Haloperidol and Clozapine Reverse MK-801-Induced Deficits in Hypoactivity, but Not the Impairment of Spatial Memory in Sprague-Dawley Rats
Blockade of the NMDA receptor by the use of MK-801 during the early postnatal
period has been proposed to be an experimental model which induces behavioural
changes that mimic positive, negative and cognitive symptoms of schizophrenia.
We provide an overview of the effects of early life MK-801 administration on
body weight, locomotor activity and spatial memory and assessed the long term
behavioural profile arising from this early life manipulation. We found that
intraperitoneal administration of MK-801 (0.35 mg kg-1) twice a day
for 2 weeks in rat pups on postnatal days 7, showed a significant weight loss,
hypoactivity and the damage of spatial memory. The long term behavioural profile
showed that hypoactivity continuously reduced until 11 weeks after MK-801 administration
in animal model. But for spatial memory, a short term damage was observed in
model rats. After the treatment with clozapine or haloperidol, a recovery in
locomotor activity was observed in the rats of model group. However, there was
no effect on the spatial memory in model rat after drug treatment. The results
of the present study demonstrated that clozapine and haloperidol might reverse
a long lasting hypoactivity induced by repeated treatment with MK-801 in neonatal
rats but no effect on a short term damage of spatial memory.
to cite this article:
Huanzhong Liu, Zhenhua Ren, Jian Zhong, Han Cai, Xuequan Chen and Jun Li, 2014. Haloperidol and Clozapine Reverse MK-801-Induced Deficits in Hypoactivity, but Not the Impairment of Spatial Memory in Sprague-Dawley Rats. International Journal of Pharmacology, 10: 120-128.
Received: March 03, 2014;
Accepted: May 10, 2014;
Published: June 09, 2014
Glutamate, an excitatory neurotransmitter that is abundantly distributed in
the central nervous system and is involved in memory processes through the N-Methyl-D-Aspartate
(NMDA) receptor (Riedel et al., 2003), a specific
type of ionotropic glutamate receptor (Pryce et al.,
2002). MK-801 is a selective, non competitive NMDA antagonist with a high
affinity for the NMDA receptor (Wong et al., 1986).
The synaptic organization takes place chiefly during the first 3 weeks of postnatal
life in rodents (Haberny et al., 2002) which
in humans extends from the sixth month of gestation to several years after birth.
During this period, particularly during postnatal days (PND) 7-14, the brain
is highly sensitive to the toxic effects of NMDA receptor modulation (Kocahan
et al., 2013). Blockade of NMDA receptor during early neonatal life
can cause long term alterations in the anatomical, neurochemical, neurophysiological
and behavioral properties of rodents (Viberg et al.,
2008). The use of NMDA receptor antagonists has since been extended to young
rodents during their early postnatal developmental period, characterising a
model which represents not only NMDA hypofunction but which is also consistent
with the neuro developmental component (Baier et al.,
2009). Rats exposed to non competitive NMDA receptor antagonists such as
MK-801 during the neonatal stage have been shown to elicit behavioral abnormalities
related to clinical symptoms of schizophrenia, such as sensorimotor gating deficits,
hyperactivity and social withdrawal in addition to spatial memory dysfunctions
(Hargreaves and Cain, 1992; Rung
et al., 2005; Manahan-Vaughan et al., 2008;
Gururajan et al., 2010).
Glutamatergic models have highlighted the role of the anterior cingulate and
other parts of the limbic system in the pathophysiology of schizophrenia (Theberge
et al., 2002). Despite a large body of research on behavioural profile,
such as, locomotor activity and spatial memory, the results were inconsistent
in the effects of neonatal repeated treatments of MK-801 in different dose.
Numerous studies carried out have failed to detect any long term consequences
on locomotor activity following early life MK-801 treatment (Stefani
and Moghaddam, 2005; Kawabe et al., 2007;
Uehara et al., 2009) and several references
in the available literature have provided evidence of either increases or decreases
in activity (Schiffelholz et al., 2004; Baier
et al., 2009). Early life MK-801 appears to result in impaired water
maze performance that is predominantly manifested only after maturity. Su
et al. (2011) observed a minor impairment in adolescent rats but a markedly
impaired performance in adulthood. However (McLamb et
al., 1990) did not detect any changes in water maze performance in adolescent
The dose and administration time of MK-801 may be main reason for inconsistent
results in behavioural profile of rats. Metabolic changes caused by MK-801 after
a single high dose (0.5 mg kg-1) (Brenner
et al., 2005) or continuous low dose (0.1 mg kg-1) (Eyjolfsson
et al., 2006) did not resemble the alterations occurring in the patients
with schizophrenia. However, repeated high dose MK-801 (0.5 mg kg-1
for six consecutive days) significantly increased the levels of glutamate, taurine
and glutathione in frontal, retrosplenial and cingulate cortices (CRFC) which
were similar to the alterations occurring in drug-naive patients with first
episode schizophrenia (Kondziella et al., 2006).
The purpose of the present study was to investigate the effect of repeated treatment
of MK-801 (0.35 mg kg-1 twice daily) on long term behavioural profile
in rats during the critical brain development period (PND7-20). Moreover it
has been shown that the cognition impairing effects of MK-801 can be ameliorated
or antagonized by clinically effective cognition enhancers (e.g., cholinesterase
inhibitors) (Boess et al., 2004; Csernansky
et al., 2005). Therefore, in order to observe whether the MK-801-induced
changes could be blocked by atypical (clozapine) and classical (haloperidol)
antipsychotic drugs, in our study, antischizophrenic drugs were used to detect
the effects on locomotor activity and spatial memory of animal model induced
by MK-801 in the early life.
MATERIAL AND METHODS
Ethics statement: The experiments were performed at the department of
anatomy of Anhui medical University. The protocol was approved by the local
ethics committees Anhui Medical University. All efforts were made to minimize
the number of animals used and to ameliorate any distress.
Housing: All rats were housed in ambient temperature (approx. 20-23°C)
and humidity (approx. 60%) controlled vivarium. Food and water were available
ad libitum, except during testing, when no food was provided. In all experiments,
animals were allowed to habituate to the housing conditions for at least 1 week
before behavioral testing. All testing was performed during the light phase
of the day/night cycle.
Subjects: Sprague-dawley pups that were fostered by their real mothers
(n = 8) and there were 5-6 offspring per litter. The pups were randomly divided
into four groups, MK-801 (M group), MK-801+Clozapine (CL group), MK-801+Haloperidol
(H group) and normal control group (N group) and each group included eleven
sprague-dawley pups. All pups from a given litter received the same treatment
and were randomly assigned to the groups, so that mean body weight in each group
was almost equal on PND7. The pups of M group, CL group and H group received
i.p., injections of the NMDA receptor antagonist dizocilpine (MK-801, 0.35 mg
kg-1 δ) and N group received i.p., injections of vehicle (0.9%
NaCl) twice a day within 8:00-10:00 am and 14:00-16:00 pm of the light phase
from postnatal days (PND)6-21 of age. The animals of CL group and H group were
treated with the administration of clozapine (1 mg kg-1 δ) or
Haloperidol (0.1 mg kg-1 hunan dongting pharm. Co. Ltd.) on PND43
and PND56 for one week. The animals were weaned at day 21. Behavioral characteristics
of each group were investigated on PND 28, 49, 63 and 84. Schematic diagram
of the experimental procedure Fig. 1. One week before the
experiments the rats adapted to its environment.
Measurement of body weight: The body weight of the pups was measured
before the treatment of MK-801, in the treatment and after the treatment. N
and M group rats were weighed during the MK-801 treatment every day and recorded
from PND7-PND20. After then, the body weight was still tested every 2 days until
9 weeks and recorded from PND22-PND84. All experiments were worked in 9:00-10:00
Locomotor activity: Locomotor activity was measured in rats using a
100×100×50 cm wooden case with 25 equal squares in 9:00-12:00 am. The case was
located in a dim and quiet room. All rats were enchased in the middle square
and recorded the number of squares which rat crossed in 3 min. During each rat
experiment, the case was cleaned by 75% ethanol. Locomotor activity was tested
every two days and recorded the last four results on PND 28, 49, 63 and 84 for
one week (Fig. 1).
Lashley water maze: The Lashley III water maze (80 cm longx50 cm widex20
cm high) was constructed of black opaque plastic with a terminal platform and
four blind alleys.
|| Schematic diagram of the experimental procedure
In this study, we filled the maze with water at a temperature of 25±1°C
to a depth of 12 cm to provide an extra incentive for the mice to escape. The
rats were placed in the maze at start point and had to swim through to the goal
box at terminal platform in 180 sec. If the animals failed to find the terminal
platform within 180 sec, they were gently guided through the maze to the end
and allowed to climb onto the platform for 20 sec during the training time.
The training started on PND28 and lasted continuous 5 days. On PND35 and PND49,
the trail was tested and recorded the time rats found the terminal platform
(Fig. 1). If rats failed to find the platform in 180 sec and
the time was regarded as 180 sec. Lashley III water maze was used for spatial
search ability testing when the body weight of rats were less than 150 g.
Morris water maze: The Morris Water Maze (MWM) consisted of a black
circular pool (160 cm in diameter, 50 cm in height) filled with water at a temperature
of 22±2°C to a depth of 30 cm. The water was rendered opaque by adding
a small amount of ink. The maze was located in a room providing an abundance
of extra maze cues. Swimming trajectories were monitored by an over head camera
connected to a digital tracking system and data acquisition program. The maze
contained a transparent plastic platform (10 cm in diameter, 28 cm in height)
located in the centre of the first quadrant that was labeled based on compass
directions. All experiments were worked in 13:00-18:00. In the visible platform
sessions, the rats were released in the water facing the section of the wall
at 1 of 4 equally quadrant of the pool and recorded the time when rats found
and climbed onto the platform in 60 sec. If a rat failed to locate the platform
within 60 sec it was placed on the platform for 10 sec. Each rat was submitted
to 4 trials in at least 15 min intervals per day and the average data of the
4 trials was regarded as the escape latency of MWM. Subjects were tested in
a continuous 5 day. On day 6-7, the platform was removed, the spatial search
ability of animals were tested. All rats were released in the water facing the
wall at the second quadrant and recorded the times which rats crossed platform
in 60 sec. On PND63 and PND84, MWM was tested and recorded the time of the escape
latency and spatial search shown in Fig. 1. MWM was used for
spatial search ability testing in 150-300 g weight rats.
Statistics: Body weight differences were analyzed by a repeated two-way
analysis of variance (ANOVA) followed by a post hoc Newman-Keuls test.
In the open field test, the numbers of traversed sections were tested by a repeated
two way ANOVA and a Newman-Keuls test and the α level set at 0.05. All
data of water maze were analyzed with repeated measures ANOVA, followed by Tukey-kramer
HSD post hoc test to compare means of interest, α level set at 0.05.
Body weights after the treatment of MK-801: Body weights of all rats
had no significant difference before experiment (p>0.05). After treating
with MK-801, the body weights of M group were increased slowly and had significant
difference from PND10 compared to N group (p<0.01) (Fig. 2a).
After the end of treatment, body weights of M group were significantly reduced
compared to N group (p<0.01) (Fig. 2a). The weights of
M group recovered gradually in the eighth week after the end of MK-801 administration
Locomotor activity after the treatment of MK-801: Locomotor activity
was tested on PND28, 49, 63 and 84. The experiment were performed every two
days and a total of 5 times in one week.
Body weight during and after the administration
of MK-801, compared to N group: *p<0.05, **p<0.01
The first time was to make animals adapted to the environment and the data
didnt collect. The data of later four experiments were recorded and the
mean value represented the scores of locomotor activity. As shown in Fig.
3, the locomotor activity of rats in N group was basically stable and the
number of crossed square was from 60-80 in different times after the administration
of MK-801. However, in rats of M group, a transient increase in locomotor activity
was detected on PND28 (Fig. 3). Then, the decreasing trend
presented in locomotor activity of M group. On PND49, 63 and 84, the locomotor
activity of M group was significantly lower than the control group (p<0.01)
Spatial memory ability after the treatment of MK-801: The spatial memory
of rats were detected by Lashley III water maze and Morris water maze respectively
on PND28, 49 and PND63, 84. As shown in Fig. 4a, compared
to N group, the escape latency of Lashley III water maze in M group rats were
significantly long on PND28 after the treatment of MK-801 (p<0.01). The data
suggested that the learning ability of M group rats was reduced significantly.
On PND49, the time of M group rats on Lashley III water maze was also significantly
long (p<0.01) (Fig. 4a).
Locomotor activity after the administration
of MK-801, compared to N group: *p<0.05, **p<0.01
The results suggested that long memory ability was damaged in M group rats.
When the body weights of rats were more than 150 g, Morris water maze were
used for the testing of animal spatial search ability. As shown in Fig.
4b, compared to N group, the escape latency of Morris water maze in M group
rats were significantly long on PND63 after the treatment of MK-801 (p<0.01).
Similarly, the dwell time in the former target quadrant and the number of platform
position crossings in Morris water maze in M group were also significantly long
on PND63 after the treatment of MK-801 (p<0.05) (Fig. 4c
and d). However, on PND84 after the treatment of MK-801, the
results had no significant difference between N group and M group (p>0.05)
(Fig. 4b). The data suggested that long memory ability gradually
recovered in M group rats. Unlike the escape latency of Morris water maze, the
inconsistent results were found in the dwell time in the former target quadrant
and the number of platform position crossings on PND84 (p<0.05) (Fig.
Effects of clozapine and haloperidol on locomotor activity: Comparison
of M group, the locomotor activity of CL group increased significantly on PND
49 after a week of treatment of clozapine (p<0.01), while H group was no
significant difference (p>0.05) (Fig. 5). Furthermore,
as shown in Fig. 5, the locomotor activity of CL group and
H group were markedly higher than M group on PND63 and 84 (p<0.01) but had
no difference compared to N group (p>0.05). The locomotor activity between
CL group and H group had no significantly difference on PND63 and 84 after the
treatment of antipsychotic drugs (p>0.05). In contrast, M group still maintained
an inferior level. hese results demonstrated that atypical (clozapine) and classical
(haloperidol) antipsychotic drugs could reverse MK-801-induced deficits in hypoactivity.
Spatial memory after the administration
of MK-801. The escape latency of (a) Lashley III water maze, (b) Morris
water maze, (c) Dwell time in the former target quadrant of Morris water
maze and (d) No. of platform position crossings in Morris water maze,
compared to N group: *p<0.05, **p<0.01
Locomotor activity after the treatment
of antipsychotic drugs, compared to N group: **p<0.01, compared to
M group: ##p<0.01
Effects of clozapine and haloperidol on spatial memory ability: Compared
to M group, the results of Lashley III water maze had no significant difference
on PND49 after one week of clozapine and haloperidol therapy (Fig.
6a). The escape latency of Morris water maze was significantly prolonged
in M group compared to N group on PND63 (p<0.01) (Fig. 4b
and 6b). Through twice treatments of clozapine and haloperidol,
respectively on PND43 and PND56, compared with M group, there had no significant
difference in the escape latency, the dwell time in the former target quadrant
and the number of platform position crossings of Morris water maze in H group
and CL group rats (p>0.05) (Fig. 4b-d).
These revealed that antipsychotic drugs clozapine and haloperidol couldnt
significantly ameliorate the spatial memory ability of schizophrenic rats. Moreover,
on PND84, the time completed the task of Morris water maze had no significantly
difference between N, M, H and CL group (p>0.05) (Fig. 4b).
Spatial memory after the treatment of
antipsychotic drugs.The escape latency of (a) Lashley III water maze on
PND49, (b) Morris water maze, (c) Dwell time in the former target quadrant
of Morris water maze and (d) No. of platform position crossings of Morris
water maze, compared to N group: **p<0.01, compared to M group: ##p<0.01
Comparison within M group, the escape latency of Morris water maze reduced
significantly in a time dependent manner (p<0.01) (Fig. 4b).
Our current findings indicated that MK-801 induced schizophrenia rats still
owned spatial memory ability and MK-801-induced deficits in spatial memory in
neonatal rats could spontaneously recover in adulthood. Although, the escape
latency of Morris water maze had no significantly difference between N and M
group on PND84, the dwell time in the former target quadrant and the number
of platform position crossings in M group were significantly longer or more
than that in N group (p<0.01) (Fig. 4c-d).
The results suggested that the damage induced by MK-801 in neonatal rats only
partially restored during adulthood.
Schizophrenia is a chronic and severe CNS disease which characterized by disturbances
of three distinct symptoms: Positive, negative and cognitive symptoms (Pearlson,
2000; Kato et al., 2011). In recent years,
the glutamatergic hypothesis of schizophrenia has received significant
attention and non competitive NMDA receptor antagonists MK-801 induced schizophrenia
is able to imitate schizophrenia like symptoms in human and animals (Reynolds
et al., 2005; Vigano et al., 2009).
In the present study, we confirmed that MK-801 chronic administration produced
lower weight, less locomotor activity and worse spatial memory ability.
Atypical antipsychotic drugs such as clozapine has superior effects on both
positive and negative schizophrenia and cognitive impairment without producing
extra pyramidal side effects, compared to haloperidol, a typical antipsychotic
drug (Arif et al., 2006). To delineate the possible
mechanisms of MK-801 induced schizophrenia, we further investigated the effect
of antipsychotic drugs and revealed whether alterations in behavior were completely
reversed by an atypical or typical antipsychotic drug.
Amounts of evidences showed that MK-801 induced schizophrenia rats had a light
weight compared to the normal rats and recovered to the regular levels in the
puberty and adults after the terminal of MK-801 treatment (Gorter
and Brady, 1994; Su et al., 2011). In the
contrast, some researchers found that the weight decrease was maintained until
adult stage and lower than normal group in the 60 days after birth (Schiffelholz
et al., 2004; Kawabe and Miyamoto, 2008).
These findings were ascribed to age depended switches after neonatal MK-801
treatment. In our study, the body weights were inhibited under neonatal MK-801
treatment and had a significant difference 4 days after treatment in comparison
of normal rats. The lower weights could last 8 weeks long in minimum and then
gradually recovered after the end of the treatment of MK-801.
The open field experiment was evaluated to the center excitability, locomotor
activity, search ability and emotion of rats in the nature condition (Beninger
et al., 2002). In the previous studies, researchers reported that locomotor
activity was double regulated by treating with MK-801, the locomotor activity
was increased in low dose treatment but decreased in high dose treatment (Lyall
et al., 2009). The reason was that high dose MK-801 was able to induced
ataxia and stereotyped behavior and interfere the locomotor activity. The researches
on MK-801induced locomotor activity were not conformity, some reported that
there was no change in the neonatal MK-801 treatment (Kawabe
et al., 2007; Uehara et al., 2009)
and others found that the locomotor activity was reduced in a short time after
treating with MK-801 (Latysheva and Rayevsky, 2003).
While our results were out line with previous studies and found that although
a transient increase in locomotor activity was detected on PND28 one week after
the end of MK-801 treatment it was significantly decreased in medium dose and
last for 6 weeks at least. This might be connected to the dose of MK-801, time
of injection etc. and still need to investigate for a long time. Furthermore,
more studies focus on different kinds of antipsychotic drugs. Mouri found that
the first and second generation antipsychotic drugs could reverse the locomotor
activity increase induced by PCP (Mouri et al.,
2007). Bradford showed that all antipsychotic drugs were able to reverse
the locomotor activity induced by MK-801 in a dose dependent manner (Bradford
et al., 2010). Our results showed that the locomotor activity was significantly
enhanced after treating with clozapine and haloperidol compared to model group
and had no significant difference between treatment group and control group.
These results suggested that both atypical and typical antipsychotic drugs were
able to ameliorate the abnormity of locomotor activity in MK-801 induced schizophrenia.
Cognitive impairments including deficits in attention, short and long-term
memory, abstract thinking ability and executive function etc., are core symptoms
of schizophrenic patients (Glahn et al., 2003;
Green et al., 2004; Harvey
et al., 2004). McLamb reported that there was no alteration of spatial
learning ability in immaturate female rats (Brenner
et al., 2005). However, Su found that, after treating with MK-801, female
rats exhibited slightly impaired working memory during adolescence but remarkably
disrupted in adult (Su et al., 2011). In our
study, Lashley III water maze results showed that the time rats searched the
platform was significantly long compared to normal group. After 5 continuous
days tested, the escape latency between model group and normal group was curtailed
gradually and had a significant difference to the previous results. These data
suggested that although spatial memory deficits were occurred in MK-801 induced
schizophrenia, the learning speed was decreased only. In the retest after 2
weeks, the scores of Morris water maze in MK-801 group rats were still higher
than normal and released that long-term memory were also damaged in model rats.
Furthermore, the effects of clozapine and haloperidol were also observed in
our study. Several studies reported that clozapine was able to improve working
memory of schizophrenia rats. In addition, Takeo Ishiyama showed the spatial
memory ability deficits were ameliorated by clozapine but not haloperidol (Ishiyama
et al., 2007), while Takeshi Enomoto found that both clozapine and haloperidol
could reverse the spatial memory impairments (Enomoto
et al., 2008). In contrast, other researches demonstrated that both
clozapine and haloperidol couldnt remedy the cognitive impairments. In
this study, we found that the escape latency had no significant difference between
model rats and therapy group after treating with clozapine and haloperidol.
It is suggested that clozapine and haloperidol had no therapeutic effects on
spatial memory. In the retests 2 weeks after treatment, results of Morris water
maze were not significantly different between model group and normal group.
These suggested that the spatial memory deficits which induced by MK-801 were
able to recover spontaneously.
In conclusion, our present study has shown that chronic neonatal MK-801 treatment
results in a minor weight, hypoactivity and spatial memory impairment. Moreover,
clozapine and haloperidol could reverse MK-801-induced deficits in hypoactivity
but not the impairment of spatial memory in neonatal rats.
We thank Xu Hui for the assistance of behavioral detection, Li Guangwu for
valuable inspiration and comments. This study was supported by the Science Foundation
of Hefei (20112562) and the Natural Science Foundation of China (81372693, 81273526).
1: Arif, M., M.M. Ahmed, Y. Kumabe, H. Hoshino, T. Chikuma and T. Kato, 2006. Clozapine but not haloperidol suppresses the changes in the levels of neuropeptides in MK-801-treated rat brain regions. Neurochem. Int., 49: 304-311.
2: Baier, P.C., A. Blume, J. Koch, A. Marx, G. Fritzer, J.B. Aldenhoff and T. Schiffelholz, 2009. Early postnatal depletion of NMDA receptor development affects behaviour and NMDA receptor expression until later adulthood in rats: A possible model for schizophrenia. Behav. Brain Res., 205: 96-101.
3: Beninger, R.J., A. Jhamandas, H. Aujla, I. Xue, R.V. Dagnone, R.J. Boegman and K. Jhamandas, 2002. Neonatal exposure to the glutamate receptor antagonist MK-801: Effects on locomotor activity and pre-pulse inhibition before and after sexual maturity in rats. Neurotoxicity Res., 4: 477-488.
CrossRef | Direct Link |
4: Boess, F.G., M. Hendrix, F.J. van der Staay, C. Erb and R. Schreiber et al., 2004. Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology, 47: 1081-1092.
5: Bradford, A.M., K.M. Savage, D.N. Jones and M. Kalinichev, 2010. Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics. Psychopharmacology, 212: 155-170.
CrossRef | Direct Link |
6: Brenner, E., D. Kondziella, A. Haberg and U. Sonnewald, 2005. Impaired glutamine metabolism in NMDA receptor hypofunction induced by MK801. J. Neurochem., 94: 1594-1603.
7: Csernansky, J.G., M. Martin, R. Shah, A. Bertchume, J. Colvin and H. Dong, 2005. Cholinesterase inhibitors ameliorate behavioral deficits induced by MK-801 in mice. Neuropsychopharmacology, 30: 2135-2143.
8: Enomoto, T., T. Ishibashi, K. Tokuda, T. Ishiyama, S. Toma and A. Ito, 2008. Lurasidone reverses MK-801-induced impairment of learning and memory in the Morris water maze and radial-arm maze tests in rats. Behav. Brain Res., 186: 197-207.
9: Eyjolfsson, E.M., E. Brenner, D. Kondziella and U. Sonnewald, 2006. Repeated injection of MK801: An animal model of schizophrenia? Neurochem. Int., 48: 541-546.
10: Glahn, D.C., S. Therman, M. Manninen, M. Huttunen, J. Kaprio, J. Lonnqvist and T.D. Cannon, 2003. Spatial working memory as an endophenotype for schizophrenia. Biol. psychiatry, 53: 624-626.
11: Gorter, J.A. and R.J. Brady, 1994. NMDA receptor responses in adult hippocampal CA1 region after neonatal treatment with MK-801: Comparison with NMDA receptor responses in the immature rat. Brain Res., 665: 63-68.
12: Green, M.F., K.H. Nuechterlein, J.M. Gold, D.M. Barch and J. Cohen et al., 2004. Approaching a consensus cognitive battery for clinical trials in schizophrenia: The NIMH-MATRICS conference to select cognitive domains and test criteria. Biol. Psychiatry, 56: 301-307.
13: Gururajan, A., D.A. Taylor and D.T. Malone, 2010. Effect of testing conditions on the propsychotic action of MK-801 on prepulse inhibition, social behaviour and locomotor activity. Physiol. Behav., 99: 131-138.
14: Haberny, K.A., M.G. Paule, A.C. Scallet, F.D. Sistare, D.S. Lester, J.P. Hanig and W. Slikker Jr., 2002. Ontogeny of the N-methyl-D-aspartate (NMDA) receptor system and susceptibility to neurotoxicity. Toxicol. Sci., 68: 9-17.
CrossRef | Direct Link |
15: Hargreaves, E.L. and D.P. Cain, 1992. Hyperactivity, hyper-reactivity and sensorimotor deficits induced by low doses of the N-methyl-d-aspartate non-competitive channel blocker MK801. Behav. Brain Res., 47: 23-33.
16: Harvey, P.D., M.F. Green, R.S. Keefe and D.I. Velligan, 2004. Cognitive functioning in schizophrenia: A consensus statement on its role in the definition and evaluation of effective treatments for the illness. J. Clin. Psychiatry, 65: 361-372.
17: Ishiyama, T., K. Tokuda, T. Ishibashi, A. Ito, S. Toma and Y. Ohno, 2007. Lurasidone (SM-13496), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning and memory in the rat passive-avoidance test. Eur. J. Pharmacol., 572: 160-170.
18: Kato, T.A., A. Monji, Y. Mizoguchi, S. Hashioka and H. Horikawa et al., 2011. Anti-inflammatory properties of antipsychotics via microglia modulations: Are antipsychotics a fire extinguisher in the brain of schizophrenia? Mini Rev. Med. Chem., 11: 565-574.
CrossRef | Direct Link |
19: Kawabe, K., T. Iwasaki and Y. Ichitani, 2007. Repeated treatment with N-methyl-d-aspartate antagonists in neonatal, but not adult, rats causes long-term deficits of radial-arm maze learning. Brain Res., 1169: 77-86.
20: Kawabe, K. and E. Miyamoto, 2008. Effects of neonatal repeated MK-801 treatment on delayed nonmatching-to-position responses in rats. Neuroreport, 19: 969-973.
21: Kocahan, S., K. Akillioglu, S. Binokay, L. Sencar and S. Polat, 2013. The effects of N-Methyl-D-Aspartate receptor blockade during the early neurodevelopmental period on emotional behaviors and cognitive functions of adolescent Wistar rats. Neurochem. Res., 38: 989-996.
CrossRef | Direct Link |
22: Kondziella, D., E. Brenner, E.M. Eyjolfsson, K.R. Markinhuhta, M.L. Carlsson and U. Sonnewald, 2006. Glial-neuronal interactions are impaired in the schizophrenia model of repeated MK801 exposure. Neuropsychopharmacology, 31: 1880-1887.
23: Latysheva, N.V. and K.S. Rayevsky, 2003. Chronic neonatal N-methyl-d-aspartate receptor blockade induces learning deficits and transient hypoactivity in young rats. Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 27: 787-794.
24: Lyall, A., J. Swanson, C. Liu, T.D. Blumenthal and C.P. Turner, 2009. Neonatal exposure to MK801 promotes prepulse-induced delay in startle response time in adult rats. Exp. Brain Res., 197: 215-222.
CrossRef | Direct Link |
25: Manahan-Vaughan, D., D. von Haebler, C. Winter, G. Juckel and U. Heinemann, 2008. A single application of MK801 causes symptoms of acute psychosis, deficits in spatial memory and impairment of synaptic plasticity in rats. Hippocampus, 18: 125-134.
26: McLamb, R.L., L.R. Williams, K.P. Nanry, W.A. Wilson and H.A. Tilson, 1990. MK-801 impedes the acquisition of a spatial memory task in rats. Pharmacol. Biochem. Behav., 37: 41-45.
27: Mouri, A., Y. Noda, T. Enomoto and T. Nabeshima, 2007. Phencyclidine animal models of schizophrenia: Approaches from abnormality of glutamatergic neurotransmission and neurodevelopment. Neurochem. Int., 51: 173-184.
28: Pearlson, G.D., 2000. Neurobiology of schizophrenia. Ann. Neurol., 48: 556-566.
Direct Link |
29: Pryce, C., A. Mohammed and J. Feldon, 2002. Environmental manipulations in rodents and primates. Insights into pharmacology, biochemistry and behaviour. Pharm. Biochem. Behav., 73: 1-5.
30: Reynolds, L.M., S.M. Cochran, B.J. Morris, J.A. Pratt and G.P. Reynolds, 2005. Chronic phencyclidine administration induces schizophrenia-like changes in N-acetylaspartate and N-acetylaspartylglutamate in rat brain. Schizophr. Res., 73: 147-152.
31: Riedel, G., B. Platt and J. Micheau, 2003. Glutamate receptor function in learning and memory. Behav. Brain Res., 140: 1-47.
32: Rung, J.P., A. Carlsson, K.R. Markinhuhta and M.L. Carlsson, 2005. (+)-MK-801 induced social withdrawal in rats: A model for negative symptoms of schizophrenia. Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 29: 827-832.
33: Schiffelholz, T., D. Hinze-Selch and J.B. Aldenhoff, 2004. Perinatal MK-801 treatment affects age-related changes in locomotor activity from childhood to later adulthood in rats. Neurosci. Lett., 360: 157-160.
34: Stefani, M.R. and B. Moghaddam, 2005. Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia. Biol. Psychiatry, 57: 433-436.
35: Su, Y.A., X.D. Wang, J.T. Li, C.M. Guo and Y. Feng et al., 2011. Age-specific effects of early MK-801 treatment on working memory in female rats. Neuroreport, 22: 402-406.
36: Theberge, J., R. Bartha, D.J. Drost, R.S. Menon and A. Malla et al., 2002. Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. Am. J. Psychiatry, 159: 1944-1946.
37: Uehara, T., T. Sumiyoshi, T. Seo, H. Itoh, T. Matsuoka, M. Suzuki and M. Kurachi, 2009. Long-term effects of neonatal MK-801 treatment on prepulse inhibition in young adult rats. Psychopharmacology, 206: 623-630.
38: Viberg, H., W. Mundy and P. Eriksson, 2008. Neonatal exposure to decabrominated diphenyl ether (PBDE 209) results in changes in BDNF, CaMKII and GAP-43, biochemical substrates of neuronal survival, growth and synaptogenesis. Neurotoxicology, 29: 152-159.
CrossRef | Direct Link |
39: Vigano, D., C. Guidali, S. Petrosino, N. Realini, T. Rubino, V. Di Marzo and D. Parolaro, 2009. Involvement of the endocannabinoid system in phencyclidine-induced cognitive deficits modelling schizophrenia. Int. J. Neuropsychopharmacol., 12: 599-614.
40: Wong, E.H., J.A. Kemp, T. Priestley, A.R. Knight, G.N. Woodruff and L.L. Iversen, 1986. The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc. Natl. Acad. Sci. USA., 83: 7104-7108.
Direct Link |