Marked inbred mouse strain difference in the expression of quinpirole induced compulsive like behavior based on behavioral pattern analysis

Article (PDF Available)inEuropean neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 22(9):657-63 · February 2012with45 Reads
DOI: 10.1016/j.euroneuro.2012.01.003 · Source: PubMed
Abstract
Obsessive-compulsive disorder (OCD) is a chronic and complex psychiatric disorder with a lifetime prevalence of 2-3%. Recent work has shown that OCD rituals were not only characterized by a high rate of repetition but also by an increased behavioral repertoire due to additional non-functional unique acts. These two behavioral characteristics may provide an ethological basis for studying compulsive behavior in an animal model of OCD. Here, quinpirole induced behavior (so far only investigated in rats) has been studied in A/J and C57BL/6J mice by using behavioral pattern analysis. The aim of this study is to investigate whether genetic background is mediating this behavior. Results showed that open field motor activity levels of saline treated C57BL/6J mice was significantly higher compared to A/J treated saline mice. Long-term quinpirole treatment increased open field motor activity levels in A/J, but not in C57BL/6J. Quinpirole treatment induced a strain dependent difference in behavioral repertoire. There was a dose dependent increase in the number of different behavioral patterns in A/J, whereas, in C57BL/6J there was a dose dependent decrease. This data suggest that genetic background is important in expressing quinpirole induced compulsive like behavior. Following quinpirole treatment, A/J mice express a greater behavioral repertoire with a high rate of repetition. This phenotype resembles that of OCD rituals in patients and indicates that this strain is very interesting to further validate for studying neurobiological mechanisms of compulsive behavior.
Marked inbred mouse strain difference in the
expression of quinpirole induced compulsive like
behavior based on behavioral pattern analysis
Ria de Haas
a, b,
, Amir Seddik
a
, Hugo Oppelaar
a
,
Herman G.M. Westenberg
b, 1
, Martien J.H. Kas
a
a
Department of Neuroscience and Pharmacology, UMC Utrecht, Rudolf Magnus Institute of Neuroscience, The Netherlands
b
Department of Psychiatry, UMC Utrecht, Rudolf Magnus Institute of Neuroscience, The Netherlands
Received 30 September 2011; received in revised form 25 November 2011; accepted 12 January 2012
KEYWORDS:
Obsessive compulsive
behavior
Animal model
T-pattern analysis
Quinpirole
Abstract
Obsessivecompulsive disorder (OCD) is a chronic and complex psychiatric disorder with a life-
time prevalence of 23%. Recent work has shown that OCD rituals were not only characterized
by a high rate of repetition but also by an increased behavioral repertoire due to additional
non-functional unique acts. These two behavioral characteristics may provide an ethological
basis for studying compulsive behavior in an animal model of OCD. Here, quinpirole induced be-
havior (so far only investigated in rats) has been studied in A/J and C57BL/6J mice by using be-
havioral pattern analysis. The aim of this study is to investigate whether genetic background is
mediating this behavior. Results showed that open field motor activity levels of saline treated
C57BL/6J mice was significantly higher compared to A/J treated saline mice. Long-term quinpir-
ole treatment increased open field motor activity levels in A/J, but not in C57BL/6J. Quinpirole
treatment induced a strain dependent difference in behavioral repertoire. There was a dose de-
pendent increase in the number of different behavioral patterns in A/J, whereas, in C57BL/6J
there was a dose dependent decrease. This data suggest that genetic background is important
in expressing quinpirole induced compulsive like behavior. Following quinpirole treatment, A/
J mice express a greater behavioral repertoire with a high rate of repetition. This phenotype re-
sembles that of OCD rituals in patients and indicates that this strain is very interesting to further
validate for studying neurobiological mechanisms of compulsive behavior.
© 2012 Elsevier B.V. and ECNP. All rights reserved.
Corresponding author at: UMC Utrecht, Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, Universiteitsweg 100, 3508 GA
Utrecht, The Netherlands. Tel.: +31 887568845; fax: +31 302129205.
E-mail address: G.G.deHaas-2@umcutrecht.nl (R. de Haas).
1
Prof. Dr. Herman Westenberg unexpectedly died on May 17th 2011.
0924-977X/$ - see front matter © 2012 Elsevier B.V. and ECNP. All rights reserved.
doi:10.1016/j.euroneuro.2012.01.003
www.elsevier.com/locate/euroneuro
European Neuropsychopharmacology (2012) xx, xxxxxx
NEUPSY-10465; No of Pages 7
Please cite this article as: de Haas, R., et al., Marked inbred mouse strain difference in the expression of quinpirole induced compulsive
like behavior based on behavioral pattern..., Eur. Neuropsychopharmacol. (2012), doi:10.1016/j.euroneuro.2012.01.003
1. Introduction
Obsessivecompulsive disorder (OCD) is a chronic and com-
plex psychiatric disorder with a lifetime prevalence of
23%. This disorder is accompanied by intrusive, unwanted
and recurrent thoughts or images (obsessions) and/or repet-
itive ritualistic behaviors (compulsions). Obsessions can be
related with the fear of being contaminated, with symmetry
or ordering. Compulsions can be hand washing, checking of
objects or locations or counting. These thoughts and ritualis-
tic behaviors become excessive, distressing and significantly
interfere with every day functioning. Recent work has shown
that behavior in OCD patients was characterized not only by
a high rate of repetition but also by addition of non-
functional unique acts, together referred to as pessimal be-
havior (Eilam et al., 2011; Zor et al., 2009a, 2009b). The ob-
served larger behavioral repertoire and higher rate of
repetition of behaviors may provide an ethological basis for
studying compulsive behavior in an animal model of OCD
(Eilam et al., 2011).
The underlying mechanism of OCD is still unknown. Suc-
cessful treatment in OCD patients with selective serotonin
re-uptake inhibitors (SSRI's) alone or in combination with
an atypical antipsychotic drug indicates a role of serotonin
and dopamine in the pathophysiology of OCD (Abudy et al.,
2011). Direct support for a role of dopamine also stems
from neuroimaging studies showing higher densities of the
dopamine transporter in tandem with a down regulation of
the D2 receptors in the basal ganglia of OCD patients.
These findings suggest a higher dopaminergic tone in this
brain circuitry (Westenberg et al., 2007).
Twin and family studies have provided convincing evi-
dence for the importance of genetic factors for the
expression of OCD. There is limited knowledge about patho-
physiological pathways and networks of interacting genes in
OCD also non-significant results from linkage and association
studies suggest it is too early to focus on specific candidate
genes associated with OCD. A genome wide association
study with a sufficient sized sample should be performed
to identify genomic regions containing promising candidate
genes (Pauls, 2010).
Animal models may be useful in unraveling genetic and
neurochemical underlying mechanisms of OCD; however
they are inappropriate to investigate the entire OCD spec-
trum (obsessions) but seem more than adequate for studying
forms of compulsivity.
The most studied animal models for OCD are; 8-OHDPAT
(8-hydroxy-2-(di-n-propylamino)-tetralin hydrobromide) in-
duced decreased alternation (Yadin et al., 1991),
quinpirole-induced compulsive checking (Szechtman et al.,
1998), marble burying (Gyertyan, 1995), signal attenuation
(Joel and Avisar, 2001) and spontaneous stereotypy in deer
mice (Korff et al., 2008; Powell et al., 1999).
Previously we have reported that long-term quinpirole
treatment induced behavior in rats mimicking only part of
the compulsive behavior as shown in OCD patients (de Haas
et al., 2011). Behavioral pattern analysis revealed that
quinpirole-induced behavior consisted, unlike OCD rituals,
of a smaller behavioral repertoire. However, similar as in
OCD patients, quinpirole treated rats performed these be-
haviors with a high rate of repetition.
In this study the effect of long-term quinpirole treatment
on behavior will be investigated in two different inbred
strains of mice. Mouse strains are widely used to study ge-
netic background effects due to the great variety and avail-
ability of resources. Previously, it has been reported that
there is a marked strain difference between C57BL/6J and
A/J mouse strains in expressing compulsive wheel running
during daily scheduled limited food access (Kas et al.,
2010). This behavior is assumed to be compulsive because
of the continuous and repetitive wheel running during the
2 h of food availability indicating the inability to stop this ac-
tivity despite the more appealing food (Altemus et al.,
1993). C57BL/6J developed high wheel running activity
prior to food access and when scheduled food restriction
prolonged they showed a strong suppression of wheel run-
ning during food availability. In contrast, A/J showed no
food anticipatory activity but did show high wheel running
levels during food availability. Thus, A/J seemed to be
more sensitive to develop compulsive-like behavior com-
pared to C57BL/6J.
The aim of this study is to investigate quinpirole-induced
behavior in A/J and C57BL/6J mice using behavioral pattern
analysis and specifically to investigate whether genetic
background is mediating this behavior. The hypothesis is
that after long-term quinpirole treatment A/J mice will be
more sensitive to develop compulsive-like behavior com-
pared to C57Bl/6J.
2. Experimental procedures
2.1. Animals
In this study female mice from two inbred mouse strains A/J and
C57BL/6J were used. Initial breeding pairs were obtained from
The Jackson Laboratory (Bar Harbor, ME, USA) and sustained in our
breeding facility. All female mice were socially housed under con-
trolled conditions (temperature 2021 °C and humidity 5070%)
with a 12-hour lightdark cycle. Food and water were given freely.
All mice were 34 months old at the start of the experiment. All ex-
periments were conducted during the light hours. The experimental
procedure was approved by the Animal Ethical Committee of
Utrecht University.
2.2. Experimental setup
At the arrival in the test room mice were injected with either quin-
pirole or saline. Immediately after the injection the animal was
placed in the middle of the open field. Quinpirole injections were
given twice a week for 4 consecutive weeks instead of 5 weeks pre-
viously used in rats. The behavior of mice was tracked for 50 min and
analyzed by EthoVison version 3.1 and Theme version 5.0 (Noldus In-
formation Technology B.V., Netherlands).
Each inbred mouse strain was divided in four treatment groups of
8 animals per group. The four treatment groups were; saline, quin-
pirole 1 mg/kg, quinpirole 3 mg/kg and quinpirole 6 mg/kg. Hereaf-
ter referred to as saline, QNP 1, QNP 3 and QNP 6 respectively.
2.3. Open field
In this study small adjustments were made concerning the experi-
mental procedure previously used for rats (de Haas et al., 2011).
The dimensions of the open field and its objects were adapted to
the size of the mice. The open field (80× 80 cm) was constructed
of PVC without walls and was placed 60 cm above the floor. The
2 R. de Haas et al.
Please cite this article as: de Haas, R., et al., Marked inbred mouse strain difference in the expression of quinpirole induced compulsive
like behavior based on behavioral pattern..., Eur. Neuropsychopharmacol. (2012), doi:10.1016/j.euroneuro.2012.01.003
test room was illuminated with indirect light. For analysis, the open
field was virtually divided in 25 zones. Four objects, all 4×4×4 cm in
size, were used as objects on the open field and located at fixed
places. There were two iron pyramids, a transparent PET house
and a PVC house (Fig. 1).
2.4. Drugs
Quinpirole (Tocris, UK) is a dopamine agonist with high affinity for
the D2 and D3 dopamine receptor subtypes. Quinpirole was dis-
solved in saline and administrated at doses 1, 3 or 6 mg/kg at a vol-
ume of 5 ml/kg and injected intraperitonially. Because this
experimental procedure was not yet described in mice, the three
doses for quinpirole were chosen based on previous rodent studies
using quinpirole (Fetsko et al., 2003; Gendreau et al., 1998;
Szechtman et al., 1998; Tammimaki et al., 2006).
2.5. Statistics
During the 50 min observation, mice will visit different zones in the
open field. The sum of all zone visits is called total frequency and is
a measure for motor activity levels (horizontal movement). In this
study open field activity was calculated as mean frequency of the
last two injections (7 and 8).
Behavioral pattern analysis results in a set of T-patterns which
are series of event types occurring at predictable time intervals
from each other. There were 25 different event types corresponding
to the 25 zones in the open field. Search parameters in Theme (ver-
sion 5.0, Noldus Information Technology Bv, Netherlands) were set
as follows; minimum occurrences =3, significance level =0.0001,
max search levels =99, lumping factor = 0.90, FARR = 90, fast-free
limit=99, exclude frequent event types, minimum samples and sim-
ulation samples were unselected. For theoretical details and expla-
nation of the T-pattern detection algorithm or Theme settings see
(Magnusson, 2000). Data from both mouse strains and all three
treatment groups from the 8th injection were used for Theme
analysis.
For statistical analysis within a strain a univariate analyses of
variance (ANOVA) was used followed with post-hoc t-testing (signif-
icance level; p =0.05) and between the two strains a two-way
analyses of variance (ANOVA) was used with two variables, strain
(A/J and C57BL/6J) and treatment (saline, QNP1, QNP3 and
QNP6), followed with post-hoc t-testing (significance level;
p=0.05).
3. Results
3.1. Strain dependent effects
Movement trajectories during the last injection of either saline,
QNP1, QNP3 or QNP6 are shown for a representative animal per
treatment group; the upper panel represents A/J mice and low-
er panel C57BL/6J mice (Fig. 2). Under saline conditions, A/J
mice had very low open field motor activity compared to
C57BL/6J. These open field motor activity levels were quanti-
fied as mean frequency of the last two injections, where fre-
quency was calculated as sum of all zone visits. Open field
motor activity levels of saline treated C57BL/6J mice was more
than 3 fold higher compared to A/J treated saline mice [two way
ANOVA; strain*treatment F = 4.706, p = 0.006; post-hoc t-test;
F=7.648, p=0.004] (Fig. 3).
Behavioral pattern analysis was performed on video tracking
data from the open field to further investigate two important
behavioral characteristics also found in OCD patients, namely
behavioral repertoire and rate of repetition. This analysis
was performed during the last injection for all treatment groups
of both mice strains. There was no difference in rate of repeti-
tion between the two strains under saline conditions [two-way
ANOVA; strain
*
treatment F = 0.332, p = 0.802] (Fig. 4A and B).
The different behavioral patterns found in both strains were
performed at the same frequency. However, there was a signif-
icant difference in the number of different behavioral patterns
found between the two saline groups. A/J mice showed a signif-
icant smaller behavioral repertoire compared to C57BL/6J [two-
way ANOVA; strain treatment F=12.796, p=0.0004; post-hoc
t-test; F = 12.374, p = 0.002] (Fig. 4C and D). Thus, under saline
conditions C57BL/6J mice had a higher open field motor activity
compared to A/J. Also the behavioral repertoire in C57BL/6J
was greater compared to A/J but rate of repetition was similar
between both strains.
3.2. Dose dependent effects
The effect of long-term quinpirole treatment (1, 3 or 6 mg/kg)
on mice behavior in the open field was compared to saline treat-
ment within each strain and between strains. Movement trajec-
tories of representative animals of each group are shown
(Fig. 2).
In A/J mice, long-term quinpirole treatment induced a dose-
dependent increase in open field motor activity levels [one-way
ANOVA; F=4.213, p = 0.018]; all three doses of quinpirole in-
duced a significant increase when compared to saline treatment
[post-hoc; p 0.05] ( Fig. 3A). Furthermore, after quinpirole
treatment, A/J mice visited a larger number of different zones
in the open field.
Saline treated C57BL/6J mice showed high open field activity
and extensive exploratory behavior. In this strain long-term
quinpirole treatment had no effect on open field motor activity
levels [one-way ANOVA; F=0.521, p = 0.672] (Fig. 3B). However,
exploratory pattern trajectories showed that the activity of
Fig. 1 The open field (80 × 80 cm) was constructed of PVC
without walls and was placed 60 cm above the floor. Four ob-
jects, all 4×4×4 cm in size, were used; two iron pyramids, a
transparent PET house and a PVC house.
3Mouse strain difference in the expression of quinpirole induced compulsive like behavior
Please cite this article as: de Haas, R., et al., Marked inbred mouse strain difference in the expression of quinpirole induced compulsive
like behavior based on behavioral pattern..., Eur. Neuropsychopharmacol. (2012), doi:10.1016/j.euroneuro.2012.01.003
C57BL/6J was now more focused within specific parts of the
open field.
A significant strain
*
treatment effect was seen, where A/J
mice showed a significant increase and C57BL/6J mice showed
no effect of quinpirole treatment on open field motor activity
levels [two-way ANOVA; strain
*
treatment F= 4.706, p=0.006].
There was a significant difference between the A/J and
C57BL/6J mice treated with 6 mg of quinpirole [post-hoc t-
test; F = 2.340, p =0.026].
Behavioral pattern analysis was conducted to provide addi-
tional quantitative insights in the complexity of behavior and
showed that the effect of long-term quinpirole treatment on
rate of repetition was similar in both strains. Quinpirole signifi-
cantly increased the rate of repetition in A/J by all three doses
[one-way ANOVA; F =5.239, p = 0.008], and in C57BL/6J by the
two lowest doses [one-way ANOVA; F=3.036, p = 0.049]
(Fig. 4A and B). There was no significant strain
*
treatment ef-
fect on rate of repetition seen [two-way ANOVA; strain
*
treat-
ment F = 0.332, p = 0.802].
The effect of quinpirole on behavioral repertoire was oppo-
site between the two strains [two-way ANOVA; strain
*
treat-
ment F =12.796, p = 0.0004]. There was a dose dependent
increase in the number of different behavioral patterns in A/J
[one-way ANOVA; F =4.783, p =0.011] (Fig. 4C). In contrast, in
C57BL/6J, there was a dose dependent decrease in behavioral
repertoire [one-way ANOVA; F=10.422, p = 0.0001] (Fig. 4D).
There was a significant difference between the A/J and
C57BL/6J mice treated with 6 mg of quinpirole [post-hoc t-
test; F = 4.594, p =0.015].
4. Discussion
Here we report the effect of long-term quinpirole treatment
in two different inbred mouse strains (C57BL/6J and A/J).
Previous studies in rats have shown that long-term quinpir-
ole treatment and exposure to a large open field
resulted in hyperactivity, and so-called, checking behav-
ior (Szechtman et al., 2001). Specifically, quinpirole treated
rats revisited two places/objects excessively often and rap-
idly, compared with other locations in the environment or
when compared to saline controls. The parameters used in
Fig. 2 Motor trajectories during the last injection of representative animals of each saline, QNP1, QNP3 and QNP6 groups per strain
are shown; the upper panel represents A/J mice and lower panel C57BL/6J mice.
Fig. 3 Open field motor activity levels are expressed as mean
frequency of the last two days, calculated as the sum of all zone
visits made in the open field. Values were expressed as mean
±standard error of the means. Significant differences within a
strain are indicated by * (p value0.05) and between strains
are indicated by
#
(p value 0.0125).
4 R. de Haas et al.
Please cite this article as: de Haas, R., et al., Marked inbred mouse strain difference in the expression of quinpirole induced compulsive
like behavior based on behavioral pattern..., Eur. Neuropsychopharmacol. (2012), doi:10.1016/j.euroneuro.2012.01.003
previous studies were based on locomotor activity and gave
less insight in behavioral patterns. Therefore, we have
reported the use of a new analysis method, called behavioral
pattern analysis, in this quinpirole induced checking be-
havior in rats (de Haas et al., 2011). Behavioral pattern anal-
ysis in SpragueDawley rats revealed that quinpirole-
induced behavior consisted, unlike OCD rituals in patients,
of a smaller behavioral repertoire. Similar as in OCD pa-
tients, quinpirole treated SpragueDawley rats performed
these behaviors with a high rate of repetition. Thus, only
part of the behavioral characteristics of OCD (repetition)
was seen in quinpirole induced behavior in this rat strain
(de Haas et al., 2011).
The aim of the present study was to investigate whether
different inbred strains of mice will develop similar repeti-
tive behavior after long-term quinpirole treatment as
shown in rats. By testing different inbred strains of mice, it
can be addressed whether genetic background mediates
the expression of this repetitive behavior following quinpir-
ole treatment.
First, open field motor activity levels were measured and
the saline groups of both strains were compared. There was
a significant strain difference in open field activity, where
A/J mice showed significant lower activity compared to
C57BL/6J. This result can be explained by the fact that it
is well known that A/J mice are more anxious compared to
other inbred strains of mice and show low motor activity
and exploration levels in the open field (Laarakker et al.,
2011; Lad et al., 2010).
Second, the effect of long term quinpirole treatment on
open field motor activity levels was compared between the
two strains. In A/J, open field motor activity levels in-
creased significantly after repeated quinpirole injections,
in contrast to C57BL/6J, where no such effect was observed.
This behavioral hyperactivity in A/J mice was consistent
with previous findings in rats (e.g., both species showed a
six-fold increase in motor activity levels when compared to
saline treatment). The reason why open field motor activity
in C57BL/6J was not affected by quinpirole treatment could
be due to the dose of quinpirole used which could be to low.
This seems very unlikely, since 6 mg/kg (the highest dose
tested) was the highest dose described in the literature for
mice. The group of Gendreau et al. showed in a social inter-
acting test that there was no effect of quinpirole treatment
with similar doses in C57BL/6J on locomotor reactivity. One
major difference between the two studies was the way of
injecting quinpirole where the present study made use of re-
peated long-term treatment and the Gendreau et al. study
used acute treatment.
Lastly, behavioral pattern analysis was conducted to pro-
vide additional quantitative insights in the complexity of be-
havior. Although open field motor activity levels did not
differ between the groups within the C57BL/6J strain, the
motor trajectories on the open field showed that the open
field motor activity of C57BL/6J treated with quinpirole
was now more focused within specific parts of the open
field compared to the saline condition. This effect of quin-
pirole on motor trajectories was also seen in Sprague Dawley
rats. In A/J mice the opposite occurred, under saline condi-
tion only specific places in the open field were visited; how-
ever, after long-term quinpirole treatment they became
hyperactive and visited most of all the zones in de open
Fig. 4 Rate of repetition is expressed as mean frequency of patterns, indicating on average how often one pattern is repeated. Be-
havioral repertoire is expressed as mean number of different patterns, indicating how many different patterns occur in their behav-
ior. Values were expressed as mean ± standard error of the means. Significant differences within a strain are indicated by * (p value
0.05) and between strains are indicated by
#
(p value 0.0125).
5Mouse strain difference in the expression of quinpirole induced compulsive like behavior
Please cite this article as: de Haas, R., et al., Marked inbred mouse strain difference in the expression of quinpirole induced compulsive
like behavior based on behavioral pattern..., Eur. Neuropsychopharmacol. (2012), doi:10.1016/j.euroneuro.2012.01.003
field. Behavioral pattern analysis revealed that the effect of
quinpirole on the rate of repetition is species- and strain in-
dependent. As in rats, long-term quinpirole treatment also
showed an increase in the rate of repetition in both mouse
strains. Whereas, the effect on the behavioral repertoire
was different between the two mouse strains, in A/J mice
there was a dose-dependent increase and in C57BL/6J a
dose dependent decrease. The increase in behavioral reper-
toire in A/J mice may be a direct consequence of the in-
creased activity levels in the open field motor activity
following quinpirole treatment. However, in a previous
study we have showed that quinpirole induced hyperactivity
in Sprague Dawley rats resulted in a decrease in behavioral
repertoire (de Haas et al., 2011). The findings indicate that
increased open field motor activity is not automatically
resulting in increased behavioral repertoire.
Thus, long-term quinpirole treatment in C57BL/6J mice
and SpragueDawley rats resulted in an increased repetition
and a decreased behavioral repertoire, indicating a more
stereotypic behavior instead of compulsive-like behavior.
Quinpirole treated A/J mice showed the same increase in
rate of repetition; in contrast, only A/J mice exhibited a sig-
nificant dose dependent increase in behavioral repertoire.
These findings indicated that quinpirole induced a species
and strain independent effect on behavior repetition. In ad-
dition, it induced an increase in behavioral repertoire in
mice that was dependent on mouse genetic background.
These features found in A/J resemble the behavioral pro-
file of OCD patients (Zor et al., 2009b). When using this quin-
pirole model as an inducer of compulsive-like behavior, A/J
mice are more sensitive to develop this compulsive like be-
havior compared to C57BL/6J. Indicating that genetic back-
ground is mediating the effect of quinpirole on repetitive
compulsive like behavior. This result is also in line with our
hypothesis based on previous work where A/J mice already
showed to be more sensitive to develop compulsive wheel
running during daily scheduled limited food access (Kas et
al., 2010).
In OCD patients the behaviors performed within a ritual
can be divided in functional and non-functional behavior
(Zor et al., 2009b). Functional behaviors are behaviors
expressed by OCD patients and healthy individuals and are
necessary to complete a certain task. Non-functional behav-
iors are expressed only by one of the two groups (mostly OCD
patients) and are not necessary to complete the task, for ex-
ample; touching, counting and checking. OCD patients
showed a higher number of non-functional behavior com-
pared to healthy individuals. It is quite difficult to distin-
guish functional and non-functional behavior in mice in the
behavioral paradigm used in this study. Future animal stud-
ies should address this issue of behavioral functionality
to further characterize the susceptibility to express
compulsive-like behavior in A/J mice.
In conclusion, this study showed that A/J mice are more
sensitive to develop compulsive behavior induced by long-
term quinpirole treatment compared to C57BL/6J. This sug-
gests that genetic background has an impact on the expres-
sion of quinpirole induced compulsive like behavior. A/J
mice express a greater behavioral repertoire and also a
high rate of behavioral repetition. These behavioral patterns
in A/J mice resembles that of OCD rituals in patients and in-
dicate that this strain is very interesting to further validate
for studying neurobiological mechanisms of compulsive
behavior.
Role of the funding source
This research received no specific grant from any funding agency in
the public, commercial, or not-for-profit sectors.
Contributors
Ria de Haas, Amir Seddik, Hugo Oppelaar, Herman Westenberg and
Martien Kas were involved in designing the study and interpretation
of the data. Data collection was performed by Ria de Haas, Amir
Seddik and Hugo Oppelaar, and was analyzed by Ria de Haas and
Amir Seddik. All authors contributed to and have approved the final
version of the manuscript (with the exception of Prof. Dr. Herman
Westenberg, who unexpectedly ceased away prior to submission of
this manuscript. We remember Herman Westenberg as a dedicated
scientist and an inspiring colleague).
Conflict of interest
All authors have no conflict of interest.
Acknowledgment
Not applicable.
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7Mouse strain difference in the expression of quinpirole induced compulsive like behavior
Please cite this article as: de Haas, R., et al., Marked inbred mouse strain difference in the expression of quinpirole induced compulsive
like behavior based on behavioral pattern..., Eur. Neuropsychopharmacol. (2012), doi:10.1016/j.euroneuro.2012.01.003
    • "Slitrk5 belongs to the same family of Slitrk1, a protein associated to TS. Dopamine, that has been largely associated to TS and ADHD, is supported by animal models findings to play a role in compulsive behaviors. The treatment with the DR2 agonist quinpirole in mice marks the expression of the behavioral repertoire and long-term exposure to this drug leads to hyperactivity in A/J mice (De Haas et al., 2012). In rats, chronic administration of the same compound causes compulsive checking (Szechtman et al., 1998; Alkhatib et al., 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Tourette’s syndrome (TS) is a neurodevelopmental disorder characterized by fluctuating motor and vocal tics, usually preceded by sensory premonitions, called premonitory urges. Besides tics, the vast majority – up to 90% - of TS patients suffer from psychiatric comorbidities, mainly attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). The etiology of TS remains elusive. Genetics is believed to play an important role, but it is clear that other factors contribute to TS, possibly altering brain functioning and architecture during a sensitive phase of neural development. Clinical brain imaging and genetic studies have contributed in elucidating TS pathophysiology and disease mechanisms; however, TS disease etiology still is poorly understood. Findings from genetic studies led to the development of genetic animal models, but they poorly reflect the pathophysiology of TS. Addressing the role of neurotransmission, brain regions and brain circuits in TS disease pathomechanisms is another focus area for pre-clinical TS model development. We are now in an interesting moment in time when numerous innovative animal models are continuously brought to the attention of the public. Due to the diverse and largely unknown etiology of TS, there is no single pre-clinical model featuring all different aspects of TS symptomatology. TS has been dissected into its key symptoms that have been investigated separately, in line with the Research Domain Criteria concept. The different rationales used to develop the respective animal models are critically reviewed, to discuss the potential of the contribution of animal models to elucidate TS disease mechanisms.
    Full-text · Article · Apr 2016
    • "The authors also suggest that, to provide information concerning the structure of the patterns, each stripe should be partnered with a table reporting all the terminal strings of the patterns represented in stripes. Another interesting application of T-pattern analysis in rodents has been recently proposed by a group from the Rudolf Magnus Institute to study quinpiroleinduced compulsive-like behavior (de Haas et al., 2011de Haas et al., , 2012). Results showed that, following drug administration, the animal performed a smaller behavioral repertoire and that, similarly to patients with obsessive–compulsive disorder, quinpirole-treated animals performed these behaviors with a high rate of repetition. "
    [Show abstract] [Hide abstract] ABSTRACT: A basic tenet in the realm of modern behavioral sciences is that behavior consists of patterns in time. For this reason, investigations of behavior deal with sequences that are not easily perceivable by the unaided observer. This problem calls for improved means of detection, data handling and analysis. This review focuses on the analysis of the temporal structure of behavior carried out by means of a multivariate approach known as T-pattern analysis. Using this technique, recurring sequences of behavioral events, usually hard to detect, can be unveiled and carefully described. T-pattern analysis has been successfully applied in the study of various aspects of human or animal behavior such as behavioral modifications in neuro-psychiatric diseases, route-tracing stereotypy in mice, interaction between human subjects and animal or artificial agents, hormonal-behavioral interactions, patterns of behavior associated with emesis and, in our laboratories, exploration and anxiety-related behaviors in rodents. After describing the theory and concepts of T-pattern analysis, this review will focus on the application of the analysis to the study of the temporal characteristics of behavior in different species from rodents to human beings. This work could represent a useful background for researchers who intend to employ such a refined multivariate approach to the study of behavior.
    Full-text · Article · Oct 2014
  • [Show abstract] [Hide abstract] ABSTRACT: The present study was designed to investigate the effect of pharmacological inhibition of endocannabinoid degradation on behavioural actions of the dopamine D2/D3 receptor agonist quinpirole in male C57Bl/6J mice. In addition, we studied the effects of endocannabinoid degradation inhibition on both cocaine-induced psychomotor activation and behavioural sensitization. We analysed the effects of inhibition of the two main endocannabinoid degradation enzymes: fatty acid amide hydrolase (FAAH), using inhibitor URB597 (1 mg/kg); monoacylglycerol lipase (MAGL), using inhibitor URB602 (10 mg/kg). Administration of quinpirole (1 mg/kg) caused a temporal biphasic response characterized by a first phase of immobility (0-50 min), followed by enhanced locomotion (next 70 min) that was associated with the introduction of stereotyped behaviours (stereotyped jumping and rearing). Pretreatment with both endocannabinoid degradation inhibitors did not affect the hypoactivity actions of quinpirole. However, this pretreatment resulted in a marked decrease in quinpirole-induced locomotion and stereotyped behaviours. Administration of FAAH or MAGL inhibitors did not attenuate the acute effects of cocaine. Furthermore, these inhibitors did not impair the acquisition of cocaine-induced behavioural sensitization or the expression of cocaine-induced conditioned locomotion. Only MAGL inhibition attenuated the expression of an already acquired cocaine-induced behavioural sensitization. These results suggest that pharmacological inhibition of endocannabinoid degradation might exert a negative feedback on D2/D3 receptor-mediated hyperactivity. This finding might be relevant for therapeutic approaches for either psychomotor disorders (dyskinesia, corea) or disorganized behaviours associated with dopamine-mediated hyperactivity.
    Full-text · Article · May 2012
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