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Influence of aversive stimulation on haloperidol-induced
catalepsy in rats
Nayara C.B. Barroca
a,b
, Mariana D. Guarda
c
, Naiara T. da Silva
c
,
Ana C. Colombo
a,b
, Adriano E. Reimer
a,b
, Marcus L. Brandão
a,b
and
Amanda R. de Oliveira
a,b,c
Catalepsy –an immobile state in which individuals fail to
change imposed postures –can be induced by haloperidol.
In rats, the pattern of haloperidol-induced catalepsy is very
similar to that observed in Parkinson’s disease (PD). As
some PD symptoms seem to depend on the patient’s
emotional state, and as anxiety disorders are common in
PD, it is possible that the central mechanisms regulating
emotional and cataleptic states interplay. Previously, we
showed that haloperidol impaired contextual-induced alarm
calls in rats, without affecting footshock-evoked calls. Here,
we evaluated the influence of distinct aversive stimulations
on the haloperidol-induced catalepsy. First, male Wistar rats
were subjected to catalepsy tests to establish a baseline
state after haloperidol or saline administration. Next,
distinct cohorts were exposed to open-field; elevated plus-
maze; open-arm confinement; inescapable footshocks;
contextual conditioned fear; or corticosterone
administration. Subsequently, catalepsy tests were
performed again. Haloperidol-induced catalepsy was
verified in all drug-treated animals. Exposure to open-field,
elevated plus-maze, open-arm confinement, footshocks, or
administration of corticosterone had no significant effect on
haloperidol-induced catalepsy. Contextual conditioned fear,
which is supposed to promote a more intense fear,
increased catalepsy over time. Our findings suggest that
only specific defensive circuitries modulate the nigrostriatal
system mediating the haloperidol-induced
cataleptic state. Behavioural Pharmacology 30:229–238
Copyright © 2019 Wolters Kluwer Health, Inc. All rights
reserved.
Behavioural Pharmacology 2019, 30:229–238
Keywords: catalepsy, dopamine, fear/anxiety, haloperidol,
Parkinson’s disease, rat, stress
a
Institute of Neuroscience and Behavior (INeC),
b
Department of Psychology,
University of São Paulo (USP), Ribeirão Preto and
c
Department of Psychology,
Federal University of São Carlos (UFSCar), São Carlos, Sao Paulo, Brazil
Correspondence to Amanda R. de Oliveira, PhD, Department of Psychology,
Federal University of São Carlos (UFSCar), km 235 Washington Luís Rd, 13565-
905 São Carlos, Sao Paulo, Brazil
E-mail: aroliveira@ufscar.br
Received 14 May 2018 Accepted as revised 28 November 2018
Introduction
Antipsychotics are drugs that are used clinically in the treat-
ment of schizophrenic symptoms that act by altering dopa-
minergic receptor signaling (Creese et al., 1976; Reynolds,
1992). Besides the clinical effects, some antipsychotic drugs
can induce unwanted extrapyramidal side effects such as
parkinsonism, akathisia, and acute dystonia by blocking striatal
dopaminergic D2 receptors (Reynolds, 1992; Kane and
Freeman, 1994; Wadenberg et al., 2001; Porsolt et al., 2013). In
rodents, haloperidol –one of the most widely used anti-
psychotics –can induce catalepsy, a state of bradykinesia and
rigidity in which individuals fail to correct externally imposed
postures (De Ryck et al., 1980; Sanberg, 1980; Wadenberg
et al., 2001; Vasconcelos et al., 2003). Drug-induced catalepsy
in rodents has been used to determine differences in potency
and extrapyramidal effects of putative antipsychotics during
the drug discovery phase (Sanberg et al., 1988; Lorenc-Koci
et al., 1996; Wadenberg et al., 2001). This drug-induced
cataleptic state also provides a simple and useful animal
model for investigating the motor impairments often observed
in Parkinson’s disease (PD) and the antiparkinsonian potential
of drugs (Sanberg et al., 1988; Lorenc-Koci et al., 1996; Trevitt
et al., 2009; Greco et al., 2010; Duty and Jenner, 2011; Ionov
and Severtsev, 2012).
PD is a progressive neurodegenerative disorder manifested
by a broad spectrum of motor and nonmotor symptoms.
Tremor at rest, rigidity, postural instability, and bradykinesia
are the most common motor symptoms (Parkinson, 2002;
Jankovic, 2008b; Broen et al., 2016). Some motor symptoms
of PD may be dependent on the emotional state of the
patient. For example, paralyzed patients can react and make
quick movements in externally driven or urgent situations.
This phenomenon, called paradoxical kinesia, suggests that
despite having a relatively intact motor function, PD
patients present difficulties in accessing motor programs
without an external trigger, such as a loud noise or an
important visual cue (Flowers, 1978; Bloxham et al., 1984;
Glickstein and Stein, 1991; Jankovic, 2008b; Melo-Thomas
and Thomas, 2015).
Nonmotor symptoms are also common in PD. Although
aspects related to disturbed emotional processing in PD
patients have attracted more attention in recent years
(Moonen et al., 2017), it is still an under-appreciated feature
Research report 229
0955-8810 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/FBP.0000000000000462
Copyright r2019 Wolters Kluwer Health, Inc. All rights reserved.
of PD, even with the possibility of becoming as disabling as
the motor deficit (Jankovic, 2008b; Broen et al., 2016). For
example, anxiety disorders are more prevalent in PD than
in non-PD individuals (Walsh and Bennett, 2001;
Leentjens et al., 2008; Broen et al., 2016; Dissanayaka et al.,
2010, 2016), with a positive correlation between the motor
performance and anxiety state being described (Siemers
et al., 1993). This suggests that pathological anxious states
should be considered in the diagnosis and treatment of PD
patients as they can have a marked effect on motivation and
rehabilitation (Siemers et al., 1993; Walsh and Bennett,
2001; Dissanayaka et al., 2010). In fact, it is still not clear
whether the increased anxiety is a reaction to the distress
caused by the motor symptoms or a byproduct of the
neurochemical changes of PD itself.
Dopamine deficiency in the nigrostriatal pathway is the
major neurochemical abnormality in PD, but a neuronal
loss in the ventral tegmental area (which gives rise to the
dopaminergic mesocorticolimbic pathway) has also been
verified (Walsh and Bennett, 2001; Remy et al., 2005;
Jankovic, 2008b; Martinez et al., 2013; Blaszczyk, 2017).
Considering the involvement of the dopaminergic
mesocorticolimbic pathway in the processing and
regulation of fear/anxiety-related responses (de Oliveira
et al., 2006, 2009, 2011, 2014), it is possible that this
deterioration leads to the elevated vulnerability of PD
patients to anxiety disorders. Given the emotional
influence on the motor aspects of PD (Glickstein and
Stein, 1991; Jankovic, 2008b; Peron et al., 2012) and the
high prevalence of anxiety symptoms in PD patients
(Walsh and Bennett, 2001; Dissanayaka et al., 2010;
Broen et al., 2016), it is possible that dopaminergic
mechanisms that regulate emotional states and cataleptic
states interplay.
The role of dopaminergic mechanisms in the regulation of
adaptive responses to threatening situations seems to
depend on the type of the aversive or stressful stimuli
triggering the coping reaction (Brandão et al., 2003, 2015).
Dopaminergic D2 antagonists, for instance, decrease con-
ditioned fear expression when administered systemically
or into the basolateral amygdala (de Oliveira et al.,2006,
2011; de Souza Caetano et al., 2013), but increase both the
switch-off response when systemically injected (Reis et al.,
2004) and defensive behaviors in the elevated plus-maze
(EPM) test when administered into the inferior colliculus
(de Oliveira et al., 2014). It appears that conditioned fear
seems to recruit tegmento-amygdalar and tegmento-
accumbal dopaminergic pathways (Martinez et al.,2008;
de Oliveira et al., 2011). Dopaminergic mediation of
unconditioned fear, however, may be associated with
dopaminergic projections to more caudal structures in the
brainstem (de Oliveira et al., 2014; Muthuraju et al.,2014).
The dual role of dopamine-mediating fear and anxiety
through distinct pathways and brain areas is, however,
less studied in the context of the cataleptic states. In this
context, previous studies suggest an association between
fear/anxiety and catalepsy in rodents (Russell et al., 1987;
Melo et al., 2010; Colombo et al., 2013; Melo-Thomas and
Thomas, 2015; Medeiros et al., 2016). Previously, we
analyzed the effects of haloperidol-induced catalepsy on
the emission of 22 kHz alarm calls during the catalepsy,
open-field (OF), and contextual conditioned fear tests
(Colombo et al., 2013). Although haloperidol had no
effects on fear-related measures immediately after
administration, or when rats were subjected to the OF
test or inescapable footshocks, it prevented the emission
of alarm calls during re-exposure to the aversive context.
In a subsequent study, intraperitoneal (i.p.) administra-
tion of haloperidol inhibited fear-potentiated startle, but
increased the auditory-evoked potentials in the inferior
colliculus (Muthuraju et al., 2014). In this case, the effects
seem to be dissociated from the motor impairments
induced by haloperidol as they were also observed with
subcataleptic doses, as well as following local injections of
this drug into the inferior colliculus, which do not cause
catalepsy (Melo et al., 2010).
The current study aimed to evaluate the influence
of diverse aversive stimulations on haloperidol-induced
catalepsy in rats. For this purpose, distinct groups of ani-
mals were exposed to (a) OF, (b) EPM, (c) confinement in
an open arm of EPM, (d) inescapable footshocks, (e) con-
textual conditioned fear, or (f) administration of corticos-
terone. The catalepsy test consisted of placing the animal
in an unusual posture, with the forepaws over an elevated
horizontal bar, and the measurement of time spent to
correct this posture (Kuschinsky and Hornykiewicz, 1972;
Sanberg et al., 1988). The OF and EPM were used here to
induce a conflict situation generated by the antagonism
between the instinctive tendency to explore a novel
environment and to avoid open/bright spaces (Walsh and
Cummins, 1976; Pellow et al., 1985). Significantly more
fear-related behaviors are observed when rats are confined
to an open arm of the EPM, suggesting that it is a more
intenseaversivestimulusthanfreeexposuretotheEPM
(Pellow et al., 1985; Salome et al., 2006). With the con-
textual conditioned fear model, two independent motiva-
tional systems are activated –one related to pain (triggered
by footshocks and generating behaviors that include
jumping and escape attempts) and the other related to
anxiety (activated by the context-CS and inducing mainly
freezing response) (Bolles and Collier, 1976; Bolles and
Fanselow, 1980; Pezze and Feldon, 2004). Finally, corti-
costerone administration was used because either innate or
conditioned fear stimuli cause the activation of the
hypothalamic–pituitary–adrenocortical axis, which leads to
the release of corticosterone in rodents, and has been
considered a key part of the stress reaction (Mason, 1968;
McEwen et al., 1969; Albrechet-Souza et al., 2007; de
Oliveira et al., 2013, 2017).
230 Behavioural Pharmacology 2019, Vol 30 No 2&3
Copyright r2019 Wolters Kluwer Health, Inc. All rights reserved.
Methods
Subjects
Two-hundred and forty-five naive male Wistar rats
weighing on average 250 g were used. The rats were
housed in groups of four per cage (polypropylene boxes,
40 ×33 ×26 cm), under a 12/12 h light/dark cycle (lights on
at 07:00 h), at 23–25°C, with constant access to food and
water. Before the experiments, the animals were allowed
to habituate to the laboratory conditions for at least 48 h.
Experiments were conducted during the light phase of the
cycle. All procedures were carried out in accordance to the
National Council for Animal Experimentation Control and
were approved by the Committees for Animal Care and
Use of University of São Paulo (protocol number
11.1.308.53.9) and Federal University of São Carlos (pro-
tocol number 6185150915). At the end of the experiments,
the animals were euthanized by CO
2
.
Drugs
Haloperidol was obtained in a commercial form for intra-
venous use (5 mg/1 ml ampoules; Janssen Pharmaceutica,
Belgium or Teuto, Brazil) and was diluted in physiological
saline (0.9%) shortly before use to obtain concentrations of
0.5 and 1.0 mg/ml. Saline was also used for control injec-
tions. Haloperidol and saline were administered 15 min
before the first catalepsy test. Corticosterone (Sigma-
Aldrich, St Louis, Missouri, USA) was dissolved in etha-
nol (10%), and then diluted in saline shortly before use to
obtain concentrations of 3.0 and 6.0 mg/ml. Control groups
received an equivalent volume of saline with ethanol (10%
–vehicle). Corticosterone and vehicle were administered
after the third catalepsy test. All drugs were administered
i.p. in a constant volume of 1 ml/kg body weight. The
drugs doses and injection time were based on previous
studies (Vasconcelos et al., 2003; Melo et al., 2010;
Colombo et al., 2013; de Oliveira et al., 2013).
Haloperidol-induced catalepsy test
The rats were tested for catalepsy 15, 30, 45, 60, and/or
75 min after saline or haloperidol administration. During
the interval between catalepsy tests, the animals
remained in their home cages. The catalepsy test con-
sisted of carefully positioning the animal’s forepaws on a
horizontal acrylic bar (8 cm above the floor), while their
hind paws were kept on the floor (Colombo et al., 2013).
The cataleptic behavior is recognized as the failure to
correct externally imposed postures; thus, the duration of
catalepsy was measured as the latency to step down from
the horizontal bar. The maximum time allowed to the
animals to remain on the bar was fixed at 10 min.
Experiment 1: effects of open-field exposure on
haloperidol-induced catalepsy
Rats were subjected to an OF test, which is considered a
mild aversive stimulus because of exposure to an open
and bright space. The OF consisted of a circular arena
made of transparent Plexiglass (60 cm in diameter and
50 cm height). Rats were subjected to the catalepsy test
15 and 30 min after haloperidol 1.0 mg/kg or saline
treatment. Next, rats were placed in the middle of the
OF and left for a 30-min period. After the OF exposure,
rats were subjected twice to the catalepsy tests (60 and
75 min after haloperidol or saline injection). Distinct
groups of animals, which served as nonexposed control-
groups, were subjected to the catalepsy test at the same
times, but were not subjected to the OF test.
Experiment 2: effects of elevated plus-maze exposure on
haloperidol-induced catalepsy
To analyze the influence on haloperidol-induced cata-
lepsy of another mild aversive stimulus, distinct groups of
animals were exposed to an EPM. The EPM was made
of wood and comprised two open and opposing arms
(50 ×10 cm each) and two closed arms (50 ×10 ×40 cm
each) also opposing each other, arranged perpendicular to
the open arms forming the shape of a cross. The EPM
was raised 50 cm from the floor. Before the EPM test, rats
were subjected to the catalepsy test 15 and 30 min after
haloperidol 0.5 mg/kg or saline treatment. Then, rats
were placed in the EPM and left for a 5-min period to
explore freely. After the exposure, rats were subjected to
three more haloperidol-induced catalepsy tests (45, 60,
and 75 min after haloperidol or saline injection). Distinct
groups were subjected to the same catalepsy tests, but
were not exposed to the EPM (nonexposed controls).
Experiment 3: effects of confinement in the open arm of
the elevated plus-maze on haloperidol-induced
catalepsy
In this experiment, animals were confined to one open
arm of the EPM, which is considered a more intense
aversive stimulus than free exposure to the EPM, on the
basis of the unconditioned fear of high and open spaces.
Rats were first subjected to the catalepsy test 15 and
30 min after haloperidol 0.5 mg/kg or saline treatment.
Then, rats were confined in the open arm and left for a
5-min period. After the open arm exposure, rats were
subjected to three more haloperidol-induced catalepsy
tests (45, 60, and 75 min after haloperidol or saline
injection). Distinct groups of nonexposed rats were sub-
jected to the same catalepsy tests, but were not subjected
to the confinement on the EPM.
Experiment 4: effects of footshock exposure on
haloperidol-induced catalepsy
To analyze the influence of a more intense aversive
situation on catalepsy, distinct groups of animals were
exposed to footshocks. 15 and 30 min after the injection
of saline or haloperidol 1.0 mg/kg, rats were subjected to
a catalepsy test, followed by exposure to footshocks. The
rats were placed in a grid floor cage (45 ×26 ×24 cm) with
black acrylic side and back walls, a transparent acrylic
ceiling door and front wall, and 36 stainless-steel rods
(1 cm apart). It was connected to a microprocessor
Aversive stimulation and catalepsy Barroca et al. 231
Copyright r2019 Wolters Kluwer Health, Inc. All rights reserved.
(Insight Equipment, Brazil) to deliver shocks through the
cage floor by a constant current generator (Albarsh
Instruments, Brazil). The cage was enclosed in a sound-
attenuating wood chamber (64 ×53 ×48 cm). After a
habituation phase of 5 min, rats received 10 presentations
of 1 s, 0.6 mA footshocks, with a 30–90 s variable inter-
shock interval. Subsequently, animals were subjected to
three additional haloperidol-induced catalepsy tests (45,
60, and 75 min after haloperidol or saline injection).
Distinct nonexposed control groups were subjected to
the same catalepsy tests, but did not receive footshocks.
Experiment 5: effects of contextual conditioned fear on
haloperidol-induced catalepsy
Another aversive situation used was the contextual con-
ditioned fear, which consists of two sessions: training and
re-exposure. During the training session, rats were con-
ditioned to the context in the same cage and conditions
as those described for the previous experiment; 24 h
later, rats were re-exposed to the aversive context, but
without footshock presentation. Fifteen and 30 min after
the injection of saline or haloperidol 1.0 mg/kg, rats were
subjected to haloperidol-induced catalepsy test. After
the second catalepsy test, rats were exposed to the
aversive context for 10 min. Next, rats were subjected to
three additional haloperidol-induced catalepsy tests (45,
60, and 75 min after haloperidol or saline injection).
Nonexposed control rats were subjected to the same
training session and catalepsy tests, but were not re-
exposed to the aversive context.
Three additional groups of animals were used to test the
aversiveness of the footshocks and the efficacy of the
conditioning protocol used. One group (nonconditioned
group) received no footshocks on the training day. The
second group (different context-conditioned group) was
subjected to the same training procedure described
above, but exposed to a cage different from the one used
for training (cage measured 25 ×39 ×25 cm, with trans-
parent Plexiglas walls and floor). The last group (same
context-conditioned group) was subjected to the same
training and testing procedures described above, but
without any treatment.
Experiment 6: effects of corticosterone administration
on haloperidol-induced catalepsy
Intraperitoneal corticosterone injection was used as a
pharmacological tool to simulate the physiological effects
of a stressful situation as the increase in this hormone is
considered an important part of the organism’s response
to stress. Before the corticosterone injection, rats were
subjected to the catalepsy test 15, 30, and 45 min after
haloperidol 0.5 mg/kg or saline treatment. Then, the
animals received an i.p. injection of corticosterone (3.0 or
6.0 mg/kg) or vehicle. After the injection, rats were sub-
jected to two more haloperidol-induced catalepsy tests
(60 and 75 min after haloperidol or saline) to check
whether corticosterone influences catalepsy behavior.
Data analysis
Data are presented as mean ±SEM. For all experiments,
two-way analysis of variance (ANOVA) with repeated
measures was used. Significant comparisons were tested
using the Newman–Keuls post-hoc test. The significance
level was set at Pvalue less than 0.05.
Results
Haloperidol-induced catalepsy
Table 1 shows the mean latency to step down in the
catalepsy test for rats that received an i.p. injection of
saline, 0.5 mg/kg haloperidol, or 1.0 mg/kg haloperidol,
and were not exposed to any aversive situation (non-
exposed groups). Two-way repeated measures ANOVA
indicated a significant effect of treatment (F
2, 101
=61.56,
P<0.05), time (F
4, 385
=30.94, P<0.05), and a significant
treatment ×time interaction (F
8, 385
=9.96, P<0.05). The
Newman–Keuls post-hoc test showed an overall increase
in the latency to step-down the bar 30, 45, 60, and 75 min
after the administration of haloperidol (0.5 and 1.0 mg/kg)
in relation to the same group at 15 min after administra-
tion (P<0.05). An increase in the latency to step-down
the bar was also observed 30, 45, 60, and 75 min after
administration of haloperidol in relation to the saline-
treated group at the respective time point (P<0.05).
Haloperidol 0.5 mg/kg-treated rats had higher catalepsy
latencies 45, 60, and 75 min after administration than the
group itself at 30 min (P<0.05). A higher catalepsy
Table 1 Latency to step down in the catalepsy test for rats that received an intraperitoneal injection of saline, 0.5 mg/kg haloperidol, or
1.0 mg/kg haloperidol and remained in the home cage (nonexposed groups)
Catalepsy (s)
15 min 30 min 45 min 60 min 75 min
Saline 17.38 ±5.93 14.13 ±2.53 10.38 ±2.21 28.69 ±6.69 24.81 ±6.34
Haloperidol 0.5 mg/kg 57.10 ±23.59 149.90 ±33.56*
,#
271.28 ±38.64*
,#, +
270.76±37.87*
,#, +
307.59 ±38.79*
,#, +
Haloperidol 1.0 mg/kg 68.81 ±20.51 241.00 ±32.74*
,#,&
225.76 ±37.30*
,#
273.96 ±35.62*
,#
281.00 ±37.71*
,#
Results are expressed as mean ±SEM. n=27–48 per group.
*P<0.05, different from the saline group at the same time.
&
P<0.05, different from the halo 0.5 group at the same time.
#
P<0.05, different from the same group at 15 min.
+
P<0.05, different from the same group at 30 min.
232 Behavioural Pharmacology 2019, Vol 30 No 2&3
Copyright r2019 Wolters Kluwer Health, Inc. All rights reserved.
latency at 30 min after administration was also observed
for the haloperidol 1.0 group in relation to haloperidol
0.5 mg/kg (P<0.05).
Experiment 1: effects of open-field exposure on
haloperidol-induced catalepsy
Figure 1a shows the data for latency to step down during
the catalepsy test in rats that received an i.p. injection of
1.0 mg/kg haloperidol and were exposed or not to the OF
aversive stimulus. Two-way repeated-measures ANOVA
indicated a significant effect of time (F
3, 105
=21.10,
P<0.05), but no significant effect of stress (F
1, 35
=1.21,
NS) or stress ×time interaction (F
3, 105
=0.70, NS). The
Newman–Keuls post-hoc test showed an overall
enhancement in the latency to step down from the bar
30, 60, and 75 min after drug administration in relation to
15 min after administration (P<0.05).
Experiment 2: effects of elevated plus-maze exposure on
haloperidol-induced catalepsy
Figure 1b shows the data for step-down latency during
the catalepsy test in rats that received 0.5 mg/kg halo-
peridol and were exposed or not to the EPM. Two-way
repeated-measures ANOVA indicated a significant effect
of time (F
4, 144
=13.76, P<0.05), but no significant effect
of stress (F
1, 36
=0.10, NS) or stress ×time interaction
(F
4, 144
=0.46, NS). The Newman–Keuls post-hoc test
showed an overall enhancement of step-down latency 30,
45, 60, and 75 min after drug administration in relation to
15 min after administration (P<0.05). A higher catalepsy
latency was also observed 45, 60, and 75 min after
administration than at 30 min (P<0.05).
Experiment 3: effects of confinement in the open arm of
the elevated plus-maze on haloperidol-induced
catalepsy
Figure 1c shows step-down latency during the catalepsy
test in rats that received an i.p. injection of 0.5 mg/kg
haloperidol and were confined in the open arm of the
EPM. Two-way repeated-measures ANOVA indicated a
significant effect of time (F
4, 148
=15.67, P<0.05), but no
significant effect of stress (F
1, 37
=0.38, NS) or stress ×
time interaction (F
4, 148
=0.63, NS). The Newman–Keuls
post-hoc test indicated an overall enhancement in step-
down latency 45, 60, and 75 min after drug administration
in relation to 15 and 30 min after administration (P<0.05).
Experiment 4: effects of footshocks exposure on
haloperidol-induced catalepsy
Figure 2a shows the latency to step down from the bar
during the catalepsy test in rats that received 1.0 mg/kg
haloperidol and were exposed to footshocks. Two-way
repeated-measures ANOVA indicated a significant effect
of time (F
4, 130
=17.32, P<0.05), but no significant effect
of stress (F
1, 35
=1.07, NS) or stress ×time interaction
(F
4, 130
=1.36, NS). The Newman–Keuls post-hoc test
showed that step-down latency was higher 30, 45, 60, and
75 min after drug administration in relation to 15 min
after administration (P<0.05). A higher catalepsy latency
was also observed 60 and 75 min after administration than
at 30 min (P<0.05).
Fig. 1
0
150
300
450
600
Open-field
Catalepsy (s)
halo-NE
halo-OF
(a)
# # #
0
150
300
450
600
Elevated plus-maze
Catalepsy (s)
halo-NE
halo-EPM
(b)
+
#
+
#
+
#
+
#
+
#
+
#
#
0
150
300
450
600
Open-arm confinement
Minutes post treatment
Catalepsy (s)
halo-NE
halo-OA
(c)
15 30 60 75
15 30 45 60 75
15 30 45 60 75
Influence of open-field, elevated plus-maze or open-arm confinement on
haloperidol-induced catalepsy. (a) Latency to step down in the catalepsy
test in rats that received an intraperitoneal injection of 1.0 mg/kg
haloperidol and were subjected to the open-field (OF) or remained in
the home cage (nonexposed –NE). (b) Latency to step down in rats that
received 0.5 mg/kg haloperidol and were exposed to the elevated plus-
maze (EPM) or remained in the home cage (N E). (c) Latency to step
down in rats that received 0.5 mg/kg haloperidol and were confined to
the open arm (OA) of the EPM or remained in the home cage (NE).
#
P<0.05, different from 15 min;
+
P<0.05, different from 30 min.
Aversive stimulation and catalepsy Barroca et al. 233
Copyright r2019 Wolters Kluwer Health, Inc. All rights reserved.
Experiment 5: effects of contextual conditioned fear on
haloperidol-induced catalepsy
Figure 2b shows the data for latency to step down during
the catalepsy test in rats that received an i.p. injection of
1.0 mg/kg haloperidol and were exposed to contextual
conditioned fear. Two-way repeated-measures ANOVA
indicated a significant effect of time (F
4, 118
=17.30,
P<0.05) and a significant stress ×time interaction
(F
4, 118
=2.98, P<0.05), but no significant effect of stress
(F
1, 32
=1.33, NS). Nonexposed rats showed higher cat-
alepsy latency 30, 45, 60, and 75 min after administration
than at 15 min after administration (P<0.05). Context-
exposed rats had higher catalepsy latencies 45, 60, and
75 min after administration at 15 and 30 min (P<0.05).
More importantly, a significant increase in catalepsy was
observed for the group exposed to the contextual con-
ditioned fear test in comparison with nonexposed rats
75 min after the administration of haloperidol (P<0.05).
No significant difference was observed between the
context-exposed group and the nonexposed rats at any
other time after the administration of haloperidol.
Table 2 shows the mean freezing response for additional
groups of rats that received no footshocks on the training
day (nonconditioned), rats that received footshocks, but
were tested in a cage different from the one used for
training (different context-conditioned group), and rats
subjected to the training and testing procedures in the
same cage (same context-conditioned group). One-way
ANOVA showed a significant effect of conditioning on
the freezing response (F
2, 21
=46.86, P<0.05). The
Newman–Keuls post-hoc test showed that the same-
context-conditioned group froze more than the non-
conditioned and different context-conditioned groups
(P<0.05) and that the different context-conditioned
group froze more than the nonconditioned animals
(P<0.05), confirming the efficacy of the conditioning
protocol used.
Experiment 6: effects of corticosterone administration
on haloperidol-induced catalepsy
Figure 3 shows the latency to step down from the bar
during the catalepsy test in rats that received an i.p.
injection of 0.5 mg/kg haloperidol and an i.p. injection of
corticosterone (3.0 or 6.0 mg/kg). Two-way repeated-
measures ANOVA indicated a significant effect of time
(F
4, 172
=13.02, P<0.05), but no significant effect of
stress (F
2, 43
=1.13, NS) or stress ×time interaction
(F
8, 172
=0.20, NS). The Newman–Keuls post-hoc test
showed an overall higher step-down latency 30, 45, 60,
and 75 min after administration in relation to 15 min after
administration (P<0.05). A greater duration of catalepsy
was also observed 45, 60, and 75 min after administration
than at 30 min (P<0.05).
Discussion
On the basis of clinical reports that the patient’s emo-
tional state could influence the motor symptoms of PD
(Glickstein and Stein, 1991; Jankovic, 2008a, 2008b;
Peron et al., 2012), as well as the common occurrence of
anxiety disorder comorbidity in PD patients (Walsh and
Bennett, 2001; Dissanayaka et al., 2010; Broen et al.,
2016), it is important to characterize how PD and anxiety
are related. Considering the motor impairments caused
by haloperidol in rats as an animal model for PD
(Lorenc-Koci et al., 1996), there is great interest in
investigating the interplay between aversive emotional
states and haloperidol-induced catalepsy (Melo et al.,
Fig. 2
0
150
300
450
600
Footshocks
Catalepsy (s)
halo-NE
halo-FS
*
(a)
+
#
+
#
#
#
0
150
300
450
600
Contextual Fear
Minutes post treatment
Catalepsy (s)
halo-NE
halo-CTX
(b)
##
#
##
##
+
+
+
*
15 30 45 60 75
15 30 45 60 75
Influence of footshocks or contextual conditioned fear on haloperidol-
induced catalepsy. (a) Latency to step down in the catalepsy test in rats
that received an intraperitoneal injection of 1.0 mg/kg haloperidol and
received footshocks (FS) or remained in the home cage (nonexposed
control –NE). (b) Latency to step down in rats that received 1.0 mg/kg
haloperidol and were re-exposed to the shock context cage (CTX) or
remained in the home cage (NE). *P<0.05, different from the halo/NE
group at the same time;
#
P<0.05, different from the same group at
15 min;
+
P<0.05, different from the same group at 3 0 min.
Table 2 Mean freezing response for rats subjected to contextual
conditioned fear under three different conditions
Freezing (s)
Nonconditioned 47.87 ±7.8 3
Different context 184.37 ±34.60*
Same context 4 04.75 ±28.59*
,#
Results are expressed as mean ±SEM. n=8 for all groups.
*P<0.05, different from the nonconditioned group.
#
P<0.05, different from the different context-conditioned group.
234 Behavioural Pharmacology 2019, Vol 30 No 2&3
Copyright r2019 Wolters Kluwer Health, Inc. All rights reserved.
2010; Muthuraju et al., 2014). Although we have inves-
tigated previously how haloperidol-induced catalepsy
could affect emotional states (Colombo et al., 2013), here,
we did the opposite: we shifted our focus on the influ-
ence of emotional states on catalepsy. We hypothesized
and confirmed that distinct aversive stimulations differ-
entially influenced the haloperidol-induced catalepsy,
probably by activating distinct structures of the defensive
neurocircuitry. Whereas re-exposure to an aversive con-
text previously associated with inescapable footshocks
exacerbated catalepsy, exposure to the OF, EPM, open-
arm confinement, or footshocks had no effect on the
cataleptic state. The administration of corticosterone also
had no influence on haloperidol-induced catalepsy.
In agreement with a substantial body of evidence, cata-
lepsy was the main overt effect produced by haloperidol
(De Ryck et al., 1980; Lorenc-Koci et al., 1996; Ozer et al.,
1997; Colombo et al., 2013). Haloperidol-induced cata-
lepsy is widely known to be caused by the blockade of
postsynaptic striatal D2 receptors (Sanberg, 1980;
Wadenberg et al., 2001). In the present study,
haloperidol-induced catalepsy was verified in all drug-
treated animals, irrespective of the exposure to the
aversive situations. Rats treated with haloperidol 0.5 and
1.0 mg/kg showed significant catalepsy from 30 min up to
75 min after treatment. Haloperidol 0.5 mg/kg, while
causing catalepsy in the same way as haloperidol 1.0 mg/
kg from 45 min of administration, seems to have a higher
latency to reach its peak effect, exerting a significantly
lower cataleptic effect than haloperidol 1.0 mg/kg at
30 min.
Exposure to the OF and EPM, two tests used to evaluate
the conflict generated by the tendency to explore a novel
environment and to avoid open/bright spaces, did not
affect the cataleptic profile irrespective of whether the
rats received haloperidol at doses of 0.5 (EPM) or 1.0 mg/
kg (OF). On the basis of the observation that, in the OF
and EPM, rats spent most of the time exploring the
periphery/closed arms, which reflects the aversion of the
open spaces (Montgomery, 1955; Pellow et al., 1985;
Treit et al., 1993), and that the motor impairment caused
by haloperidol led to a reduced number of crossings in
the OF and entrances in the EPM arms (data not shown),
we conducted an experiment in which the rat could not
avoid the open space. Again, no significant effect of stress
exposure was observed between the group confined to
the open arm of the maze and the nonexposed control
group. Therefore, the present results did not adduce
evidence that the aversiveness of new/open spaces could
influence haloperidol-induced catalepsy in rats, leaving
this issue open to further investigation.
In our next approach, we used a contextual conditioned
fear protocol, in which two distinct motivational systems
are recruited: one associated with a mild pain (elicited by
footshocks) and another more closely related to anxiety
(context re-exposure) (Bolles and Collier, 1976; Bolles
and Fanselow, 1980; Pezze and Feldon, 2004). Under our
experimental conditions, footshocks did not seem to
strongly influence haloperidol-induced catalepsy. Only a
mild and statistically nonsignificant increase in catalepsy
could be observed for the footshock-exposed animals
compared with the pre-footshock condition and the
nonexposed control group.
Re-exposure to the aversive context, however, caused a
significant increase in catalepsy in relation to the 30 min
pre-exposure condition. No increase in catalepsy was
observed for nonexposed controls. More importantly, the
catalepsy lasted significantly longer for the haloperidol
group exposed to the aversive context compared with the
nonexposed group, particularly 75 min after drug
administration. Therefore, our data indicate that the
conditioned fear exerted some influence on the cataleptic
state. We confirmed that the conditioning protocol used
in this study was effective in increasing freezing response
in animals re-exposed to the aversive context, similar to
other studies that have consistently used the aversive
contextual conditioning as a way to elicit defensive
responses in rodents (Davis, 1990; Pezze and Feldon,
2004; de Souza Caetano et al., 2013).
Specific brain structures and neural circuits seem to
respond differently according to the nature of the stimuli
to which the individual is exposed (Brandão et al., 2003,
2005, 2015). This can be understood in the context of the
two-dimensional theory of defense proposed by
McNaughton and Corr (2004), which states that fear and
anxiety are mapped as a function of a rostrocaudal gra-
dient in the brain, with the former engaging more caudal
and the latter more rostral neural structures. Extending
this theory, the recruitment of dopaminergic mechanisms
Fig. 3
Minutes post treatment
0
150
300
450
600
Corticosterone
Catalepsy (s)
halo-NE
halo-CORT3
halo-CORT6
#
#+#+#+
15 30 45 60 75
Influence of corticosterone administration on haloperidol-induced
catalepsy. Latency to step down in the catalepsy test in rats that
received an intraperitoneal injection of 0.5 mg/kg haloperidol and an
intraperitoneal injection of 3.0 mg/kg (CORT3) or 6.0 mg/kg
corticosterone (CORT6).
#
P<0.05, different from 15 min;
+
P<0.05,
different from 30 min. N E, nonexposed.
Aversive stimulation and catalepsy Barroca et al. 235
Copyright r2019 Wolters Kluwer Health, Inc. All rights reserved.
during adaptive responses to threatening situations also
seems to depend on the type of aversive stimulus, for
example for unconditioned or conditioned stimuli
(Brandão et al., 2015). In fact, the classic literature shows
that subcataleptic doses of dopaminergic antagonists
selectively suppress conditioned avoidance behavior
while not altering escape from footshocks (Cook and
Weidley, 1957; Miller et al., 1957; Posluns, 1962; Arnt,
1982).
In general, in anatomically more rostral structures, such as
the amygdala, dopaminergic neurotransmission seems to
mediate the expression of conditioned fear responses,
whereas in more caudal structures, such as the inferior
colliculus, dopaminergic activity would regulate the
expression of unconditioned fear (Pezze and Feldon,
2004; de Oliveira et al., 2009, 2011, 2014; Brandão et al.,
2015). Colombo et al. (2013) found that only conditioned
fear responses were altered by the haloperidol-induced
cataleptic state, whereas unconditioned responses
remained unaffected. Also, Muthuraju et al. (2014)
showed that the administration of haloperidol reduced
conditioned fear (fear-potentiated startle test), probably
by acting in rostral neural substrates, but increased
unconditioned fear (auditory evoked potential test) by
blocking D2 receptors in the inferior colliculus. These
results are consistent with our present data, in which
unconditioned and conditioned aversive stimuli differ-
entially affected haloperidol-induced catalepsy.
Stressful experiences are often associated with the acti-
vation of the hypothalamic–pituitary–adrenocortical axis,
leading to elevations of adrenal steroid secretion.
Recognizing the role of corticosteroids as a direct
response to stress (Joels and Baram, 2009; de Quervain
et al., 2017), as well as their involvement in the mod-
ulation of emotional behavior and interactions with
dopaminergic activity (de Oliveira et al., 2013, 2014), we
also examined the effect of corticosterone administration.
No effect of corticosterone on catalepsy was observed for
any of the doses, compared with the control nonexposed
group, which does not allow us to infer a direct influence
of corticosterone concentration on cataleptic behavior in
our experimental conditions. In contrast to this result,
subcutaneous administration of corticosterone (1 or 2 mg/
kg) 30 min before the administration of haloperidol, or
when the haloperidol-induced catalepsy score was max-
imal, attenuated the catalepsy without producing any
effect per se (Chopde et al., 1995). Thus, it is evident that
specific aspects of the manipulation, such as route and
time of administration and/or dosage used, can influence
the effects of corticosterone on haloperidol-induced
catalepsy.
Although several studies have shown an association
between anxiety and increased motor symptoms in the
clinic, others failed to show this type of relationship
(Dissanayaka et al., 2010). This highlights the importance
of research on anxiety-PD comorbidity, as well as rein-
forcing the need to identify anxiety symptoms when
treating PD patients. In general, the results presented
here can be associated with clinical descriptions showing
that anxiety in PD is linked to aggravation of motor
symptoms, greater difficulty in walking and dyskinesias,
and immobility (Siemers et al., 1993; Leentjens et al.,
2008).
We should consider, however, the limitation of our
experimental design for studying aspects related to the
paradoxical kinesia phenomenon, particularly regarding
the occurred when the aversive exposure happened.
Clinically, paradoxical kinesia is described as the fast and
accurate responding of patients in the face of an external
stimulus during an episode of immobility (Jankovic,
2008b; Melo-Thomas and Thomas, 2015). In our study,
the aversive stimuli were presented before the catalepsy
test rather than at the same time and, as a result, the
aversive exposure seems to increase the immobility
rather than promoting movement. In fact, in an ongoing
study, the presentation of a brief aversive stimulation
during the catalepsy test seems to disrupt the cataleptic
state, which is more in line with the paradoxical kinesia
phenomenon (Isabelle Waku, Amanda R. de Oliveira,
unpublished data). Previously, Keefe et al. (1989) showed
that nigrostriatal dopamine-depleted cataleptic rats swam
effectively when placed in deep water and escaped suc-
cessfully from a shallow floating ice bath. These beha-
viors were not blocked by haloperidol, suggesting that
other circuits might be engaged during paradoxical
kinesia. Further evidence showed that haloperidol-
induced catalepsy is reduced by microinjections of
NMDA antagonists or deep brain stimulation of the
inferior colliculus, suggesting that this structure may be
one relevant target for manipulations aiming at a better
understanding of paradoxical kinesia (Melo et al., 2010;
Melo-Thomas and Thomas, 2015).
There are reports of haloperidol-induced catalepsy last-
ing for up to 180 min (Morelli and Di Chiara, 1985; Greco
et al., 2010). Some studies have shown that there is a
learning component to the catalepsy produced by dopa-
mine antagonists, so that the duration of catalepsy pro-
duced by haloperidol could be prolonged by retesting
(Sanberg et al., 1988; Klemm, 1989). This retesting sen-
sitization effect has been explored more in the context of
chronic treatment with haloperidol (Barnes et al., 1990;
Schmidt et al., 1999; Amtage and Schmidt, 2003). Under
these circumstances, however, the effects also seem to
depend on the sensitization of dopaminergic receptors
induced by the chronic administration, rather than being
a solely learning-dependent effect. Here, using a single
administration, for the nonexposed haloperidol-treated
groups, we found differences between the latter (45, 60,
and/or 75 min) versus initial test timepoints (15 and
30 min), rather than a gradual increase across test
repetitions. Therefore, these results could be better
236 Behavioural Pharmacology 2019, Vol 30 No 2&3
Copyright r2019 Wolters Kluwer Health, Inc. All rights reserved.
interpreted by the pharmacokinetics of haloperidol rather
than by a retesting effect. Klemm (1989) also suggest that
even saline-control animals may show an unusual cata-
leptic state as the tests are repeated. For our saline
groups, only a minor nonsignificant increase could be
observed in the step-down latency with re-exposure to
the catalepsy test. Although limited, haloperidol-induced
catalepsy remains a recurrent, simple, and effective ani-
mal model of PD (Lorenc-Koci et al., 1996; Duty and
Jenner, 2011; Peron et al., 2012).
Conclusion
In general, our data point to a possible potentiating effect
of fear/anxiety states on haloperidol-induced catalepsy
that seems to be linked to the nature of the aversive
situation. An important finding was that only the expo-
sure to contextual conditioned fear increased haloperidol-
induced catalepsy compared with the nonexposed
control. It is possible that only certain aversive stimuli
can influence the haloperidol-induced cataleptic state,
presumably because only specific defensive circuitries
modulate the nigrostriatal system mediating the
haloperidol-induced catalepsy. However, the specific
nature of these mechanisms and how they interact
remain to be clarified. Indeed, a recent review by
Moonen et al. (2017) highlights the fact that, although
some studies show a more generalized altered emotional
function in PD patients and others report no change at
all, the majority show specific deficits related to intense
emotional stimulation.
Acknowledgements
This work was supported and funded by FAPESP (Proc.
2013/19280-3, 2016/05544-7, 2016/13141-0, and 2016/04620-
1) and CNPq (Proc. 401032/2016-7).
Conflicts of interest
There are no conflicts of interest.
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