the animais 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 ofthe fifth toe) (Ilha et ai., 2008) (Fig. 2).
ln the bar test, akinesia was evaluated by placing both forelimbs on a
9 cm high horizontal bar and measuring the time taken by the animais
to remove both paws from the bar (Ohno et ai., 2010; Vasconcelos et al.,
2003; Wu et ai., 2009).
Start of exercise protocol
and drug/saline
administration. One day
! !
after PT behavioral tests
1 1
t
lW 2W
l
PT:
OF
2W:
Bar test
lnk-paw
Bar test
Fig. 1. A timeline ofthe experimental design. PT=pre-training, OF=open field test, W=weeks.
The open-field apparatus consisted of a 50 cm high, 60 cmx40 cm
box made of plywood, with one glass side. Toe floor was divided by
drawn lines, composing 12 equal rectangles. Animais were individually
placed in a comer of the apparatus and their behavior was recorded for
3 min. Ali 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 ali 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 sarne period, while the differences in the sarne
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. Ali procedures were performed in the
SPSS 11.0 software (P<0.05).
3. Results
3.1. Weight
ln this study no significant change to the animais' weight was ob­
served (data not shown).
3.2. lnk-paw test
Toe 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, P<0.05) and
larger stance width (Fc3•46i = 11.14, P<0.001) when compared to ali
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 ofthe groups (see Fig. 3C and D).
3.3. Bar test
Toe 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. Toe bar test results showed a significant effects in
End of exercise protocol and
drug/saline administration.
3W 4W
l
4W:
·OF
•lnk-paw
·Bar test
One day after
the end of
protocols
 P.PA. Baptista et ai./ Pharmacology, Biochemistry and Behavior 104 (2013) 113-118 115

1- Stride length the 2 week (F { 3.46) = 10.36, P<0.001) and 4 week (Fc3.46) = 15.70,
2- Stance width P<0.001) measurements. ln the Haloperidol group, PT was different
from the 2 week and 4 week measurements (P<0.05 and P<0.001 re­
3-Paw length spectively), and the 2 week measurements differed from the 4 week
,. 4-Paw width measurements (P<0.05). The Hal + Exe group demonstrated a less
intense progression of akinesia, PT being statistically different only to
4 weeks (P<0.05) (Fig. 4). These results show a down-regulation of
akinesia in animais treated with haloperidol and exercise.
When the groups were compared in the sarne period of treatment
(2 weeks ar 4 weeks) a significant increase in the time spent on the
bar was observed in both haloperidol treated groups in comparison
with the Contrai (P<0.001; P<0.001 respectively) and Exercise groups
(P<0.05; P<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).
1
4 3.4. Open-field test

The open-field test showed a significant decrease in exploratory

behavior when PT and 4 week measurements were compared within
groups. It was observed a decrease in the number of tines crossed
(Fc3,46l = 0.52 P= 0.66), total traveled distance (Fc3,46l = 0.63 P= 0.59),
average speed (Fc3.46) = 0.67 P= 0.57), mobile time (Fc3.46) = 0.62
P=0.60), and rearing (Fc3.46)=0.13 P=0.93), and an increase in
.,,1 the time immobile (F(3 ,46) = 0.60 P= 0.61) over the course of 4 weeks
2 and no alteration to time in center (data not shown). Intergroup anal­
ysis showed no differences in the sarne period (PT ar 4 weeks)
Fig. 2. Schematic view of paw prints and measures. 1 - Stride length, 2 - Stance (Fig. 5).
width, 3 - Paw length, and 4 - Paw width.

A Stride Length B Stance Width

9 4,5
a

r
8 4
7 3,5

4
3
2
;,: 1,5
2

1
1 0,5
o o
PT 4W PT 4W

Paw Length PawWidth

e D
2,5
a b

r
2,5 2

1,5

0,5
r 1

0,5
o
PT 4W

PT 4W
□ Control ■ Exercise ■ Haloperidol ■ Hal+Exe

Fig. 3. Effects of haloperidol and exercise on gait in the ink-paw test. Where (A) a= P<0.01 when compared to all other groups; (B) a= P<0.001 when compared to all other groups;
(C) a=P<0.01 when compared to the Control and Hal + Exe groups, b=P<0.05 when compared to the Control and Hal + Exe groups; (D) a=P<0.01 when compared to the Exercise
and Hal + Exe groups (mean distance±SE).
116 P.PA. Baptista eta/. / Pharmacology, Biochemistry and Behavior 104 (2013) 113-118

BarTest haloperidol (Leucht et ai., 2009). lt is possible that the combination

6 of a typical APD, such as haloperidol, with the short treatment interval
used in our study was insufficient to induce significant changes in rat
5 body weight. The Jack ofweight changes observed could also be attrib­
uted to the use of male rats, since a previous study using rats showed
4 that APD affected females more rapidly than males (Pouzet et ai., 2003).
Our study shows that haloperidol is responsible for reducing stride
length and increasing stance width, however these changes are alleviated
)3 by associated exercise. Currently, haloperidol-induced gait alterations are
poorly understood. Comparison is traditionally made with PD-models be­
2
cause ofthe similarities between EPS/PLS and the symptoms ofPD. ln PD
animal models, the gait presents a faster stride frequency, a shorter stride
1
length, and smaller stance width (Amende et ai., 2005; Guillot et ai., 2008;
Kapur et ai., 2003; Pothakos et ai., 2009), conditions which are consistent
PT 2W 4W with findings in humans. Toe reduced stride length found in our study is
□ Control ■ Exercise ■ Haloperidol ■ Hal+Exe similar to the findings obtained using PD animal models (Amende et ai.,
2005; Hansen et ai., 1997; Kurz et ai., 2007). This similarity between clas­
Fig. 4. Effect of haloperidol and exercise on akinesia in the bar test a= P<0.001 when sical PD and haloperidol-induced PLS could be explained by nigrostriatal
compareci to the Control and Exercise groups, b = P<0.05 when compared to the Control
dysfunction. A previous study has shown that measuring stride length is a
and Exercise groups, and c=P<0.05 when compared to ali other groups. "P<0.05, and
"""P<0.001 when compared to the groups indicated by the lines (mean time on bar±SE). simple method of obtaining an index of motor disorders related to the
nigrostriatal system in mice (Femagut et ai., 2002).
A previous study showed that a single, acute, dose of haloperidol
4. Discussion was able to reduce the stride length ofmice and that 24 h alter the hal­
operidol administration the stride length returned to normal (Fernagut
Regarding the animais' weight, our findings are in accordance with a et ai., 2002). In our study, we observed that the shortening ofthe stride
previous study that showed that despite increased fat deposition, the length was present 24 h alter haloperidol administration, but, in con­
weight in male rats does not change with typical APD (Minet-Ringuet trast to the previous study, our treatment was carried out chronically
et ai., 2006). These results agree partially with what is known about for 30 days. Thus, this alteration is, perhaps, a side-effect produced by
antipsychotic-induced weight gain (Babes et ai., 2003; Covell et ai., the chronic use of haloperidol.
2004; Lieberman et ai., 2005). For example, a previous meta-analysis Furthermore, our findings showed an increase in stance width, which
has shown that atypical APD induced greater weight gain than usually indicates loss ofbalance (Cheng et ai., 1997). Our study is, to the

Total Distance
A Lines Crossed B Travelled e Average Speed
90
0,05

Í
80
70 0,04
60
0,03
� 50
:::. 40
0,02

0,01

PT 4W PT 4W PT 4W

Time Mobile lmmobile Episodes

E Time lmmobile F G Rearing
160
140
140
120 .. 7

6
20

g 15

f:
120
100

j
80
� 10
60

40 ·e
40
a: 5
20 20
o o o
PT 4W PT 4W PT 4W PT 4W
□ Control ■ Exeràse ■ Haloperldol ■ Hal+Exe

Fig. S. Effects of haloperidol and exercise on bradykinesia in the open-field test. ln ali graphs "P<0.05, ""P<0.01, and """P<0.001 when PT was compared with 4 weeks in ali groups
(mean values ±SE).
 P.PA. Baptista et ai./ Phannacology, 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 ai., 2005; Guillot et ai.,
2008; Metz et ai., 2005; Pothakos et ai., 2009). ln these studies, reductions
in stance width are normally observed (Amende et ai., 2005; Guillot et ai.,
2008). These PD models are based on specific damaged dopaminergic
neurons in the substantia nigra (Amende et ai., 2005; Metz et ai.,
2005; Pothakos et ai., 2009), whereas the use of haloperidol affects dif­
ferent neuronal populations (Huang et ai., 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 (lwahashi et
ai., 1996) and chronic haloperidol treatment resulted in decreased
striatal nitric-oxide (NO) leveis in rats (Bishnoi et ai., 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 ai. (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 ai., 2009). lt might contribute
to adjusting DA neurotransmission within an adequate range in re­
sponse to exercise velocity and intensity (Hattori et ai., 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 ai., 2008; Metz et ai., 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 ai., 2010)-and the interval between the last
dose and locomotor tests was unable to induce catalepsy.
ln 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 animais 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 ai., 2006; Vasconcelos et ai., 2003; Wu
et ai., 2009). Our results for akinesia are similar to those reported using
sarne drug dose (Ohno et ai., 2010). Typically, catalepsy is seen after
acute administration of typical APD (Vasconcelos et ai., 2003; Wu et
ai., 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 sarne intensity of symptoms (Kapur et ai., 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 ai., 2001).
ln the open-field test, we observed that motor exploratory behavior
was significantly reduced in ali the groups. ln our study the control
group, as well as ali 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 pote test, with
a similar dose of haloperidol, was found to be insufficient to promote
bradykinesia (Ohno et ai., 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 ai., 2000).
Long-term habituation to novel stimuli is one of the most elementary
forms of nonassociative leaming and has been shown to be long-lasting
even in its most elementary forms (Carew et ai., 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).
References
Amende 1, Kale A, McCue S, Glazier S, Morgan JP, Hampton TG. Gait dynamics in mouse
models of Parkinson's disease and Huntington's disease. J Neuroeng Rehabil
2005;2:20.
Bishnoi M, Chopra K, Hulkami SK Co-administration of nitric oxide (NO) donors prevents
haloperidol-induced orofacial dyskinesia, oxidative damage and change in striatal
dopamine leveis. Phannacol Biachem Behav 2009;91 :423-9.
Bobes J,Rejas J, Garcia-Carda M, Rico-Villademoros F,Garáa-Portilla MP, Femandéz 1, et ai.
Weight gain in patients with schizophrenia treated with risperidone, olanzapine,
quetiapine or haloperidol: results for the EIRE study. Schizorphr Res 2003;62:77-88.
Boye SM, Rompré PP. Behavioral evidence of depolarization block of dopamine neurons
alter chronic treatrnent with haloperidol and clozapine.J Neurosci 2000;20:1229-39.
Carew TJ, Pinsker ER, Kadel ER. Long-term habituation of a defensive withdraw reflex
in aplysia. Science 1972;175:451-4.
Cheng H, Almstrom S, Giménez-Llort L,Chang R, Ogren SO, Hoffer B, et ai. Gait analysis
of adult paraplegic rats after spinal cord repair. Exp Neurol 1997:148:544-57.
Covell NH, Weissman EM, Essock SM. Weight gain with clozapine compared to first
generation antipsychotic medications. Schizophr Buli 2004;30:229-40.
Fernagut PO,Diguet E, Labattu B, Tison F. A simple method to measure stride length as an
index ofnigrostriatal dysfunction in mice.J Neurosci Methods 2002;113:123-30.
Fowler SC, Zarcone TJ, Vorontsova E. Haloperidol-induced microcatalepsy differs in
CD-1, BALB/c, and C57BL/6 mice. Exp Clin Psychopharmacol 2001 ;9(3):277-84.
Guillot TS, Asress SA, Richardson JR, Glass JD, Miller GW. Treadmill gait analysis does
not detect motor in animal models of Parkinson's disease or amyotrophic lateral
sclerosis. J Mot Behav 2008;40(6):568-77.
Hansen TE, Casey DE, Hoffman WF. Neuroleptic intolerance. Schizophr Buli 1997;23:
567-82.
Hattori S, Naoi M, Nishino H. Striatal dopamine turnover during treadmill running in
the rat: relation to the speed of running. Brain Res Buli 1994;35(1 ):41-9.
Herman T,Giladi N, Hausdorff JM. Treadmill training for the treatrnent ofgait disturbances
in people with Parkinson's disease: a mini review.J Neural Transm 2008;116:307-18.
Huang ACW, Shyu BC, Hsiao S. Dose-dependent dissociable effects of haloperidol on lo­
comotion, apetitive response, and consummatory behavior in water-deprived rats.
Pharmacol Biachem Behav 2010;95:285-91.
Ilha J,Araujo RT,Malysz T, Hermel EES,Rigon P,Xavier LI., et ai. Endurance and resistance
exercise training programs elicits specific effects on sciatic nerve regeneration alter
experimental traumatic lesion in rats. Neurorehabil Neural Repair 2008;22:355-66.
!nada T, Vagi G, Miura S. Extrapyramidal symptom profiles in Japanese patients with
schizophrenia treated with olanzapine or haloperidol. Schizophr Res 2002;57:
227-38.
lwahashi K, Yoneyama H,Ohnishi T, Nakamura K, Miyatake R,Suwaki H, et ai. Haloperidol
inhibits neuronal nitric oxide synthase activity by preventing electron transfer.
Neuropsychobiology 1996;33:76-9.
Kapur S, Vanderspek SC, Brownlee BA, Nobrega JN. Antipsychotic dosing in preclinical
models is often unrepresentative of the clinicai condition: a suggested solution
based on in vivo occupancy. J Pharmacol Exp Ther 2003;305:625-31.
Karl T, Duffy L, O'Brien E,Matsumo 1, Dedova 1. Behavioural effects ofchronic haloperidol
and risperidone treatrnent in rats. Behav Brain Res 2006;305:286-94.
Knab AM, Bowen RS, Hamilton AT, Gulledge M, Lightfoot JT. Altered dopaminergic
profiles: implications for the regulation of voluntary physical activity. Behav
Brain Res 2009;204:147-52.
Kurz MJ, Pothakos K,Jamaluddin S, Scott-PandorfM, Arellano C,Lau YS. A chronic mouse
model of Parkinson's disease das a reduced gait certainty. Neurosci Lett 2007;429:
39-42.
Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus
first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet
2009;373:31-41.
118 P.PA. Baptista eta/. / Pharmacology, Biochemistry and Behavior 104 (2013) 113-118
Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et ai. Ef­
fectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl
J Med 2005;353:1209-23.
McCue RE, Waheed R, Urcuyo L, Orendain G, Joseph MD, Charles R. et ai. Comparative
effectiveness of second-generation antipsychotics and haloperidol in acute schizo­
phrenia. Br J Psychiatry 2006;189:433-40.
Metz GA, Tse A, Ballermann M, Smith LK, Fouad K. The unilateral 6-OHDA rat model
of Parkinson's disease revisited: an electromyographic and behavioural analysis.
Eur J Neurosci 2005;22:735-44.
Minet-Ringuet J, Even PC, Goubern M, Tomé D, de Beaurepaire R. Long term treatment
with olanzapine mixed with food in male rats induces body fat deposition with no
increase in body weight and no thermogenic alteration. Appetite 2006;46:254-62.
Miyamoto S, Duncan GE, Marx CE, Lleberman JA Treatments for schizophrenia: a criticai re­
view of pharrnacology and mechanisms ofaction of antipsychotic drugs. Mol Psychiatry
2005;10:79-104.
Ohno Y, Okano M, lmaki J, Tatara A, Okumura T, Shimizu S. Atypical antipsychotic properties
of blonanserin, a novel dopamine D2 and 5-HT2A antagonist Pharmacol Biachem
Behav 2010;9:421-6.
Peluso MJ, Lewis SW, Barnes TRE, Jones PB. Extrapyramidal motor side-effects of first­
and second-generation antipsychotic drugs. Br J Psychiatry 2012;200:387-92.
Pothakos K, Kurz MJ, Lau Y. Restorative effect ofendurance exercise on behavioral deficits
in the chronic mouse model of Parkinson's disease with severe neurodegeneration.
BMC Neurosci 2009; 10:6.
Pouzet B, Mow T, Kreilgraad M, Velschow S. Chronic treatment with antipsychotic in rats
as a model for antipsychotic-induced weight gain in human. Pharmacol Biochem
Behav 2003;75:133-40.
Putzhammer A, Perfahl M, Píeiff L, Hajak G. Gait disturbances in patients with schizophrenia
and adaptation to treadmill walking. Psychiatry Clin Neurosci 2005;59:303-10.
Teixeira A, Muller LG, Reckziegel P, Boufleur N, Pase CS, Villarinho JG, et ai. Beneficial
effects of an innovative exercise model on motor and oxidative disorders induced
by haloperidol in rats. Neuropharmacology 2011 ;60:432-8.
Uitti RJ. Treatment of Parkinson's disease: focus on quality of life issues. Parkinsonism
Related Ois 2012; 18S1:S34-6.
Vasconcelos SMM, Nascimento SV, Nogueira RA, Vieira CMAG, Sousa FCF, Fonteles
MMF, et ai. Effects of haloperidol on rats behavior and density of dopaminergic
D2-like receptors. Behav Process 2003;63:45-52.
Vianna MRM, Alonso M, Viola H, Quevedo J, de Paris F, Furman M, et ai. Role ofhippocampal
signaling pathways in long-term memory formations of a nonassociative leaming task
in the rat Leam Mem 2000:333-40.
Wu YN, Chen llJ, Zhang LQ. Hyland BI. Regulation of hind-limb tone by adenosine A2A
receptor in rats. Neuroscience 2009;159:1408-13.
Yoon MC, Shin MS, Kim TS, Kim BK, Ko IG, Sung YH, et ai. Treadmill exercise suppresses
nigrostriatal dopaminergic neuronal loss on 6--hidroxydopamine-induced Parkinson's
rats. Neurosci Lett 2007;423:12-7.