farmacologia

1. Behavioural Brain Research 298 (2016) 241–245
Contents lists available at ScienceDirect
Behavioural Brain Research
journal homepage: www.elsevier.com/locate/bbr
Behavioural sensitisation to MK-801 is dose-dependent and
independent of environmental context
Emilia M. Lefevrea
, Darryl W. Eylesa,b
, Thomas H.J. Burnea,b,∗
a
Queensland Brain Institute, The University of Queensland, St Lucia, QLD 4072, Australia
b
Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Richlands, QLD 4076, Australia
h i g h l i g h t s
• Repeated exposure to the NMDA receptor antagonist MK-801 induced locomotor sensitisation in male Sprague Dawley rats.
• Sensitisation to MK-801 was dose-dependent.
• MK-801 induced sensitisation was not affected by the environmental context in which drug exposure occurred.
a r t i c l e i n f o
Article history:
Received 18 September 2015
Received in revised form 6 November 2015
Accepted 10 November 2015
Available online 28 November 2015
Keywords:
Sensitisation
MK-801
NMDA receptor
Environmental context
Animal model
Schizophrenia
a b s t r a c t
The pathophysiology of schizophrenia is associated with disturbed glutamate signalling, particularly
via a dysfunction of the N-methyl-d-aspartate (NMDA) receptor. In rodents, behavioural sensitisation
to the NMDA receptor antagonist MK-801 is proposed to recapitulate aspects of the NMDA receptor
hypofunction hypothesis of schizophrenia. The aim of this study was to determine the modulatory role
of MK-801 dose and environmental context on the development and expression of MK-801-induced
behavioural sensitisation. Sprague Dawley rats were administered saline or varying doses of MK-801
(i.p.) once daily for 7 days and locomotor activity was recorded. After 5 days of withdrawal, rats were
challenged with their respective dose to test for sensitisation. From this experiment a sensitising dose was
obtained. In the second experiment the magnitude of sensitisation was compared between rats that were
treated in either a home or test environmental context. Rats treated with 0.25 mg/kg MK-801 developed
robust sensitisation when challenged after withdrawal. Rats treated with lower (0.1 mg/kg) or higher
(0.5 mg/kg) doses of MK-801 did not develop locomotor sensitisation. Sensitisation to 0.25 mg/kg MK-801
developed equally between rats treated in the home or test context. The study shows that male Sprague
Dawley rats develop behavioural sensitisation to repeated injections of MK-801. The development of
sensitisation is selective to MK-801 dose in an inverted-U dose response fashion. In this paradigm MK-
801 induced sensitisation was expressed similarly between groups treated in two distinct environmental
contexts.
© 2015 Elsevier B.V. All rights reserved.
1. Introduction
When rodents are exposed to a drug in a repetitive and inter-
mittent paradigm, the response to the drug can be augmented
after its withdrawal. This phenomenon, termed behavioural sen-
sitisation, occurs with many drugs of abuse, including cocaine,
amphetamine, morphine, ethanol, nicotine and MK-801 [27]. Drug
sensitisation is divided into two key phases, induction and expres-
sion, which are mediated by distinct anatomical and neurochemical
substrates [24]. The induction of sensitisation refers to the neuro-
∗ Corresponding author at: Queensland Brain Institute, The University of Queens-
land, St Lucia, Qld 4072, Australia. Fax: +61 7 3346 6301
E-mail address: t.burne@uq.edu.au (T.H.J. Burne).
logical changes that develop with repeated drug exposure, whereas
the expression of sensitisation is characterized as the enhanced
response to a drug challenge following a period of drug absti-
nence [17]. Behavioural sensitisation in laboratory rodents has been
used to model disorders, such as schizophrenia and drug addiction
[29].
Animal models of behavioural sensitisation have predominately
focused on the psychostimulants amphetamine and cocaine, and
have led to a substantial understanding of the neural mecha-
nisms involved in this phenomenon. Furthermore, the impact
of factors such as pattern of administration, drug dosage and
environmental context on modulating the onset of tolerance or
sensitisation to these commonly abused stimulants have been
extensively characterised. For example, continuous intravenous
http://dx.doi.org/10.1016/j.bbr.2015.11.014
0166-4328/© 2015 Elsevier B.V. All rights reserved.

2. 242 E.M. Lefevre et al. / Behavioural Brain Research 298 (2016) 241–245
cocaine administration in rodents has been shown to induce
tolerance to the behavioural effects of cocaine, whereas intermit-
tent intraperitoneal administration led to behavioural sensitisation
[8,26,18]. Furthermore, higher levels of drug intake appear to
induce tolerance and lower levels induce sensitisation [8].
Sensitisation to a number of drugs, such as amphetamine,
cocaine, morphine and nicotine, is facilitated by environmental
context [5]. It is consistently reported that sensitisation to drugs
of abuse is modulated by environmental context. Rodents display
a greater sensitisation when repeated drug administration occurs
in a context-paired environment (novel test cage) compared to
drug administration occurring in a context-unpaired environment
(home cage) [2–4]. Studies also report context-paired drug admin-
istration produces a conditioned response when a saline injection
is given in the drug-associated context [23,2,21]. Therefore, con-
textual conditioning is proposed to have an enhancing effect on
locomotor sensitisation to drugs of abuse.
Few studies have investigated MK-801 (non-competitive
N-methyl-D-aspartate (NMDA) receptor antagonist)-induced
behavioural sensitisation. However, MK-801-induced behavioural
sensitisation in rodents is proposed to recapitulate aspects of
the NMDA receptor hypofunction hypothesis of schizophrenia,
warranting further investigation using this agent. In order to
investigate the neural mechanisms of MK-801 sensitisation,
and its potential relevance to schizophrenia, it is first critical to
characterize external factors that may modulate sensitisation.
Studies examining the effect of MK-801 on methamphetamine
[19] or morphine-induced [16] behavioural sensitisation give an
indication to the role of drug dose on the development or expres-
sion of MK-801 sensitisation. In a paradigm used to induce
methamphetamine sensitisation, mice repeatedly injected with
MK-801 every few days were shown to develop a progressive tol-
erance to a high dose of MK-801 (1 mg/kg), locomotor sensitisation
with an intermediate dose (0.3 mg/kg) and no behavioural change
with a low dose of MK-801 (0.1 mg/kg) [19]. Although this study did
not demonstrate whether this dose response holds true subsequent
to drug withdrawal, Jeziorski et al. [16] reported the expression
of behavioural sensitisation was evident in rats after 5 days with-
drawal from repeated daily (7–10) administrations of 0.25 mg/kg
but not 0.1 mg/kg MK-801. No studies to date have examined the
role of environmental context on the development and expression
of MK-801 induced sensitisation. The modulatory effect of envi-
ronmental context is thought to involve associative learning via
activation of the NMDA receptors [12]. It is therefore hypothesised
that the use of a drug that antagonizes NMDA-receptors may not
be affected by environmental context.
The purpose of this report was to determine the modulatory role
of drug dose and environmental context on the development and
expression of MK-801 induced sensitisation. The first experiment
manipulated the doses of MK-801 in the sensitisation paradigm.
We identified an inverted-U dose response in the development
of behavioural sensitisation, whereby only one dose was suffi-
cient to induce sensitisation. The dose that induced sensitisation
was selected to assess whether MK-801-induced sensitisation was
dependent on environmental context. This was achieved by treat-
ing separate groups of rats in one of two environments during the
induction phase.
2. Methods and materials
2.1. Animals
Adult (70 days of age) male Sprague Dawley rats (ARC, WA,
Australia) were pair housed and allowed at least 1-week habitua-
tion to the homeroom. Rats were kept on a constant 12 h light/dark
cycle (light phase 0600-1800) with food and water ad libitum. All
testing was conducted during the light phase between 0800 and
1700 h (room temperature 24 ◦C, 50% humidity). All procedures
were performed with the approval from The University of Queens-
land Animal Ethics Committee, under the guidelines of the National
Health and Medical Research Council of Australia.
2.2. Apparatus
Locomotor activity was assessed with Ethovision auto-
mated video tracking software (Noldus Information Technology,
Wageningen, Netherlands). The experimental context consisted of
black Perspex chambers (45 × 45 × 60 cm) illuminated by a central
LED strip (17 lux). Data was collected via a centrally placed video
camera (Vivotek) situated above the chamber. The apparatus were
located in a behavioural testing room, separate to the housing room.
All chambers were cleaned with 70% ethanol after each test.
2.3. General procedure and drugs
Except when otherwise stated in the following sections, the
same experimental protocol was used to induce and test the
behavioural sensitisation to MK-801 in male Sprague Dawley rats.
The general sensitisation paradigm was similar to protocols utilised
by Yang et al. [35] and Jeziorski et al. [16]. The behavioural sensitisa-
tion paradigm consists of three key phases; induction, withdrawal
and expression. The induction phase involved once-daily injections
for 7 consecutive days in the test cage. Over the 5-day withdrawal
phase, rats were left untreated in their home cages. On Day 13 of
the behavioural paradigm, the expression of locomotor sensitisa-
tion was observed by challenging rats with MK-801 in the test cage.
Each experimental day, rats were weighed in their homeroom. They
were then moved to the experimental room and allowed a 30 min
acclimation period. Rats were placed individually into a test cage.
After a 30 min period of habituation to the test cage, rats were
injected with either saline or MK-801. MK-801 has an elimination
half life in plasma and brain of 1.9 and 2.05 h, respectively [30].
MK-801 induced locomotor activity lasts approximately 2–3 h [1];
therefore MK-801 induced locomotor activity was recorded for 3 h
post-injection. MK-801 (Sigma) was dissolved in 0.9% saline solu-
tion. Injections were administered at 1 ml/kg via the intraperitoneal
(i.p.) route in all experiments.
2.4. Experiment 1: dose-dependent effects on MK-801 induced
sensitisation
The first experiment was designed to determine at which dose
MK-801 induces behavioural sensitisation in male Sprague Daw-
ley rats. The rats were divided into four dose treatment groups
(n = 7–8/group). The four treatment groups were saline, low dose
MK-801 (0.1 mg/kg), intermediated dose MK-801 (0.25 mg/kg) and
high dose MK-801 (0.5 mg/kg). The dose used within each group
remained constant between the induction and expression phases.
Behavioural sensitisation paradigms to other stimulant drugs may
often use a lower dose for challenge. Due to the hyperlocomotor
inducing effects of MK-801 occurring within a tight range win-
dow [1], a lower dose challenge was not ideal in this paradigm.
This design has previously been implemented in other research
inducing MK-801 locomotor sensitisation [32,35,31].
2.5. Experiment 2: effect of environmental context on MK-801
induced sensitisation
Experiment 2 aimed to test whether the behavioural sensiti-
sation to MK-801 (0.25 mg/kg) in Sprague Dawley male rats was
altered by environmental context. Saline and MK-801-treated rats

3. E.M. Lefevre et al. / Behavioural Brain Research 298 (2016) 241–245 243
0 0.1 0.25 0.5
0
100
200
300
400
500
MK-801 Dose (mg/kg)
Distance
Travelled
(m/3hr)
Induction (Day 1)
Expression (Day 13)
*
#
30 60 90 120 150 180
0
20
40
60
80
Time Post Injection (min)
Distance
travelled
(m)
Saline
MK-801 (0.1mg/kg)
MK-801 (0.25mg/kg)
MK-801 (0.5mg/kg)
*
*
* *
*
*
*
*
*
A B
Fig. 1. The effect of dose on MK-801 induced behavioural sensitisation. (A) Acute response (±SEM) to increasing doses of MK-801 (0, 0.1, 0.25 and 0.5 mg/kg) on day
1 of induction. Rats were injected with saline or MK-801 after a 30 min habituation period to the novel environment. A steep dose–response curve to the locomotor
stimulating effects of MK-801. p < 0.01 significantly different to saline controls. (B) Comparison of total distance travelled over the 180 min post-injection testing period
(mean response ± SEM post-injection) on Day 1 of induction (white bars) and Day 13 at expression (dark grey bars). *p < 0.05 significantly different between test days.
#p < 0.05 significantly different from the saline control group.
were subdivided into two context groups (n = 20/group); home and
test. During the induction phase the test group received the 7 daily
injections in the test chamber as described above. The home group
however, received the same 7 daily injections in the homeroom and
were placed immediately back into their home cage after injection.
On Day 13, both context groups were placed in the test cage and
challenged with MK-801 (0.25 mg/kg). Experiment 2 also exam-
ined whether repeated administration of MK-801 (0.25 mg/kg) in
the test cage produces a conditioned response upon re-exposure
subsequent to withdrawal. This phenomenon has previously been
observed in sensitisation to other stimulant drugs. A simultaneous
separate cohort was also treated with saline or MK-801 under home
or test conditions (n = 8/group). On Day 13, all rats were challenged
with a saline injection in the test cage to assess for a conditioned
response.
2.6. Statistical analysis
Statistical comparisons on the total distance travelled were
made using mixed subjects ANOVA. MK-801 treatment and envi-
ronmental context pre-treatment served as between-subjects
factors. Day served as a within-subjects factor.
The presence of sensitisation from Day 1 to Day 13 was com-
puted using repeated measures ANOVA. A Bonferroni correction
was used to control for multiple comparisons where appropriate. A
Pearson correlation analysis was performed for locomotor activity
on Day 1 and Day 13. Statistical significance was set at p < 0.05. All
data are reported as mean ± SEM. Statistical analyses were made
using the SPSS statistics (version 20) program.
3. Results
3.1. Experiment 1: dose-dependent effects on MK-801 induced
sensitisation
Male Sprague Dawley rats were administered either saline or
one of three doses of MK-801 (0.1, 0.25 and 0.5 mg/kg) once daily
for 7 days. Subsequent to a 5-day period of abstinence, rats were
re-exposed to the same dose of saline or MK-801. On Day 1, a sig-
nificant effect of MK-801 dose on locomotor activity was observed
(F(3,28) = 8.8, p < 0.01). The highest dose, 0.5 mg/kg, elicited hyper-
locomotion compared to saline (Fig. 1a,b). Neither of the lower
doses (0.1 and 0.25 mg/kg) significantly increased locomotor activ-
ity on the first day of induction. To determine the presence of
sensitisation, repeated measures ANOVA was performed on the
total distance travelled between Days 1 and 13 (Fig. 1b) of testing
revealing a main effect of dose (F(3,27) = 5.16, p = 0.006). Sensitisa-
tion defined as a significant increase in locomotor activity on Day
13 compared to Day 1, was only evident in rats treated with the
intermediate dose (0.25 mg/kg) of MK-801 (t6 = 2.5, p < 0.05). There
was a significant positive correlation (R2 = 0.84, p = 0.001) between
the acute response to 0.25 mg/kg MK-801 on Day 1 and the sen-
sitised response on Day 13. There was no significant increase (or
decrease) in locomotor activity from Day 1 to Day 13 in rats treated
with 0.1 mg/kg and 0.5 mg/kg MK-801 (Fig. 1b). This indicates that
neither locomotor sensitisation nor tolerance developed to these
doses of MK-801. Overall, the development of MK-801-induced
sensitisation displayed an inverted-U dose response. Therefore, the
subsequent experiment utilised only the 0.25 mg/kg dose of MK-
801 to investigate the role of environmental context.
3.2. Experiment 2: effect of environmental context on MK-801
induced sensitisation
The main aim of this experiment was to characterize the effect
environmental context had on the development of MK-801 induced
sensitisation. Rats received saline or MK-801 (0.25 mg/kg) injec-
tions in either the home or test environment during the induction
phase. At expression, all rats were challenged with MK-801 in the
test environment and locomotor activity assessed (Fig. 2a). Two-
way ANOVA revealed a significant effect of drug treatment (saline
vs. MK-801; F(1,76) = 5.23, p = 0.023). In contrast, there was no sig-
nificant main effect of environmental context and no significant
interaction between drug treatment and environmental context.
The expression of locomotor sensitisation to MK-801 was not sig-
nificantly different between MK-801 groups treated in either the
home or test environmental context (Fig. 2a).
It has been shown that repeated administration of drugs of abuse
potentiates the response to saline challenge given in the same envi-
ronment [21]. Thus, the secondary aim of this experiment was to
determine whether repeated MK-801 injections in the test cage
would enhance response to saline challenge and a second cohort
of rats was treated with saline or MK-801 in the home or test envi-
ronmental context during induction. At expression, this cohort was
instead challenged with saline in the text environment and loco-
motor activity assessed (Fig. 2b). The two-way ANOVA revealed
no significant main effects of drug treatment or environmental

4. 244 E.M. Lefevre et al. / Behavioural Brain Research 298 (2016) 241–245
Saline MK-801
0
100
200
300
400
500
Induction Treatment
Distance
Travelled
(m/3hr)
Sensitisation Test
(MK-801 0.25mg/kg)
Home
Test
*
Saline MK-801
0
100
200
300
400
500
Induction Treatment
Conditioning test
(Saline 1ml/kg)
Home
Test
Fig. 2. Effect of environmental context on the expression of MK-801 sensitisation.
(A) At the expression phase rats that were previously treated in the home (white
bars) or test (light grey bars) context were challenged with 0.25 mg/kg MK-801 to
test for sensitisation or (B) challenged with Saline to test for contextual conditioning.
*p < 0.05 compared to saline treated controls.
context and no significant interaction between the two. Sprague-
Dawley rats treated with MK-801 in the test cage did not produce a
conditioned response to saline challenge compared to either their
MK-801 treated home cage counterparts (Fig. 2b). Furthermore,
there was no difference in response to saline challenge between
rats treated with MK-801 or saline in the test environment.
4. Discussion
Our results show that adult male Sprague Dawley rats develop
behavioural sensitisation after repeated MK-801 exposure. Sensiti-
sation occurred when an intermediate dose of 0.25 mg/kg MK-801
was repeatedly injected. We found that using a lower or higher
MK-801 dose did not induce locomotor sensitisation, at least in the
current paradigm. The results of the second experiment demon-
strate that the expression of sensitisation to MK-801 was unaltered
between rats treated in two different environmental contexts. The
magnitude of locomotor sensitisation was similar between Sprague
Dawley rats receiving MK-801 treatment in the home or test cage
during the induction phase. To the best of our knowledge this is
the first study to assess whether MK-801 induced sensitisation is
modulated by environmental context.
In Experiment 1, we report a steep dose-response curve to
the acute locomotor stimulatory effects of MK-801 and this find-
ing was consistent with a multitude of acute MK-801 studies
[13,14,20,11,28]. This experiment also found the development
of sensitisation to MK-801 in Sprague Dawley rats showed an
inverted-U shape dose response curve, similar to what has been
reported in mice [19]. Kuribara et al. [19] demonstrated that in
the ddY mouse strain, an intermittent sensitisation paradigm only
resulted in locomotor sensitisation with an intermediate dose of
MK-801 (0.3 mg/kg), compared to low (0.1 mg/kg) or high (1 mg/kg)
doses. Furthermore, [16] reported that locomotor sensitisation
was observed in Sprague Dawley rats 5 days after repeated daily
(7–10 days) administrations of 0.25 mg/kg but not 0.1 mg/kg MK-
801. In the current study, repeated administration of 0.1 mg/kg or
0.5 mg/kg did not produce sensitisation, nor was there a significant
decrease in response to indicate the development of tolerance. This
would suggest tolerance was not a competing mechanism.
In the present study, we found no evidence that behavioural
sensitisation to MK-801 was dependent on or modulated by envi-
ronmental context. Firstly, rats treated with the sensitising dose
(0.25 mg/kg) of MK-801 in the home cage developed locomotor
sensitisation to the same extent as the rats treated in the test con-
text. Secondly, MK-801 sensitised rats did not display a conditioned
hyperlocomotor response to a saline challenge when re-exposed
to the drug-paired context. This study is the first to report a lack of
environmental dependency for MK-801 sensitisation and is consis-
tent with that described for sensitisation to another NMDA receptor
antagonist, PCP [9,34]. Taken together, these results suggest that
sensitisation to MK-801 is not influenced by the environmental
context in which the drug is administered, contrary to the literature
on behavioural sensitisation to other drugs of abuse.
A number of studies have demonstrated that environmen-
tal context modulates the susceptibility to sensitisation induced
by psychostimulant drugs including amphetamine, cocaine and
morphine [5]. Pairing the repeated drug exposure with a novel
context was found to further augment the sensitised response in
rodents compared to the drug treatment occurring in the home
cage. Although not completely understood, the modulatory role
of environmental context is thought to involve a number of fac-
tors including associative learning, as well as gene expression and
synaptic plasticity in brain regions associated with reward. Fur-
thermore, NMDA receptor activation is known to play a critical
role in context-dependent sensitisation [6,7] and contextual con-
ditioning [25,33]. For example, co-administration of MK-801 with
amphetamine during the induction phase was shown to specif-
ically attenuate the development of amphetamine sensitisation
in a context-dependent paradigm, without affecting sensitisation
in a context-independent paradigm [6]. Thus it would appear
that antagonism of the NMDA receptor abolishes contextual con-
ditioning. In mice, the development of behavioural sensitisation
to ethanol, an indirect NMDA receptor antagonist, was recently
reported to also be independent of environmental context [10]
as has been observed with the direct NMDA receptor antago-
nists MK-801 (present study) and PCP [9,34]. Overall, the absence
of environmental contextual modulation on MK-801 sensitisation
reported in this study is congruent with the literature.
In conclusion, the present report demonstrates that sensiti-
sation to repeated administrations of MK-801 in male Sprague
Dawley rats develops at selective doses. Sensitisation was only
observed with an intermediate MK-801 dose of 0.25 mg/kg,
whereas repeated injections of a lower dose (0.1 mg/kg) or higher
(0.5 mg/kg) produced neither sensitisation nor tolerance. In this
paradigm, behavioural sensitisation is not modulated by the envi-
ronmental context in which drug administration occurs. [15] first
suggested that long-term exposure to NMDA receptor antagonists
more qualitatively represented symptoms of schizophrenia com-
pared to acute exposure. In animals, withdrawal from repeated
NMDA receptor antagonist treatment has been proposed to present
with neurochemical, neuroanatomical and behavioural alterations
closely correlated to clinical observations of schizophrenia [22]. In
this study we have established a model of MK-801 induced sen-
sitisation incorporating both features of long-term exposure and
withdrawal. This model will be useful in future studies of putative
NMDA-mediated pathological mechanisms in schizophrenia and
can also be used to evaluate novel therapeutics.
Conflict of interest
The authors report no conflict of interest.
Acknowledgement
This work was supported by NHMRC project grant 1024239.
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