Neuropharmacological effects of brexpiprazole on animal ... · recognition, in untreated mice....
Transcript of Neuropharmacological effects of brexpiprazole on animal ... · recognition, in untreated mice....
Neuropharmacological effects of brexpiprazole
on animal models of cognitive impairment
(認知機能障害における新規抗精神病薬ブ
レクスピプラゾールの神経薬理学的研究)
千葉大学大学院医学薬学府
先端医学薬学専攻
(主任:橋本 謙二 教授)
吉見 典子
CONTENTS
I. GENERAL INTRODUCTION……………………………………………………1
II. CHAPTER 1
Improvement of dizocilpine-induced social recognition deficits in mice by
brexpiprazole, a novel serotonin-dopamine activity modulator……………… 8
1. ABSTRACT…………………………………………………………………….8
2. INTRODUCTION……………………………………………………………….9
3. EXPERIMENTAL PROCEDURES…………………………………………...10
3.1. Animals……………………………………………………………10
3.2. Drugs……………………………………………………………….11
3.3. Apparatus………………………………………………………….11
3.4. Behavioral procedures………………………………………………12
3.4.1. Habituation…………………………………………………………12
3.4.2. Sociability test……………………………………………………12
3.4.3. Social recognition test……………………………………………12
3.5. Statistical analyses…………………………………………………13
4. RESULTS………………………………………………………………………13
4.1. Effects of brexpiprazole on dizocilpine-induced social recognition
deficits………………………………………………………………13
4.2. Brexpiprazole alone did not affect social recognition deficits………14
4.3. Risperidone and olanzapine had no effect on dizocilpine-induced
social recognition deficits…………………………………………16
4.4. Role of the 5-HT1A receptor in brexpiprazole's effects on
dizocilpine-induced social recognition deficits……………………19
5. DISCUSSION…………………………………………………………………21
6. REFERENCES…………………………………………………………………25
III. CHAPTER 2
Effects of brexpiprazole, a novel serotonin-dopamine activity modulator, on
phencyclidine-induced cognitive deficits in mice: A role for serotonin 5-HT1A
receptors………………………………………………………………………….. 34
1. ABSTRACT…………………………………………………………………35
2. INTRODUCTION……………………………………………………………37
3. EXPERIMENTAL PROCEDURES………………………………………….37
3.1. Animals……………………………………………………………………37
3.2. Drugs…………………………………………………………………….37
3.3. Drug administration……………………………………………………….38
3.4. Novel object recognition test (NORT)……….……….……….…………39
3.5. Statistical analysis………………………………………………………..40
4. RESULTS…………………………………………………………………….41
4.1. Effects of brexpiprazole on PCP-induced cognitive deficits in mice……41
5. DISCUSSION…………………………………………………………….……43
6. REFERENCES……………………………………………………………….45
IV. CONCLUSIONS………………………………………………………………..54
V. AKNOWLEGEMENTS…………………………………………………………..55
1
I. GENERAL INTRODUCTION
Cognitive deficits in patients of psychiatric disorders including schizophrenia and
major depressive disorder are recognized as a serious social problem in recent years.
Especially in schizophrenia, it is thought that cognitive deficits are not epiphenomena
arising from positive and negative symptoms but one of the main symptoms of
schizophrenia. The Measurement and Treatment Research to Improve Cognition in
Schizophrenia (MATRICS) developed by the US National Institute of Mental Health
(NIMH) defined that there are several main cognitive domains easily impaired by
schizophrenia such as attention/vigilance, working memory, verbal learning and
memory, visual learning and memory, reasoning and problem solving, speed of
processing and social cognition (Table 1).
Cognitive domains Example
attention/vigilance ability to response appropriately to series of stimuli appeared
quickly
ex) reading book, watching movie
working memory ability to memorize information for short-time (about 5-20
seconds) and process it
ex) memorizing phone number newly taught
verbal learning
verbal memory
ability to memorize verbal information for long-time (a few
minutes- a few years)
ex) memorizing someone’s request to buy in the store
visual learning
visual memory
ability to memorize visual information for long-time (a few
minutes- a few years)
2
ex) memorizing what and where to store
reasoning
problem solving
ability to carry out a project effectively
ex) getting workplace in time despite of changing time of the
usual bus
speed of processing ability to process the information exactly and response it
quickly
ex) serving a customer with touch panel operation
social cognition ability to process and memorize social information such as
expressions, emotions and meaning of social interaction
ex) memorizing someone’s face or ability of recognizing
someone’s feeling from his/her expression
Table 1. Cognitive domains impaired in patients with schizophrenia
These cognitive domains are necessary for working. Therefore cognitive deficits
constitute a major cause of low employment rate in patients of psychiatric disorders
(Mueser et al, 2002). Social isolation by disemployment might decrease patient’s
motivation, and has possibility to result in worsening of symptoms. Additionally,
cognitive deficits cause a decrease in the drug adherence rate of patients and might
prevent improvement of symptoms (Patterson et al, 2002). Treatment for cognitive
deficits is needed for not only improvement of cognitive deficits itself, but also
improvement of other symptoms of psychiatric disorders. There is no antipsychotic drug
having enough therapeutic effect for cognitive deficits despite of challenging for
development of novel drugs. Development of effective drugs for cognitive deficits is
critically-needed by psychiatric patients.
3
Brexpiprazole , 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}
quinolin-2(1H)-one (Figure 1) , is a novel serotonin-dopamine activity modulator
developed within recent years. Brexpiprazole has higher serotonin 5-HT1A receptor and
dopamine D2 receptor binding affinity than an atypical antipsychotic drug, aripiprazole
(Figure 1, Table 2). Brexpiprazole has a slightly higher binding affinity for h5-HT1A
receptors than hD2 receptors, whereas aripiprazole has reverse effect (Table 2).
Additionally, the inhibitory activity for hD2L receptor on brexpiprazole was a little
weaker than that on aripiprazole which indicates that the intrinsic activity for D2 on
brexpiprazole is slightly lower than that on aripiprazole (Figure 2). As brexpiprazole
has lower intrinsic activity at D2 receptor compared with aripiprazole, it can expect to
have fewer adverse effects by D2 receptor agonism and antagonism than aripiprazole. It
is also an antagonist at 5-HT2A receptors and adrenergic α1B/2C receptors (Maeda et al.,
2014a). The 5-HT1A receptor agonism is focused on the ability for improvement of
several clinical and non-clinical reports.
4
Figure 1. Chemical structure of brexpiprazole and aripiprazole
aData from Maeda et al., 2014a.
bData from Shapiro et al., 2003.
5
Table 2. Binding affinities for cloned human receptors in vitro (Maeda et al. 2014a)
Data are calculated by nonlinear regression analysis using data from three assays performed in
duplicate or triplicate and expressed as mean values.
Figure 2. Partial agonist activity of brexpiprazole and reference drugs on human
cloned D2L receptors in vitro (Maeda et al. 2014a)
Concentration-response curves are shown for brexpiprazole and aripiprazole on forskolin induced
cAMP accumulation in hD2L receptor–expressing CHO cells. Data are mean 6 S.D. of three assays
performed in duplicate. Cyclic AMP accumulation was normalized to the percentage of
forskolin-induced cAMP accumulation (set at 100%).
The research in animal model reflecting clinical cognitive deficits is critically important
to evaluate the effects of drugs. However, there is no unified classification whether
which animal model for testing cognitive deficits match which domains in listed in
Table 1. Multiple testing for one drug can resolve this problem.
6
In the present study, we investigated the therapeutic effects of a novel
antipsychotic drug brexpiprazole on social recognition impaired by the
N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine, and cognitive deficits
in mice after administration of the NMDA receptor antagonist phencyclidine (PCP). We
divided our study into the following two chapters.
CHAPTER 1
We investigated the effects of brexpiprazole, olanzapine and risperidone, on
dizocilpine-induced social recognition impairment, in mice. Furthermore, we also
investigated the effect of brexpiprazole, olanzapine, and risperidone on social
recognition, in untreated mice. Moreover, we investigated the role of serotonin 5-HT1A
receptor on the effect of brexpiprazole on dizocilpine-induced social recognition
impairment.
CHAPTER 2
Using the novel object recognition test (NORT), we investigated the effects of
subsequent subchronic brexpiprazole on PCP -induced cognitive deficits in mice.
Furthermore, we investigated the role of 5-HT1A receptor on the effect of brexpiprazole
in this model.
REFERENCES
Maeda, K., Sugino, H., Akazawa, H., Amada, N., Shimada, J., Futamura, T., Yamashita,
H., Ito, N., McQuade, R.D., Mork, A., Pehrson, A.L., Hentzer, M., Nielsen, V.,
Bundgaard, C., Arnt, J., Stensbol, T.B., Kikuchi, T., 2014a. Brexpiprazole I: in
7
vitro and in vivo characterization of a novel serotonin-dopamine activity
modulator. The Journal of pharmacology and experimental therapeutics 350,
589-604.
Mueser, K.T., Salyers, M.P., Mueser, P.R., 2001. A prospective analysis of work in
schizophrenia. Schizophrenia bulletin 27, 281-296.
Patterson, T.L., Lacro, J., McKibbin, C.L., Moscona, S., Hughs, T., Jeste, D.V., 2002.
Medication management ability assessment: results from a performance-based
measure in older outpatients with schizophrenia. Journal of clinical
psychopharmacology 22, 11-19.
Shapiro, D.A., Renock, S., Arrington, E., Chiodo, L.A., Liu, L.X., Sibley, D.R., Roth,
B.L., Mailman, R., 2003. Aripiprazole, a novel atypical antipsychotic drug with a
unique and robust pharmacology. Neuropsychopharmacology : official
publication of the American College of Neuropsychopharmacology 28,
1400-1411.
8
II. CHAPTER 1
Improvement of dizocilpine-induced social recognition deficits in mice by
brexpiprazole, a novel serotonin-dopamine active modulator
1. ABSTRACT
Cognitive impairment, including impaired social cognition, is largely responsible for the
deterioration in social life suffered by patients with psychiatric disorders, such as
schizophrenia and major depressive disorder (MDD). Brexpiprazole
(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one), a novel
serotonin-dopamine activity modulator, was developed to offer efficacious and tolerable
therapy for different psychiatric disorders, including schizophrenia and adjunctive
treatment of MDD. In this study, we investigated whether brexpiprazole could improve
social recognition deficits (one of social cognition deficits) in mice, after administration
of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine).
Dosing with dizocilpine (0.1 mg/kg) induced significant impairment of social
recognition in mice. Brexpiprazole (0.01, 0.03, 0.1 mg/kg, p.o.) significantly
ameliorated dizocilpine-induced social recognition deficits, without sedation or a
reduction of exploratory behavior. In addition, brexpiprazole alone had no effect on
social recognition in untreated control mice. By contrast, neither risperidone (0.03
mg/kg, p.o.) nor olanzapine (0.03 mg/kg, p.o.) altered dizocilpine-induced social
recognition deficits. Finally, the effect of brexpiprazole on dizocilpine-induced social
recognition deficits was antagonized by WAY-100,635, a selective serotonin 5-HT1A
antagonist. These results suggest that brexpiprazole could improve dizocilpine-induced
social recognition deficits via 5-HT1A receptor activation in mice. Therefore,
9
brexpiprazole may confer a beneficial effect on social cognition deficits in patients with
psychiatric disorders.
2. INTRODUCTION
Cognitive impairment describes a diverse range of deficits, seen in psychiatric
disorders. Of these, impaired social cognition greatly hampers everyday life, resulting
in poor work productivity or underemployment of patients with schizophrenia and
major depressive disorder (MDD) (Tandberg et al, 2011; Tse et al, 2013; Horan et al,
2012; Lo and Siu, 2014). It is generally accepted that reducing social cognitive
dysfunction is an important factor in assisting psychiatric patients to make healthy
adjustments in their social lives (Tandberg et al, 2011; Tse et al, 2013; Horan et al,
2012; Trapp et al, 2013). Current reports suggest that training of social cognition may
help to improve functional outcome in patients with schizophrenia (Henderson, 2013).
To complement this, the development of novel drugs to improve social cognition
deficits in patients with schizophrenia is also imperative.
Social recognition testing is designed to measure the propensity of a mouse to
make contact with a novel rather than familiar mouse. This testing therefore represents a
cognitive model that reflects innate ability to communicate with others (Moy et al,
2004; van der Kooij and Sandi, 2012). Social recognition test in rodents is also one of
the assays for evaluating social cognition in humans (Millan and Bales, 2013). Based on
the N-methyl-D-aspartate (NMDA) hypofunction hypothesis of schizophrenia
(Hashimoto, 2006; 2014; Hashimoto et al, 2013), the NMDA receptor antagonist,
(+)-MK-801 (dizocilpine), is widely used to induce schizophrenia-like behavioral
abnormalities, including positive and negative symptoms and cognitive deficits in
10
rodents (Hashimoto et al, 2009; Karasawa et al, 2008; Rajagopal et al, 2013; Meltzer et
al, 2011; Okamura et al, 2004; Rogoz, 2013; Zhang et al, 2007). Furthermore,
dizocilpine also impairs social interaction and social recognition (Maehara et al, 2011;
Oh et al, 2013; Hikichi et al, 2013).
Brexpiprazole, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}
quinolin-2(1H)-one, is a novel serotonin-dopamine activity modulator with high affinity
for serotonin, dopamine and noradrenaline receptors (Maeda et al, 2014a). It is a partial
agonist at serotonin 5-HT1A and dopamine D2 receptors, with a relatively equal potency,
and an antagonist at 5-HT2A receptors and adrenergic α1B/2C receptors. Brexpiprazole is
currently under clinical evaluation and expected to show efficacy and tolerability when
used as therapy for different psychiatric disorders, including schizophrenia and
adjunctive treatment for MDD. Very recently, brexpiprazole was shown to improve the
NMDA receptor antagonist phencyclidine-induced cognitive deficits in the novel object
recognition test in rodents (Maeda et al, 2014b; Yoshimi et al, 2014). To date, the effect
of brexpiprazole on social recognition has not been investigated. In this study, we
evaluated the effects of brexpiprazole on dizocilpine-induced social recognition deficits
in mice.
3. EXPERIMENTAL PROCEDURES
3.1. Animals
Male C57BL/6NCrSlc mice (Japan SLC Inc., Shizuoka, Japan) aged between 4
and 5 weeks old were selected as stranger mice, while animals between 8 and 10 weeks
old were used for this study. All mice were housed in groups of five per cage, in a room
maintained at 23 ± 2 °C and 60 ± 10 % humidity, with a 12/12 hour light/dark cycle
11
(lights on at 7:00 a.m.). The mice were given free access to food and water. Animal care
and use were conducted in accordance with the Institutional Guidelines for Animal Care
and Use (Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan).
3.2. Drugs
(+)-MK-801 hydrogen maleate (dizocilpine) was purchased from Sigma-Aldrich
Co., Ltd (Tokyo, Japan). Brexpiprazole, risperidone, olanzapine and WAY-100,635
were synthesized at Otsuka Pharmaceutical Co., Ltd (Tokyo, Japan). Dizocilpine was
dissolved in saline and administered intraperitoneally (i.p.) at 10 ml/kg, twice daily, on
the day before and 30 minutes prior to sociability testing. Brexpiprazole, risperidone,
olanzapine and WAY-100,635 were dissolved in 5% (w/v) gum Arabic and
administered orally (p.o.), at 10 ml/kg, 1 hour prior to sociability testing. The doses of
dizocilpine (0.1 mg/kg) and WAY-100,635 (1.0 mg/kg) were selected from previously
published reports in mice (Hagiwara et al, 2008; Hashimoto et al, 2009; Takatsu et al,
2011; Yoshimi et al, 2014; Zhang et al, 2007). The doses of antipsychotic drugs were
selected based on doses that did not impact locomotion (data not shown).
3.3. Apparatus
The test apparatus consisted of a rectangular, three-chambered box, and a lid with
an attached infrared video camera (O’Hara & Co., Tokyo, Japan). The apparatus was
610W x 400D x 220H mm, and the dividing walls were made from clear Plexiglass,
with small square openings (3 x 5 cm) allowing access into each chamber. The stranger
mouse was enclosed in a small, round wire cage (diameter, 10 cm; height, 12 cm),
allowing olfactory, visual, auditory, and tactile contact, but no deep contact. Using a
CCD camera, measures were taken of the amount of time spent around the wire cage.
The total distance traveled was calculated based on traced mice movement and
12
presented as the locomotor activity in this study. All data were computerized. Activity
was monitored and analyzed using applications based on the public domain NIH Image
or Image J program (developed by Wayne Rasband at the U.S. National Institute of
Mental Health and available on the Internet at http://rsb.info.nih.gov/nih-image/)
(O’Hara & Co., Tokyo, Japan).
3.4. Behavioral procedures
The measurement of sociability and social recognition was performed using the
same procedure described in previous reports (Moy et al, 2007; Nakatani et al, 2009;
Matsuo et al, 2009; Riedel et al, 2009). In this study, we focused on a narrowly defined
set of parameters.
3.4.1. Habituation
Mice were randomly assigned to groups. Mice were first placed in the middle
compartment of the apparatus and allowed to explore freely for 6 minutes. All other
compartments were empty during this habituation period.
3.4.2. Sociability test
An unfamiliar male (stranger) that had no prior contact with the mouse was placed
in one of the side chambers. After the habituation period, the unfamiliar male juvenile
mouse (stranger 1) was placed inside the round wire cage, in one of the side
compartments (randomly selected and counterbalanced for each group). The opposite
compartment was empty. The mice were able to freely explore all three compartments
of the apparatus for 6 minutes. The time spent around cages (stranger 1 or empty) was
calculated as direct contact.
3.4.3. Social recognition test
After sociability testing, a novel unfamiliar juvenile mouse (stranger 2) was
13
placed inside a new round wire cage and introduced to the ‘empty compartment’ of the
apparatus. Mice were confined to the central compartment and were able to explore
freely in all compartments for 10 min.
The recognition index (RI) was calculated using parameters measured during
social recognition sessions and was defined as the quotient of the time the mouse spent
around the novel juvenile (stranger 2) divided by the sum of the time spent around the
familiar (stranger 1) and novel (stranger 2) juvenile mice.
3.5. Statistical analyses
All statistical analyses were performed using Prism 5 (GraphPad Software Inc., La
Jolla, USA). Data are presented as mean ± standard error of the mean (S.E.M.). To
determine the effects of drug treatment, one-way ANOVA, followed by the post hoc
Bonferroni test (for RI and total distance) or a two-tailed paired t-test (for RI and time
spent around cage), was used. P values of less than 0.05 were considered statistically
significant.
4. RESULTS
4.1 Effects of brexpiprazole on dizocilpine-induced social recognition deficits
Mice in all groups spent significantly more time around stranger 1, than the empty
area in sociability sessions (data not shown). A one-way ANOVA on RI in social
recognition session showed a significant effect of treatment (F (4, 56) = 5.83, p <
0.001)(Figure 1A). Saline-treated control mice had a significant preference for
spending more time with the novel unfamiliar stranger 2, in comparison with familiar
stranger 1, in the social recognition session (Figure 1B). Treatment with dizocilpine
(0.1 mg/kg, i.p.) significantly decreased the total time spent around stranger 2 in social
14
recognition sessions. A paired t-test showed a significant (p < 0.01) impairment of RI in
the dizocilpine-treated group. Mice spent the same amount of time interacting with
stranger 1 and stranger 2 mice (Figure 1A, and 1B). The total distance moved
(exploratory behavior), indicative of locomotor activity, was significantly increased by
dizocilpine administration (Figure 1C).
Next, we examined whether brexpiprazole attenuated dizocilpine-induced social
recognition deficits in mice. Neither dizocilpine (0.1 mg/kg, i.p.) nor brexpiprazole
(0.01, 0.03 and 0.1 mg/kg, p.o) altered the amount of time spent around stranger 1 mice
in sociability sessions (data not shown). However, at all three doses of brexpiprazole,
mice treated with brexpiprazole showed a significant preference for spending more time
with novel unfamiliar stranger 2 mice, compared with familiar stranger 1 mice in social
recognition sessions (Figure 1B), and additionally, impaired RI was significantly
restored by treatment with brexpiprazole at the same doses used in sociability testing
(Figure 1A). Furthermore, brexpiprazole (0.01, 0.03 and 0.1 mg/kg) did not temper the
increased locomotor activity induced by dizocilpine in social recognition sessions
(Figure 1C).
4.2 Brexpiprazole alone did not affect social recognition or exploratory behavior
We examined the effect of brexpiprazole on social recognition in untreated control
mice. Treatment with brexpiprazole (0.01, 0.03 and 0.1 mg/kg) had no effect on the
time spent around stranger 1 mice in either sociability (data not shown) or social
recognition sessions (Figure 1D, and 1E). Brexpiprazole did not alter RI in social
recognition sessions (Figure 1D), nor did it have an effect on exploratory behavior
during either session (Figure 1F).
15
Figure 1. Effects of brexpiprazole on dizocilpine-induced social recognition
deficits
Dizocilpine (0.1 mg/kg, i.p.) or saline (10 ml/kg, i.p.) was administered twice daily on the day
before and 30 minutes prior to sociability testing. Brexpiprazole (0.01, 0.03, 0.1 mg/kg, p.o.) or
vehicle (5% (w/v) gum Arabic, p.o.) was administrated 1 hour prior to sociability testing. (A)
Social recognition was measured by the recognition index (RI), that is, the quotient of time the
subject mouse spent around the novel juvenile (stranger 2) mouse divided by the sum of the time
spent around the familiar (stranger 1) and novel juvenile (stranger 2) mice during social
recognition sessions. (B) Duration of time spent around each stranger during the social
recognition sessions and, (C) exploratory behavior during social recognition sessions. Values are
the mean S.E.M (n = 11-15). *p < 0.05, **p < 0.01, ***p < 0.001 compared with dizocilpine +
vehicle group (A and C, one-way ANOVA, followed by post hoc Bonferroni test). **p < 0.01,
***p < 0.001 compared with stranger 1 mice (B, two-tailed paired t-test). Brexpiprazole (0.01,
0.03, 0.1 mg/kg, p.o.) or vehicle (5% (w/v) gum Arabic, p.o.) was administrated 1 hour prior to
sociability testing. The effects of brexpiprazole on the RI (D), duration of time spent around each
stranger mouse (E), and exploratory behavior (F), during social recognition sessions. Values are
the mean S.E.M (n = 7-14). *p < 0.05, **p < 0.01, ***p < 0.001 compared with stranger 1 (E,
two-tailed paired t-test). N.S.: not significant.
16
4.3 Risperidone and olanzapine had no effect on dizocilpine-induced social
recognition deficits
We examined whether the atypical antipsychotic drugs, risperidone and
olanzapine, affected dizocilpine-induced social recognition deficits in mice. A one-way
ANOVA on RI in social recognition session showed a significant effect of treatment (F
(2, 31) = 4.60, p < 0.05)(Figure 2A). Pot-hoc analysis showed that risperidone (0.03
mg/kg, p.o.) did not ameliorate dizocilpine-induced social recognition deficits (Figure
2A, 2B), and dizocilpine-induced hyperlocomotion in the recognition sessions (Figure
2C). When administered alone, risperidone (0.03 mg/kg, p.o.) significantly decreased
both RI and locomotor activity in untreated control mice (Figure 2D, 2E, and 2F).
17
A one-way ANOVA on RI in social recognition session showed a significant
effect of treatment (F (2, 27) = 7.72, p < 0.01)(Figure 3A). Post-hoc analysis showed that
olanzapine (0.03 mg/kg, p.o.) did not affect time spent around stranger 2 mice, nor did it
reverse dizocilpine-induced impairment of the RI (Figure 3A, and 3B). Furthermore,
olanzapine had no effect on dizicilpine-induced hyperlocomotion in the recognition
sessions (Figure 3C). Olanzapine (0.03 mg/kg, p.o.) alone was incapable of altering RI,
the time spent around stranger 2 mice, or exploratory behavior in untreated control mice
(Figure 3D, 3E, and 3F).
Figure 2. Effect of risperidone on dizocilpine-induced social recognition deficits
Dizocilpine (0.1 mg/kg, i.p.) or saline (10 ml/kg, i.p.) was administered twice daily on the day
before and 30 minutes prior to sociability testing. Risperidone (0.03 mg/kg, p.o.) or vehicle (5%
(w/v) gum Arabic, p.o.) was administrated 1 hour prior to sociability testing. The effects of
risperidone on RI (A), duration of time spent around each stranger mouse (B), and exploratory
behavior (C) during social recognition sessions. Values are the mean S.E.M (n = 11 or 12). *p
< 0.05 compared with dizocilpine + vehicle group (A and C, one-way ANOVA, followed by post
hoc Bonferroni test). N.S.: not significant. **p < 0.01 compared with stranger 1 mice (B,
two-tailed paired t-test). Risperidone (0.03 mg/kg, p.o.) or vehicle (5% (w/v) gum Arabic, p.o.)
was administrated 1 hour prior to sociability testing. The effects of risperidone on RI (D),
duration of time spent around each stranger mouse (E) and exploratory behavior (F) during
social recognition sessions. Values are the mean S.E.M (n=7). *p < 0.05 compared with the
vehicle-treated control group (D and F, two-tailed paired t-test). *p < 0.05, ***p < 0.001
compared with stranger 1 mice (E, two-tailed paired t-test).
18
Figure 3. Effect of olanzapine on dizocilpine-induced social recognition deficits
Dizocilpine (0.1 mg/kg, i.p.) or saline (10 ml/kg, i.p.) administered twice daily on the day before
and 30 minutes prior to sociability testing. Olanzapine (0.03 mg/kg, p.o.) or vehicle (5% (w/v)
gum Arabic, p.o.) was administrated 1 hour prior to sociability testing. The effects of olanzapine
on RI (A), duration of time spent around each stranger mouse (B) and exploratory behavior (C)
during social recognition sessions. Values are the mean S.E.M (n=10). **p < 0.01, ***p <
0.001 compared with vehicle-treated control group for (A) and (C) (one-way ANOVA, followed
by post hoc Bonferroni test). ***p < 0.001 compared with stranger 1 mice for (B) (two-tailed
paired t-test). Olanzapine (0.03 mg/kg, p.o.) or vehicle (5% (w/v) gum Arabic, p.o.) was
administrated 1 hour prior to sociability testing. The effects of olanzapine on RI (D), duration of
time spent around each stranger mouse (E) and exploratory behavior (F) during social
recognition sessions. Values are the mean S.E.M (n=7). **p < 0.01, ***p < 0.001 compared
with stranger 1 mice for (E) (two-tailed paired t-test). N.S.: not significant.
19
4.4 Role of the 5-HT1A receptor in brexpiprazole's effects on dizocilpine-induced
social recognition deficits
To investigate the function of serotonin 5-HT1A receptors in the pharmacological
effect of brexpiprazole on dizocilpine-induced social recognition deficits, we examined
the effect of WAY-100,635, a selective 5-HT1A receptor antagonist. A one-way
ANOVA on RI in social recognition session showed a significant effect of treatment (F
(4, 57) = 7.82, p < 0.0001)(Figure 4A). Post-hoc analysis showed that WAY-100,635 (1.0
mg/kg, p.o.) significantly antagonized the effect of brexpiprazole on
dizocilpine-induced social recognition deficits (Figure 4A, and 4B). Treatment with
WAY-100,635 alone did not alter RI and locomotion in dizocilpine-treated mice
(Figure 4A, and 4C). Furthermore, treatment with WAY-100,635 alone did not affect
RI, the time spent around stranger 2 mice, or exploratory behavior in untreated control
mice (Figure 4D, 4E and 4F).
20
Figure 4. Effect of a 5-HT1A antagonist on brexpiprazole's action in the
dizocilpine-induced social recognition deficits model
Dizocilpine (0.1 mg/kg, i.p.) or saline (10 ml/kg, i.p.) was administered twice daily on the day
before and 30 minutes prior to sociability testing. Brexpiprazole (Brex: 0.03 mg/kg, p.o.),
WAY-100,635 (WAY: 1 mg/kg, p.o.), or vehicle (5% (w/v) gum Arabic, p.o.) was administrated 1
hour prior to sociability testing. The effects of brexpiprazole on RI (A), duration of time spent
around each stranger mouse (B) and exploratory behavior (C) during social recognition sessions.
Values are the mean S.E.M (n = 11-13). *p < 0.05, ***p < 0.001 compared with dizocilpine
plus vehicle group, ###p < 0.001 compared with the dizocilpine plus brexpiprazole-treated group
(A, one-way ANOVA, followed by post hoc Bonferroni test). *p < 0.05, ***p < 0.001 compared
with stranger 1 mice (B, two-tailed paired t-test). N.S.: not significant. WAY-100,635 (WAY: 1.0
mg/kg, p.o.), or vehicle (5% (w/v) gum Arabic, p.o.) was administrated 1 hour prior to sociability
testing. The effects of WAY-100,635 on RI (D), duration of time spent around each stranger
mouse (E) and exploratory behavior (F) during social recognition sessions were shown. Values
are the mean S.E.M (n = 7). ***p < 0.001 compared with stranger 1 mice (E, two-tailed paired
t-test). N.S.: not significant.
21
5. DISCUSSION
The two major findings of this study are that the novel serotonin-dopamine
activity modulator brexpiprazole, but not risperidone or olanzapine, improved social
recognition deficits in mice after the administration of dizocilpine, and that 5-HT1A
receptors are critical to this beneficial effect. Antipsychotic drugs, such as risperidone
and olanzapine, are known to show limited efficacy in cognitive impairment, including
social recognition in schizophrenia and depression (Sergi et al, 2007; Krakowski and
Czobor, 2011; Suzuki et al, 2011; Remberk et al, 2012), despite improving various
cognitive functions in rodent disease models (Wang et al, 2007; Gumuslu et al, 2013;
Mutlu et al, 2011; 2012; Wolff and Leander, 2003). It is of considerable clinical
importance to find new ways of improving social recognition deficits in patients with
psychiatric diseases, such as schizophrenia and MDD, because of their huge negative
impact on the social functioning of patients (Tandberg et al, 2011; Tse et al, 2013;
Horan et al, 2012). There are noted discrepancies in antipsychotic drug effects between
rodents and humans, increasing the need for further detailed clinical studies on the
effects of brexpiprazole on social recognition in patients with psychiatric diseases.
Social recognition testing is a paradigm capable of evaluating social recognition,
based on the propensity of an individual mouse to spend more time with an unfamiliar
mouse than with a familiar mouse (Riedel et al, 2009; Nakatani et al, 2009). In other
cognitive tests performed in rodents, mice discriminate objects by vision in the novel
objective recognition test, by hearing in the fear conditioning test and by odor in the
social transmission food preference test (Hashimoto et al, 2005; 2007; Boix-Trelis et al,
2007; Amann et al, 2010). However, since social recognition testing incorporates
various factors such as visual, auditory and olfactory function and some tactile stimuli
22
needed for mouse sociability, this test provides a comprehensive evaluation of
cognition in rodents, compared with other cognitive tests (Nadler et al, 2004; Moy et al,
2004; 2007). Therefore, the social recognition test in mice may represent a translational
rodent model for human social cognition, since the model utilizes multiple aspects of
mice socialization.
Here, we evaluated social recognition using an automated three-chambered
apparatus system. This apparatus is capable of measuring the time and distance a subject
mouse covers in approaching a novel mouse, thereby evaluating the subject’s
motivation to interact with the novel mouse. Furthermore, this system can also measure
exploratory behavior by producing a representative trace of locomotor activity. This
means that effects on locomotion, such as, sedation by a drug, can be easily detected.
Since stranger mice were isolated individually in a wire cage, the subject mouse could
interact with a stranger mouse without attack or aversive stimuli. This makes the social
recognition test in mice a potential tool for assessing the efficacy of new drugs on social
recognition.
We found that the 5-HT1A antagonist, WAY-100,635, reversed the effects of
brexpiprazole on dizocilpine-induced social recognition deficits, indicating that 5-HT1A
receptors are critical to brexpiprazole’s mechanism of action. A report suggests that
5-HT1A receptor agonism is related to social recognition in rats (Millan et al, 2004). In
addition, it is reported that 5-HT1A receptors are important in the action of other
antipsychotic drugs (perospirone, aripiprazole, blonanserin), when tested in a
phencyclidine-induced cognitive deficits model (Hagiwara et al, 2008; Nagai et al,
2009; Horiguchi and Meltzer, 2012; 2013). In contrast, WAY-100,635 could alleviate
cognitive deficits in monkeys after administration of dizocilpine (Harder and Ridley,
23
2000), suggesting pro-cognitive effect of 5-HT1A receptor antagonist. However, in this
study, WAY-100,635 alone was no effect in social recognition in both dizocilpine-treated
and vehicle-treated control mice. Further studies of the effects of 5-HT1A receptor
agonists and antagonists on social recognition are needed. Previously, Sumiyoshi et al.
(2001a; 2001b; 2007) reported that treatment with tandospirone (or buspirone), 5-HT1A
receptor agonists, improved cognition including executive function and verbal learning
in patients with schizophrenia, indicating a key role of 5-HT1A receptor in cognition in
patients (Meltzer and Sumiyoshi, 2008; Sumiyoshi et al, 2013). Taken together, it seems
that brexpiprazole can ameliorate cognitive deficits associated with NMDA receptor
dysfunction, via its 5-HT1A agonistic activity. Further studies are needed to clarify the
effects of other antipsychotic drugs with 5-HT1A agonistic activity, on social cognition
in patients.
Previous reports demonstrated that 5-HT1A receptor antagonists impair sociability
in rodents, and that 5-HT1A receptor agonists improved sociability in the social
interaction in rodents (File and Seth, 2003; Bruins Slot et al, 2005; Snigdha and Neil,
2008; Gould et al, 2011). These findings suggest an important role of 5-HT1A receptors
in social behaviors. A recent study showed that the rewarding properties of social
interaction in mice require the coordinated activity of oxytocin and 5-HT1B receptor in
the nucleus accumbens, which are implicated in the social cognitive dysfunction in
patients with a number of psychiatric diseases (Dölen et al, 2013). Since brexpiprazole
has a moderate affinity at 5-HT1B receptor (Ki = 32 nM) (Maeda et al, 2014a), it is
possible that 5-HT1B receptor may, in part, be involved in the mechanisms of action of
brexpiprazole on social recognition deficits. Nonetheless, further studies on the role of
5-HT1B receptors in the mechanisms of action of brexpiprazole would be needed to
24
confirm this hypothesis.
In conclusion, brexpiprazole ameliorated social recognition deficits in mice after
administration of dizocilpine, and the 5-HT1A receptor antagonist WAY-100,635
reversed the effects of brexpiprazole in this model. Our results imply that brexpiprazole
could potentially serve as a therapeutic drug to treat social cognitive deficits in patients
with schizophrenia and MDD.
25
6. REFERENCES
Amann, L.C., Gandal, M.J., Halene, T.B., Ehrlichman, R.S., White, S.L., McCarren,
H.S., Siegel, S.J., 2010. Mouse behavioral endophenotypes for schizophrenia.
Brain Res. Bull. 83, 147-161.
Boix-Trelis, N., Vale-Martinez, A., Guillazo-Blanch, G., Marti-Nicolovius, M., 2007.
Muscarinic cholinergic receptor blockade in the rat prelimbic cortex impairs the
social transmission of food preference. Neurobiol. Learn. Mem. 87, 659-668.
Bruins Slot, L.A., Kleven, M.S., Newman-Trancredi, A., 2005. Effects of novel
antipsychotics with mixed D2 antagonist/5-HT1A agonist properties on
PCP-induced social interaction deficits on the rat. Neuropharmacology 49,
996-1006.
Dolen, G., Darvishzadeh, A., Huang, K.W., Malenka, R.C., 2013. Social reward
requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature
501, 179-184.
File, S.E., Seth, P., 2003. A review of 25 years of the social interaction test. Eur. J.
Pharmacol. 463, 35-53.
Gould, G.G., Hensler, J.G., Burke, T.F., Benno, R.H., Onaivi, E.S., Daws, L.C., 2011.
Density and function of central serotonin (5-HT) transporters, 5-HT1A and 5-HT2A
receptors, and effects of their targeting on BTBR T+tf/J mouse social behavior. J.
Neurochem. 116, 291-303.
Gumuslu, E., Mutlu, O., Sunnetci, D., Ulak, G., Celikyurt, I.K., Cine, N., Akar, F., 2013.
The effects of tianeptine, olanzapine and fluoxetine on the cognitive behaviors of
unpredictable chronic mild stress-exposed mice. Drug Res. 63, 532-539.
26
Hagiwara, H., Fujita, Y., Ishima, T., Kunitachi, S., Shirayama, Y., Iyo, M., Hashimoto,
K., 2008. Phencyclidine-induced cognitive deficits in mice are improved by
subsequent subchronic administration of the antipsychotic drug perospirone: role
of serotonin 5-HT1A receptors. Eur. Neuropsychopharmacol. 18, 448-454.
Harder, J.A, Ridley, R.M., 2000. The 5-HT1A antagonist, WAY 100,635, alleviates
cognitive impairments induced dizocilpine (MK-801) in monkeys.
Neuropharmacology 39, 547-55.
Hashimoto, K., 2006. The NMDA receptor hypofunction hypothesis for schizophrenia
and glycine modulatory sites on the NMDA receptors as potential therapeutic
drugs. Clin. Psychopharmacol. Neurosci. 4, 3-10.
Hashimoto, K., 2014. Targeting of NMDA receptors in new treatments for
schizophrenia. Expert. Opin. Ther. Targets in press
Hashimoto, K., Fujita, Y., Shimizu, E., Iyo, M., 2005. Phencyclidine-induced cognitive
deficits in mice are improved by subsequent subchronic administration of
clozapine, but not haloperidol. Eur. J. Pharmacol. 519, 114-117.
Hashimoto, K., Fujita, Y., Iyo, M., 2007. Phencyclidine-induced cognitive deficits in
mice are improved by subsequent subchronic administration of fluvoxamine: role
of sigma-1 receptors. Neuropsychopharmacology 32, 514-521.
Hashimoto, K., Fujita, Y., Horio, M., Kunitachi, S., Iyo, M., Ferraris, D., Tsukamoto, T.,
2009. Co-administration of a D-amino acid oxidase inhibitor potentiates the
efficacy of D-serine in attenuating prepulse inhibition deficits after administration
of dizocilpine. Biol. Psychiatry 65, 1103-1106.
Hashimoto, K., Malchow, B., Falkai, P., Schmitt, A., 2013. Glutamate modulators as
potential therapeutic drugs in schizophrenia and affective disorders. Eur. Arch.
27
Psychiatry Clin. Neurosci. 263, 367-377.
Henderson, A.R., 2013. The impact of social cognition training on recovery from
psychosis. Curr. Opin. Psychiatry 26, 429-432.
Hikichi, H., Kaku, A., Karasawa, J., Chaki, S., 2013. Stimulation of metabotropic
glutamate (mGlu) 2 receptor and blockade of mGlu1 receptor improve social
memory impairment elicited by MK-801 in rats. J. Pharmacol. Sci. 122, 10-16.
Horan, W.P., Green, M.F., DeGroot, M., Fiske, A., Hellemann, G., Kee, K., Kern, R.S.,
Lee, J., Sergi, M.J., Subotnik, K.L., Sugar, C.A., Ventura, J., Nuechterlein, K.H.,
2012. Social cognition in schizophrenia, Part 2: 12-month stability and prediction
of functional outcome in first-episode patients. Schizophr. Bull. 38, 865-872.
Horiguchi, M., Meltzer, H.Y., 2012. The role of 5-HT1A receptors in phencyclidine
(PCP)-induced novel object recognition (NOR) deficit in rats.
Psychopharmacology (Berl). 221, 205-215.
Horiguchi, M., Meltzer, H.Y., 2013. Blonanserin reverses the phencyclidine
(PCP)-induced impairment in novel object recognition (NOR) in rats: role of
indirect 5-HT1A partial agonism. Behav. Brain Res. 247, 158-164.
Karasawa, J., Hashimoto, K., Chaki, S., 2008. D-Serine and a glycine transporter
inhibitor improve MK-801-induced cognitive deficits in a novel object recognition
test in rats. Behav. Brain Res. 186, 78-83.
Krakowski, M., Czobor, P., 2011. Cholesterol and cognition in schizophrenia: a
double-blind study of patients randomized to clozapine, olanzapine and
haloperidol. Schizophr. Res. 130, 27-33.
Lo, P., Siu, A.M., 2014. Social cognition and work performance of persons with
schizophrenia in a Chinese population. Work (Reading, Mass.). in press.
28
Maeda, K., Sugino, H., Akazawa, H., Amada, N., Shimada, J., Futamura, T., Yamashita,
H., Ito, N., McQuade, R.D., Mørk, A., Pehrson, A.L., Hentzer, M., Nielsen, V.,
Bundgaard, C., Arnt, J., Stensbøl, T.B., Kikuchi, T., 2014a. Brexpiprazole I: In
vitro and in vivo characterization of a novel serotonin-dopamine activity modulator.
J. Pharmacol. Exp. Ther. 350, 589-604.
Maeda, K., Lerdrup,L., Sugino, H., Akazawa, H., Amada, N., McQuade, R.D., Stensbøl,
T.B., Bundgaard, C., Arnt J., Kikuchi, T., 2014b. Brexpiprazole II:
Antipsychotic-like profile and pro-cognitive effects of a novel serotonin-dopamine
activity modulator. J. Pharmacol. Exp. Ther. 350, 604-614.
Maehara, S., Okuda, S., Ohta, H., 2011. Ameliorative effect of N-desmethylclozapine in
animal models of social deficits and cognitive functions. Brain Res. Bull. 86,
146-151.
Matsuo, N., Tanda, K., Nakanishi, K., Yamasaki, N., Toyama, K., Takao, K., Takeshima,
H., Miyakawa, T., 2009. Comprehensive behavioral phenotyping of ryanodine
receptor type 3 (RyR3) knockout mice: decreased social contact duration in two
social interaction tests. Front. Behav. Neurosci. 3, 3.
Meltzer, H.Y., Horiguchi, M., Massey, B.W., 2011. The role of serotonin in the NMDA
receptor antagonist models of psychosis and cognitive impairment.
Psychopharmacology (Berl) 213, 289-305.
Meltzer, H.Y., Sumiyoshi, T., 2008. Does stimulation of 5-HT1A receptors improve
cognition in schizophrenia? Behav. Brain Res. 195, 98-102.
Millan, M.J., Bales, K.L., 2013. Towards improved animal models of evaluating social
cognition and its disruption in schizophrenia: The CNTRICS initiative. Neurosci.
Biobehav. Rev. 37, 2166-2180.
29
Millan, M.J., Gobert, A., Roux, S., Porsolt, R., Meneses, A., Carli, M., Di Cara, B.,
Jaffard, R., Rivet, J.M., Lestage, P., Mocaer, E., Peglion, J.L., Dekeyne, A., 2004.
The serotonin1A receptor partial agonist S15535
[4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine] enhances cholinergic transmission
and cognitive function in rodents: a combined neurochemical and behavioral
analysis. J. Pharmacol. Exp. Ther. 311, 190-203.
Moy, S.S., Nadler, J.J., Perez, A., Barbaro, R.P., Johns, J.M., Magnuson, T.R., Piven, J.,
Crawley, J.N., 2004. Sociability and preference for social novelty in five inbred
strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav. 3,
287-302.
Moy, S.S., Nadler, J.J., Young, N.B., Perez, A., Holloway, L.P., Barbaro, R.P., Barbaro,
J.R., Wilson, L.M., Threadgill, D.W., Lauder, J.M., Magnuson, T.R., Crawley,
J.N., 2007. Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred
strains. Behav. Brain Res. 176, 4-20.
Mutlu, O., Celikyurt, I.K., Ulak, G., Tanyeri, P., Akar, F.Y., Erden, F., 2012. Effects of
olanzapine and clozapine on radial maze performance in naive and
MK-801-treated mice. Arzneimittelforschung. 62, 4-8.
Mutlu, O., Ulak, G., Celikyurt, I.K., Akar, F.Y., Erden, F., 2011. Effects of olanzapine,
sertindole and clozapine on learning and memory in the Morris water maze test in
naive and MK-801-treated mice. Pharmacol. Biochem. Behav. 98, 398-404.
Nadler, J.J., Moy, S.S., Dold, G., Trang, D., Simmons, N., Perez, A., Young, N.B.,
Barbaro, R.P., Piven, J., Magnuson, T.R., Crawley, J.N., 2004. Automated
apparatus for quantitation of social approach behaviors in mice. Genes Brain
Behav. 3, 303-314.
30
Nagai, T., Murai, R., Matsui, K., Kamei, H., Noda, Y., Furukawa, H., Nabeshima, T.,
2009. Aripiprazole ameliorates phencyclidine-induced impairment of recognition
memory through dopamine D1 and serotonin 5-HT1A receptors.
Psychopharmacology (Berl) 202, 315-328.
Nakatani, J., Tamada, K., Hatanaka, F., Ise, S., Ohta, H., Inoue, K., Tomonaga, S.,
Watanabe, Y., Chung, Y.J., Banerjee, R., Iwamoto, K., Kato, T., Okazawa, M.,
Yamauchi, K., Tanda, K., Takao, K., Miyakawa, T., Bradley, A., Takumi, T., 2009.
Abnormal behavior in a chromosome-engineered mouse model for human
15q11-13 duplication seen in autism. Cell 137, 1235-1246.
Oh, H.K., Park, S.J., Bae, S.G., Kim, M.J., Jang, J.H., Ahn, Y.J., Woo, H., Kwon, G.,
Ryu, J.H., 2013. Kami-ondam-tang, a traditional herbal prescription, attenuates the
prepulse inhibition deficits and cognitive impairments induced by MK-801 in mice.
J. Ethnopharmacol. 146, 600-607.
Okamura, N., Hashimoto, K., Shimizu, E., Kumakiri, C., Komatsu, N., Iyo, M., 2004.
Adenosine A1 receptor agonists block the neuropathological changes in rat
retrosplenial cortex after administration of the NMDA receptor antagonist
dizocilpine. Neuropsychopharmacology 29, 544-550.
Rajagopal, L., Massey, B.W., Huang, M., Oyamada, Y., Meltzer, H.Y., 2013. The novel
object recognition test in rodents in relation to cognitive impairment in
schizophrenia. Curr. Pharm. Des. In press
Remberk, B., Namyslowska, I., Rybakowski, F., 2012. Cognition and communication
dysfunctions in early-onset schizophrenia: effect of risperidone. Prog.
Neuropsychopharmacol. Biol. Psychiatry 39, 348-354.
Riedel, G., Kang, S.H., Choi, D.Y., Platt, B., 2009. Scopolamine-induced deficits in
31
social memory in mice: reversal by donepezil. Behav. Brain Res. 204, 217-225.
Rogoz, Z., 2013. Effect of combined treatment with mirtazapine and risperidone on the
MK-801-induced changes in the object recognition test in mice. Pharmacol. Rep.
65, 1401-1406.
Sergi, M.J., Green, M.F., Widmark, C., Reist, C., Erhart, S., Braff, D.L., Kee, K.S.,
Marder, S.R., Mintz, J., 2007. Social cognition [corrected] and neurocognition:
effects of risperidone, olanzapine, and haloperidol. Am. J. Psychiatry 164,
1585-1592.
Snigdha, S., Neill, J.C., 2008. Improvement of phencyclidine-induced social behavior
deficits in rats: involvement of 5-HT1A receptors. Behav. Brain Res. 191, 26-31.
Sumiyoshi, T., Higuchi, Y., Uehara, T., 2013. Neural basis for the ability of atypical
antipsychotic drugs to improve cognition in schizophrenia. Front. Behav. Neurosci.
7, 140.
Sumiyoshi, T., Matsui, M., Nohara, S., Yamashita, I., Kurachi, M., Sumiyoshi, C.,
Jayathilake, K., Meltzer, H.Y., 2001a. Enhancement of cognitive performance in
schizophrenia by addition of tandospirone to neuroleptic treatment. Am. J.
Psychiatry 158, 1722-1725.
Sumiyoshi, T., Matsui, M., Yamashita, I., Nohara, S., Kurachi, M., Uehara, T.,
Sumiyoshi, S., Sumiyoshi, C., Meltzer, H.Y., 2001b. The effect of tandospirone, a
serotonin1A agonist, on memory function in schizophrenia. Biol. Psychiatry 49,
861-868.
Sumiyoshi, T., Park, S., Jayathilake, K., Roy, A., Ertugrul, A., Meltzer, H.Y., 2007.
Effect of buspirone, a serotonin1A partial agonist, on cognitive function in
schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr.
32
Res. 95, 158-168.
Suzuki, H., Gen, K., Inoue, Y., 2011. An unblinded comparison of the clinical and
cognitive effects of switching from first-generation antipsychotics to aripiprazole,
perospirone or olanzapine in patients with chronic schizophrenia. Prog.
Neuropsychopharmacol. Biol. Psychiatry 35, 161-168.
Takatsu, Y., Fujita, Y., Tsukamoto, T., Slusher, B.S., Hashimoto, K., 2011. Orally
active glutamate carboxypeptidase II inhibitor 2-MPPA attenuates
dizocilpine-induced prepulse inhibition deficits in mice. Brain Res. 1371, 82-86.
Tandberg, M., Ueland, T., Sundet, K., Haahr, U., Joa, I., Johannessen, J.O., Larsen,
T.K., Opjordsmoen, S., Rund, B.R., Rossberg, J.I., Simonsen, E., Vaglum, P.,
Melle, I., Friis, S., McGlashan, T., 2011. Neurocognition and occupational
functioning in patients with first-episode psychosis: a 2-year follow-up study.
Psychiatry Res. 188, 334-342.
Trapp, W., Landgrebe, M., Hoesl, K., Lautenbacher, S., Gallhofer, B., Gunther, W.,
Hajak, G., 2013. Cognitive remediation improves cognition and good cognitive
performance increases time to relapse--results of a 5 year catamnestic study in
schizophrenia patients. BMC Psychiatry 13, 184.
Tse, S., Chan, S., Ng, K.L., Yatham, L.N., 2013. Meta-analysis of predictors of
favorable employment outcomes among individuals with bipolar disorder. Bipolar
Disord. 16, 217-229.
van der Kooij, M.A., Sandi, C., 2012. Social memories in rodents: methods,
mechanisms and modulation by stress. Neurosci. Biobehav. Rev. 36, 1763-1772.
Wang, D., Noda, Y., Zhou, Y., Nitta, A., Furukawa, H., Nabeshima, T., 2007.
Synergistic effect of combined treatment with risperidone and galantamine on
33
phencyclidine-induced impairment of latent visuospatial learning and memory:
Role of nAChR activation-dependent increase of dopamine D1 receptor-mediated
neurotransmission. Neuropharmacology 53, 379-389.
Wolff, M.C., Leander, J.D., 2003. Comparison of the effects of antipsychotics on a
delayed radial maze task in the rat. Psychopharmacology (Berl). 168, 410-416.
Yoshimi, N., Fujita, Y., Ohgi, Y., Futamura, T., Kikuchi, T., Hashimoto, K., 2014.
Effects of brexpiprazole, a novel serotonin-dopamine activity modulator, on
phencyclidine-induced cognitive deficits in mice: a role for serotonin 5-HT1A
receptors. Pharmacol. Biochem. Behav. 124, 245-249.
Zhang, L., Shirayama, Y., Iyo, M., Hashimoto, K., 2007. Minocycline attenuates
hyperlocomotion and prepulse inhibition deficits in mice after administration of
the NMDA receptor antagonist dizocilpine. Neuropsychopharmacology 32,
2004-2010.
34
III. CHAPTER 2
Effects of brexpiprazole, a novel serotonin-dopamine activity modulator, on
phencyclidine-induced cognitive deficits in mice: a role for serotonin 5-HT1A
receptors.
1. ABSTRACT
Brexpiprazole, a serotonin-dopamine activity modulator, is currently being
tested in clinical trials as a new therapy for a number of neuropsychiatric diseases,
including schizophrenia and major depressive disorder. Accumulating evidence suggests
that 5-hydroxytryptamine (5-HT)1A receptors play a role in cognition. This study was
undertaken to examine whether brexpiprazole, a novel drug with 5-HT1A receptor partial
agonism, could improve cognitive deficits in mice, induced by repeated administration
of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP).
Subsequent subchronic (14 days) oral administration of brexpiprazole (0.3, 1, or 3.0
mg/kg/day) significantly attenuated PCP (10 mg/kg/day for 10 days)-induced cognitive
deficits in mice, in a dose-dependent manner. The effects of brexpiprazole (3.0 mg/kg)
were significantly antagonized by co-administration of the selective 5-HT1A receptor
antagonist, WAY-100,635 (1.0 mg/kg), although WAY-100,635 alone was not effective
in this model. These findings suggest that brexpiprazole can ameliorate PCP-induced
cognitive deficits in mice via 5-HT1A receptors. Therefore, brexpiprazole could
ameliorate cognitive deficits as seen in schizophrenia and other neuropsychiatric
diseases.
35
2. INTRODUCTION
Cognitive deficits are a core feature in people with schizophrenia, leading to both
vocational and social disabilities (Coyle and Tsai, 2004; Freedman, 2003; Green et al,
2004; Niitsu et al, 2012; Sumiyoshi et al, 2013; Yoshida et al, 2012b). Current evidence
suggests that dysfunctional glutamatergic neurotransmission, via N-methyl-D-aspartate
(NMDA) receptors is instrumental in the pathophysiology of schizophrenia (Coyle and
Tsai, 2004; Hashimoto et al, 2004; 2005b; 2013; Heresco-levy and Javitt, 1998; Krystal
et al, 1999; Javitt and Zukin, 1991; Javitt et al, 2012). Antagonists at the NMDA
receptor, such as phencyclidine (PCP), are known to induce schizophrenia-like
symptoms, including cognitive deficits in healthy subjects (Javitt and Zukin, 1991). This
has led to the use of sub-chronic administration of PCP, as an animal model of cognitive
deficits in schizophrenia (Fujita et al, 2008; Hagiwara et al, 2008; Hashimoto et al,
2005a; 2006; 2007a; 2007b; Kunitachi et al, 2009; Javitt et al, 201; Jentsch and Roth,
1999; Tanibuchi et al, 2009). In the novel object recognition test (NORT), PCP (10
mg/kg/day for 10 days)-induced cognitive deficits were significantly ameliorated by
subsequent, subchronic (14 days) doses of clozapine, but not haloperidol (Hashimoto et
al, 2005a). These findings suggest that this reversal of PCP-induced cognitive deficits as
measured by the NORT, may represent a potential animal model of atypical
antipsychotic activity, in the amelioration of schizophrenia related cognitive deficits
(Hagiwara et al., 2008; Hashimoto et al, 2005a; 2006; 2007a; 2007b; 2007c; Tanibuchi
et al, 2009).
Several lines of evidence show that 5-hydroxytryptamine (5-HT)1A receptors play
a role in the pathophysiology of neuropsychiatric diseases including schizophrenia, and
that 5-HT1A receptors are important targets for emotion and cognition (Bantick et al,
36
2001; Meltzer, 1999; Ogren et al, 2008; Sumiyoshi et al, 2013). Early evidence comes
from findings that the density of 5-HT1A receptor binding is altered in the hippocampus
and cerebral cortex of postmortem brains from schizophrenia patients (Burnet et al,
1996; Gurevich and Joyce, 1997; Joyce et al, 1993; Lopez-Figueroa et al, 2004). A
positron emission tomography study demonstrated increased cortical 5-HT1A receptor
binding in drug-naive patients with schizophrenia (Borg, 2008; Tauscher et al, 2002). In
contrast, other studies found no changes in 5-HT1A receptor density between
schizophrenia and control samples (Bantick et al, 2004; Borg, 2008; Frankle et al, 2006).
Second, atypical antipsychotic drugs, such as clozapine, ziprasidone, aripiprazole and
quetiapine are all partial 5-HT1A receptor agonists, a property which may be relevant for
their therapeutic actions in schizophrenia (Jordan et al, 2002; Newman-Tancredi et al,
2001; Rollema et al, 2000; Sprouse et al, 1999). Third, Sumiyoshi and colleagues
(2001a; 2001b) reported that adjunctive treatment with tandospirone, a selective 5-HT1A
receptor agonist, induced improvements in some types of memory function, as well as
cognitive performance in schizophrenia. Taken together, findings to date suggest
5-HT1A receptor agonists as potential therapeutic drugs for treating cognitive deficits in
schizophrenia (Meltzer and Sumiyoshi, 2008; Newman-Tancredi, 2010; Yoshida et al.,
2012b; Sumiyoshi et al, 2013).
Brexpiprazole,
7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one (Figure 1), is
a potent partial agonist at human 5-HT1A (Ki = 0.12 nM), and dopamine D2L (Ki = 0.3
nM), and an antagonist at 5-HT2A receptors (Ki = 0.47 nM)(Maeda et al, 2014).
Considering the high affinity of brexpiprazole for 5-HT1A receptors, it would be of
interest to study the effects of brexpiprazole on PCP-induced cognitive deficits in mice.
37
In the present study, using the NORT, we examined the effects of subchronic treatment
(14 days) with brexpiprazole on cognitive deficits in mice, induced after repeated
administration of PCP. Furthermore, we examined the role of 5-HT1A receptors in the
action of brexpiprazole on the PCP-induced cognitive deficit model.
3. EXPERIMENTAL PROCEDURES
3.1. Animals
Male ICR mice (6 weeks old) weighing 25–30 g were purchased from SLC Japan
(Hamamatsu, Shizuoka, Japan). The mice were housed in clear polycarbonate cages
(22.5×33.8×14.0 cm) in groups of 5 or 6 individuals under a controlled 12/12-h
light–dark cycle (light from 7:00 AM to 7:00 PM), with the room temperature kept at 23
± 1°C and humidity at 55 ± 5%. The mice were given free access to water and food
pellets specifically designed for mice. The experimental procedure was approved by the
Animal Care and Use Committee of Chiba University Graduate School of Medicine.
3.2. Drugs
PCP hydrochloride was synthesized in our laboratory at Chiba University.
Brexpiprazole was provided from Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan).
WAY-100,635 maleate, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-
(2-pyridinyl)cyclohexanecarboxamide maleate salt), was purchased from Sigma-Aldrich
Corporation (St. Louis, MO, USA). Other drugs were purchased from commercial
sources.
38
3.3. Drug administration
Saline (10 ml/kg/day) or PCP (10 mg/kg/day expressed as a hydrochloride salt)
was administered subcutaneously (s.c.) for 10 days (once daily on days 1-5, 8-12) with
no treatment on days 6, 7, 13, and 14 (Figure 5). The treatment schedule was designed
in the manner of a previous PCP-induced cognitive deficit model (Hashimoto et al,
2005a; 2006; 2007a; 2007b; 2007c). After the final administration of saline or PCP,
vehicle (10 ml/kg/day; 0.5% methylcellulose), brexpiprazole (0.3, 1, or 3.0 mg/kg/day),
brexpiprazole (3.0 mg/kg/day) plus WAY-100,635 (1 mg/kg/day), or WAY-100,635 (1
mg/kg/day) alone was administered orally for 14 consecutive days (once daily on days
15-28) (Figure 5). The dose (1 mg/kg) chosen for WAY-100,635 was selected because
this dose was found to attenuate PCP-induced cognitive deficits via 5-HT1A receptor
mechanisms in vivo (Hagiwara et al, 2008).
39
3.4. Novel object recognition test (NORT)
The NORT was administered as previously reported (Hashimoto et al, 2005a;
2006; 2007a; 2007b; 2007c). As shown in Figure 5, the training session of NORT was
carried out 1 day (day 29) after the final administration of vehicle, brexpiprazole, or
WAY-100,635. The apparatus for this task consisted of a black open-field box
(50.8×50.8×25.4 cm). Before the test, mice were habituated to the box for 3 days.
During the training session, two objects (various objects were used that differed with
respect to shape and color, but that were similar in size) were placed in the box at a
35.5-cm distance from each other, and in a symmetrical fashion, and each animal was
Figure 5. Treatment schedule
Saline (10 ml/kg/day) or PCP (10 mg/kg/day) was administered subcutaneously (s.c.) to mice for
10 days (once daily, on days 1-5, 8-12). Three days (day 15) after the final dose of saline or PCP,
vehicle (10 ml/kg/day), brexpiprazole (0.3, 1.0, or 3.0 mg/kg/day), brexpiprazole (3.0 mg/kg/day)
plus WAY-100,635 (1.0 mg/kg/day), or WAY-100,635 (1.0 mg/kg/day) was administered orally,
for 14 consecutive days (once daily on days 15-28). On days 29 and 30, the novel object
recognition test (NORT) was carried out.
40
allowed to explore the interior of the box for 10 min (5 min x 2). The animals were
considered to be investigating the object when the head of the animal was either facing
the object and was located within an inch of the object, or if any part of the body, except
for the tail, was touching the object. The time that the mice spent exploring each object
was recorded. After the training session, the mice were immediately returned to their
home cages, and the box and objects were cleaned with 75% ethanol to avoid any
possible pheromonal cues. The retention test session was carried out 1 day after the
respective training sessions. During each retention test session, each mouse was placed
back into the same box it had previously encountered, but in which one of the two
objects used during training had been replaced by a novel object. The mice were then
allowed to freely explore the interior for 5 min, and the time spent exploring each object
was recorded. Throughout the experiments, the objects were used in a counter-balanced
manner in terms of their physical complexity. In order to measure memory performance,
a preference index was used, i.e., the ratio of the amount of time the mouse spent
exploring any one of the two objects (training session) or the novel object (retention
session) to the total time spent exploring both objects.
3.5. Statistical analysis
The data are expressed as mean S.E.M. Statistical analysis was performed using
one-way analysis of variance (ANOVA) and the post hoc Bonferroni test. The P values
of less than 0.05 were considered statistically significant.
41
4. RESULTS
4.1. Effects of brexpiprazole on PCP-induced cognitive deficits in mice
In the NORT, repeated administration of PCP (10 mg/kg/day for 10 days) led to
cognitive deficits in mice, consistent with previous reports (Hashimoto et al, 2005a;
2006; 2007a; 2007b). During the training session, there were no differences in
exploratory preferences among the eight groups of mice (F (7, 96) = 0.444, p=0.872)
(Figure 6A). Subsequent subchronic (14 days) administration of brexpiprazole
significantly attenuated PCP-induced cognitive deficits in mice, in a dose-dependent
manner. However, during the test session, ANOVA analysis revealed significant
differences in the exploratory preferences among the eight groups (F (7, 96) = 15.52, p
< 0.001) (Figure 6B). Post hoc Bonferroni test results indicated that subchronic dosing
with brexpiprazole increased exploratory preferences in the PCP-treated group, in a
dose dependent manner (Figure 6B). In addition, the effect of brexpiprazole (3.0
mg/kg) on PCP-induced cognitive deficits was significantly antagonized by
co-administration of the selective 5-HT1A receptor antagonist, WAY-100,635 (1.0
mg/kg/day) (Figure 6B). Moreover, a 14 day dosing with WAY-100,635 (1.0
mg/kg/day) alone did not reverse PCP-induced cognitive deficits in mice (Figure 6B).
Neither did a 14 day dosing with brexpiprazole (3.0 mg/kg/day) alone alter exploratory
preferences in control (saline-treated) mice (Figure 6B).
42
Figure 6. Effects of subchronic administration of brexpiprazole on PCP-induced
cognitive deficits in mice
Treatments were performed as shown in Figure 2. On days 29 and 30, the NORT was performed.
Values are the mean S.E.M (n = 10-16). N.S.: not significant, Brex: brexpiprazole, WAY:
WAY-100,635. **P < 0.01, ***P < 0.001 compared with the PCP plus vehicle-treated group. ###
P
< 0.001 compared with the PCP plus brexpiprazole (3.0 mg/kg)-treated group.
43
5. DISCUSSION
This study found that brexpiprazole was able to ameliorate PCP-induced
cognitive deficits in mice, via 5-HT1A receptors. Previously, we reported that
PCP-induced cognitive deficits as demonstrated on the NORT could be improved by
subsequent subchronic (14 days) administration of clozapine, but not haloperidol. This
suggested that the reversal of these deficits may represent a potential animal model of
atypical antipsychotic activity, for use in the ongoing investigations aimed at restoring
cognitive deficits in schizophrenia (Hashimoto et al, 2005a). Given the role of 5-HT1A
receptors in cognition (Bantick et al, 2001; Meltzer, 1999; Ogren et al, 2008; Yoshida et
al., 2012b; Sumiyoshi et al, 2013), it is likely that brexpiprazole confers a beneficial
effect on cognitive deficits in patients with neuropsychiatric diseases, such as
schizophrenia.
In an earlier report, we found that repeated dosing with PCP (10 mg/kg/day for 10
days) significantly reduced the density of 5-HT1A receptors in mouse hippocampus,
although the precise mechanisms underlying this action are currently unknown
(Hagiwara et al., 2008). Furthermore, we found that repeated PCP administration
significantly altered the response to 8-OH-DPAT (8-hydroxy-2-(dipropylamino)tetralin
hydrobromide: a 5-HT1A agonist)-induced hypothermia in mice (Hagiwara et al., 2008).
We also reported that perospirone, an antipsychotic drug with 5-HT1A receptor agonism,
could attenuate PCP-induced cognitive deficits via 5-HT1A receptors (Hagiwara et al.,
2008). Together, these findings imply that altered 5-HT1A receptor function resulting
from repeated PCP treatment may add to the dysregulation of glutamatergic
neurotransmission in the brain.
Sumiyoshi et al. (2001a; 2001b) reported that adjunctive treatment with the
44
5-HT1A receptor agonist, tandospirone, improves certain types of memory function, as
well as cognitive performance in patients with schizophrenia. In a later study,
Sumiyoshi et al. (2007) also reported that adjunctive treatment with buspirone, a widely
available 5-HT1A receptor agonist, significantly enhanced attention compared with the
placebo control group, highlighting a possible benefit for buspirone augmentation of
atypical antipsychotic drugs, to enhance attention. These findings suggest that 5-HT1A
receptor agonists, including brexpiprazole, may be useful for treating cognitive deficits
in schizophrenia.
Cognitive deficits are well documented in patients with other neuropsychiatric
diseases, including major depressive disorder (Porter et al., 2003; Hindmarch and
Hashimoto, 2010; Hasselbalch et al., 2011; Yoshida et al., 2012a), bipolar disorder
(Harvey et al., 2010; Bourne et al., 2013), and substance abuse (Dean et al., 2013). In
some ways, rodent NORT performance is analogous to human declarative (episodic)
memory, one of the seven cognitive domains impaired in patients with schizophrenia
(Rajagopal et al., 2014). It is therefore possible that brexpiprazole could be an equally
useful therapeutic drug in these patients.
In conclusion, our findings showed that PCP-induced cognitive deficits in mice
could be improved by subchronic treatment with brexpiprazole. Therefore,
brexpiprazole which acts as a 5-HT1A receptor partial agonist, could potentially serve as
a therapeutic drug for the treatment of cognitive deficits in patients with schizophrenia
and other neuropsychiatric diseases.
45
6. REFERENCES
Bantick, R.A., Deakin, J.F., Grasby, P.M., 2001. The 5-HT1A receptor in schizophrenia:
a promising target for novel atypical neuroleptics? Journal of
psychopharmacology (Oxford, England) 15, 37-46.
Bantick, R.A., Montgomery, A.J., Bench, C.J., Choudhry, T., Malek, N., McKenna, P.J.,
Quested, D.J., Deakin, J.F., Grasby, P.M., 2004. A positron emission tomography
study of the 5-HT1A receptor in schizophrenia and during clozapine treatment.
Journal of psychopharmacology (Oxford, England) 18, 346-354.
Borg, J., 2008. Molecular imaging of the 5-HT(1A) receptor in relation to human
cognition. Behavioural brain research 195, 103-111.
Bourne, C., Aydemir, O., Balanza-Martinez, V., Bora, E., Brissos, S., Cavanagh, J.T.,
Clark, L., Cubukcuoglu, Z., Dias, V.V., Dittmann, S., Ferrier, I.N., Fleck, D.E.,
Frangou, S., Gallagher, P., Jones, L., Kieseppa, T., Martinez-Aran, A., Melle, I.,
Moore, P.B., Mur, M., Pfennig, A., Raust, A., Senturk, V., Simonsen, C., Smith,
D.J., Bio, D.S., Soeiro-de-Souza, M.G., Stoddart, S.D., Sundet, K., Szoke, A.,
Thompson, J.M., Torrent, C., Zalla, T., Craddock, N., Andreassen, O.A., Leboyer,
M., Vieta, E., Bauer, M., Worhunsky, P.D., Tzagarakis, C., Rogers, R.D., Geddes,
J.R., Goodwin, G.M., 2013. Neuropsychological testing of cognitive impairment
in euthymic bipolar disorder: an individual patient data meta-analysis. Acta
psychiatrica Scandinavica 128, 149-162.
Burnet, P.W., Eastwood, S.L., Harrison, P.J., 1996. 5-HT1A and 5-HT2A receptor
mRNAs and binding site densities are differentially altered in schizophrenia.
Neuropsychopharmacology : official publication of the American College of
Neuropsychopharmacology 15, 442-455.
46
Coyle, J.T., Tsai, G., 2004. The NMDA receptor glycine modulatory site: a therapeutic
target for improving cognition and reducing negative symptoms in schizophrenia.
Psychopharmacology 174, 32-38.
Dean, A.C., Groman, S.M., Morales, A.M., London, E.D., 2013. An evaluation of the
evidence that methamphetamine abuse causes cognitive decline in humans.
Neuropsychopharmacology : official publication of the American College of
Neuropsychopharmacology 38, 259-274.
Frankle, W.G., Lombardo, I., Kegeles, L.S., Slifstein, M., Martin, J.H., Huang, Y.,
Hwang, D.R., Reich, E., Cangiano, C., Gil, R., Laruelle, M., Abi-Dargham, A.,
2006. Serotonin 1A receptor availability in patients with schizophrenia and
schizo-affective disorder: a positron emission tomography imaging study with
[11
C]WAY 100635. Psychopharmacology 189, 155-164.
Freedman, R., 2003. Schizophrenia. The New England journal of medicine 349,
1738-1749.
Fujita, Y., Ishima, T., Kunitachi, S., Hagiwara, H., Zhang, L., Iyo, M., Hashimoto, K.,
2008. Phencyclidine-induced cognitive deficits in mice are improved by
subsequent subchronic administration of the antibiotic drug minocycline. Progress
in neuro-psychopharmacology & biological psychiatry 32, 336-339.
Green, M.F., Nuechterlein, K.H., Gold, J.M., Barch, D.M., Cohen, J., Essock, S., Fenton,
W.S., Frese, F., Goldberg, T.E., Heaton, R.K., Keefe, R.S., Kern, R.S., Kraemer,
H., Stover, E., Weinberger, D.R., Zalcman, S., Marder, S.R., 2004. Approaching a
consensus cognitive battery for clinical trials in schizophrenia: the
NIMH-MATRICS conference to select cognitive domains and test criteria.
Biological psychiatry 56, 301-307.
47
Gurevich, E.V., Joyce, J.N., 1997. Alterations in the cortical serotonergic system in
schizophrenia: a postmortem study. Biological psychiatry 42, 529-545.
Hagiwara, H., Fujita, Y., Ishima, T., Kunitachi, S., Shirayama, Y., Iyo, M., Hashimoto,
K., 2008. Phencyclidine-induced cognitive deficits in mice are improved by
subsequent subchronic administration of the antipsychotic drug perospirone: role
of serotonin 5-HT1A receptors. European neuropsychopharmacology : the journal
of the European College of Neuropsychopharmacology 18, 448-454.
Harvey, P.D., Wingo, A.P., Burdick, K.E., Baldessarini, R.J., 2010. Cognition and
disability in bipolar disorder: lessons from schizophrenia research. Bipolar
disorders 12, 364-375.
Hashimoto, K., Okamura, N., Shimizu, E., Iyo, M., 2004. Glutamate hypothesis of
schizophrenia and approach for possible therapeutic drugs. Curr. Med. Chem. -
CNS Agents 4, 147-154.
Hashimoto, K., Fujita, Y., Shimizu, E., Iyo, M., 2005. Phencyclidine-induced cognitive
deficits in mice are improved by subsequent subchronic administration of
clozapine, but not haloperidol. European journal of pharmacology 519, 114-117.
Hashimoto, K., Shimizu, E., Iyo, M., 2005b. Dysfunction of glia-neuron communication
in pathophysiology of schizophrenia. Curr. Psychiatry Rev. 1, 151-163.
Hashimoto, K., Fujita, Y., Ishima, T., Hagiwara, H., Iyo, M., 2006.
Phencyclidine-induced cognitive deficits in mice are improved by subsequent
subchronic administration of tropisetron: role of alpha7 nicotinic receptors.
European journal of pharmacology 553, 191-195.
Hashimoto, K., Fujita, Y., Iyo, M., 2007. Phencyclidine-induced cognitive deficits in
mice are improved by subsequent subchronic administration of fluvoxamine: role
48
of sigma-1 receptors. Neuropsychopharmacology : official publication of the
American College of Neuropsychopharmacology 32, 514-521.
Hashimoto, K., Fujita, Y., Ishima, T., Chaki, S., Iyo, M., 2008. Phencyclidine-induced
cognitive deficits in mice are improved by subsequent subchronic administration
of the glycine transporter-1 inhibitor NFPS and D-serine. European
neuropsychopharmacology : the journal of the European College of
Neuropsychopharmacology 18, 414-421.
Hashimoto, K., Ishima, T., Fujita, Y., Matsuo, M., Kobashi, T., Takahagi, M., Tsukada,
H., Iyo, M., 2008. Phencyclidine-induced cognitive deficits in mice are improved
by subsequent subchronic administration of the novel selective alpha7 nicotinic
receptor agonist SSR180711. Biological psychiatry 63, 92-97.
Hashimoto, K., Malchow, B., Falkai, P., Schmitt, A., 2013. Glutamate modulators as
potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch
Psychiatry Clin Neurosci 263, 367-377.
Hasselbalch, B.J., Knorr, U., Kessing, L.V., 2011. Cognitive impairment in the remitted
state of unipolar depressive disorder: a systematic review. Journal of affective
disorders 134, 20-31.
Heresco-Levy, U., Javitt, D.C., 1998. The role of N-methyl-D-aspartate (NMDA)
receptor-mediated neurotransmission in the pathophysiology and therapeutics of
psychiatric syndromes. European neuropsychopharmacology : the journal of the
European College of Neuropsychopharmacology 8, 141-152.
Hindmarch, I., Hashimoto, K., 2010. Cognition and depression: the effects of
fluvoxamine, a sigma-1 receptor agonist, reconsidered. Human
psychopharmacology 25, 193-200.
49
Javitt, D.C., Zukin, S.R., 1991. Recent advances in the phencyclidine model of
schizophrenia. The American journal of psychiatry 148, 1301-1308.
Javitt, D.C., Zukin, S.R., Heresco-Levy, U., Umbricht, D., 2012. Has an angel shown
the way? Etiological and therapeutic implications of the PCP/NMDA model of
schizophrenia. Schizophrenia bulletin 38, 958-966.
Jentsch, J.D., Roth, R.H., 1999. The neuropsychopharmacology of phencyclidine: from
NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.
Neuropsychopharmacology : official publication of the American College of
Neuropsychopharmacology 20, 201-225.
Jordan, S., Koprivica, V., Chen, R., Tottori, K., Kikuchi, T., Altar, C.A., 2002. The
antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A
receptor. European journal of pharmacology 441, 137-140.
Joyce, J.N., Shane, A., Lexow, N., Winokur, A., Casanova, M.F., Kleinman, J.E., 1993.
Serotonin uptake sites and serotonin receptors are altered in the limbic system of
schizophrenics. Neuropsychopharmacology : official publication of the American
College of Neuropsychopharmacology 8, 315-336.
Krystal, J.H., D'Souza, D.C., Petrakis, I.L., Belger, A., Berman, R.M., Charney, D.S.,
Abi-Saab, W., Madonick, S., 1999. NMDA agonists and antagonists as probes of
glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders.
Harvard review of psychiatry 7, 125-143.
Kunitachi, S., Fujita, Y., Ishima, T., Kohno, M., Horio, M., Tanibuchi, Y., Shirayama, Y.,
Iyo, M., Hashimoto, K., 2009. Phencyclidine-induced cognitive deficits in mice
are ameliorated by subsequent subchronic administration of donepezil: role of
sigma-1 receptors. Brain research 1279, 189-196.
50
Lopez-Figueroa, A.L., Norton, C.S., Lopez-Figueroa, M.O., Armellini-Dodel, D., Burke,
S., Akil, H., Lopez, J.F., Watson, S.J., 2004. Serotonin 5-HT1A, 5-HT1B, and
5-HT2A receptor mRNA expression in subjects with major depression, bipolar
disorder, and schizophrenia. Biological psychiatry 55, 225-233.
Maeda, K., Sugino, H., Akazawa, H., Amada, N., Shimada, J., Futamura, T., Yamashita,
H., Ito, N., McQuade, R.D., Mork, A., Pehrson, A.L., Hentzer, M., Nielsen, V.,
Bundgaard, C., Arnt, J., Stensbol, T.B., Kikuchi, T., 2014. Brexpiprazole I: in vitro
and in vivo characterization of a novel serotonin-dopamine activity modulator.
The Journal of pharmacology and experimental therapeutics 350, 589-604.
Meltzer, H.Y., 1999. The role of serotonin in antipsychotic drug action.
Neuropsychopharmacology : official publication of the American College of
Neuropsychopharmacology 21, 106S-115S.
Meltzer, H.Y., Sumiyoshi, T., 2008. Does stimulation of 5-HT(1A) receptors improve
cognition in schizophrenia? Behavioural brain research 195, 98-102.
Newman-Tancredi, A., 2010. The importance of 5-HT1A receptor agonism in
antipsychotic drug action: rationale and perspectives. Current opinion in
investigational drugs (London, England : 2000) 11, 802-812.
Newman-Tancredi, A., Verriele, L., Touzard, M., Millan, M.J., 2001. Efficacy of
antipsychotic agents at human 5-HT(1A) receptors determined by
[3H]WAY100,635 binding affinity ratios: relationship to efficacy for G-protein
activation. European journal of pharmacology 428, 177-184.
Niitsu, T., Iyo, M., Hashimoto, K., 2012. Sigma-1 receptor agonists as therapeutic drugs
for cognitive impairment in neuropsychiatric diseases. Current pharmaceutical
design 18, 875-883.
51
Ogren, S.O., Eriksson, T.M., Elvander-Tottie, E., D'Addario, C., Ekstrom, J.C.,
Svenningsson, P., Meister, B., Kehr, J., Stiedl, O., 2008. The role of 5-HT(1A)
receptors in learning and memory. Behavioural brain research 195, 54-77.
Porter, R.J., Gallagher, P., Thompson, J.M., Young, A.H., 2003. Neurocognitive
impairment in drug-free patients with major depressive disorder. The British
journal of psychiatry : the journal of mental science 182, 214-220.
Rajagopal, L., Massey, B.W., Huang, M., Oyamada, Y., Meltzer, H.Y., 2013. The Novel
Object Recogniton Test in Rodents in Relation to Cognitive Impairment in
Schizophrenia. Current pharmaceutical design.
Rollema, H., Lu, Y., Schmidt, A.W., Sprouse, J.S., Zorn, S.H., 2000. 5-HT(1A) receptor
activation contributes to ziprasidone-induced dopamine release in the rat
prefrontal cortex. Biological psychiatry 48, 229-237.
Sprouse, J.S., Reynolds, L.S., Braselton, J.P., Rollema, H., Zorn, S.H., 1999.
Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine:
inhibition of dorsal raphe cell firing and the role of 5-HT1A receptor activation.
Neuropsychopharmacology : official publication of the American College of
Neuropsychopharmacology 21, 622-631.
Sumiyoshi, T., Matsui, M., Nohara, S., Yamashita, I., Kurachi, M., Sumiyoshi, C.,
Jayathilake, K., Meltzer, H.Y., 2001. Enhancement of cognitive performance in
schizophrenia by addition of tandospirone to neuroleptic treatment. The American
journal of psychiatry 158, 1722-1725.
Sumiyoshi, T., Matsui, M., Yamashita, I., Nohara, S., Kurachi, M., Uehara, T.,
Sumiyoshi, S., Sumiyoshi, C., Meltzer, H.Y., 2001. The effect of tandospirone, a
serotonin(1A) agonist, on memory function in schizophrenia. Biological
52
psychiatry 49, 861-868.
Sumiyoshi, T., Park, S., Jayathilake, K., Roy, A., Ertugrul, A., Meltzer, H.Y., 2007.
Effect of buspirone, a serotonin1A partial agonist, on cognitive function in
schizophrenia: a randomized, double-blind, placebo-controlled study.
Schizophrenia research 95, 158-168.
Sumiyoshi, T., Higuchi, Y., Uehara, T., 2013. Neural Basis for the Ability of Atypical
Antipsychotic Drugs to Improve Cognition in Schizophrenia. Frontiers in
behavioral neuroscience 7, 140.
Tanibuchi, Y., Fujita, Y., Kohno, M., Ishima, T., Takatsu, Y., Iyo, M., Hashimoto, K.,
2009. Effects of quetiapine on phencyclidine-induced cognitive deficits in mice: a
possible role of alpha1-adrenoceptors. European neuropsychopharmacology : the
journal of the European College of Neuropsychopharmacology 19, 861-867.
Tauscher, J., Kapur, S., Verhoeff, N.P., Hussey, D.F., Daskalakis, Z.J.,
Tauscher-Wisniewski, S., Wilson, A.A., Houle, S., Kasper, S., Zipursky, R.B.,
2002. Brain serotonin 5-HT(1A) receptor binding in schizophrenia measured by
positron emission tomography and [11C]WAY-100635. Archives of general
psychiatry 59, 514-520.
Yoshida, T., Ishikawa, M., Niitsu, T., Nakazato, M., Watanabe, H., Shiraishi, T., Shiina,
A., Hashimoto, T., Kanahara, N., Hasegawa, T., Enohara, M., Kimura, A., Iyo, M.,
Hashimoto, K., 2012. Decreased serum levels of mature brain-derived
neurotrophic factor (BDNF), but not its precursor proBDNF, in patients with
major depressive disorder. PloS one 7, e42676.
Yoshida, T., Iyo, M., Hashimoto, K., 2012b. Recent advances in the potential
therapeutic drugs for cognitive deficits in schizophrenia. Curr. Psychiatry Rev. 8,
54
IV. CONCLUSION
Brexpiprazole improved social recognition deficits impaired by dizocilpine in
social recognition test. This effect was antagonized by 5-HT1A receptor antagonist
WAY-100,635, suggesting that brexpiprazole can improve social recognition deficits
impaired by N-methyl-D-aspartate antagonist via 5-HT1A agonistic activity. Additionally,
brexpiprazole improved cognitive deficits impaired by PCP in NORT. This effect was
also antagonized by WAY-100,635, suggesting that brexpiprazole can improve cognitive
deficits impaired by N-methyl-D-aspartate antagonist throughout 5-HT1A agonistic
activity. Taken together, these studies suggest that brexpiprazole has ability to improve
cognitive deficits in animal models of psychiatric disorders. Therefore, brexpiprazole
would have beneficial effects for cognitive deficits in the patients with a number of
psychiatric disorders.
55
V. ACKNOWLEGEMENT
I owe my gratitude to all the people who helped me, though it will not be enough
to express my gratitude in words. First of all, I would like to gratefully and sincerely
thank my supervisor Professor Kenji Hashimoto for his continuous guidance and
understanding. I have learned a lot from him and felt motivated by his thoughtful
message. He provided me a new challenge and gave me a chance to grow as a
researcher. Additionally, I also gratefully acknowledge the work of past and present
members in his laboratory. Especially, Dr. Yuko Fujita and Dr. Tamaki Ishima
supported my work and gave me warm words of encouragement. I also appreciate the
clerical support of Ms. Rie Kamijo.
I am also deeply grateful to Dr. Tetsuro Kikuchi for actively supporting attempts
to my taking a doctoral degree. Special thanks are also given to Dr. Takashi Futamura
for helping me to find my supervisor. He always gave me valuable advice and a
precious time on discussions. I also express my gratitude to Dr. Kenji Maeda for telling
me about pharmacological profile of brexpiprazole and helpful discussions. I really
hope brexpiprazole will help many patients to improve their symptoms. I would also
like to thank Dr. Yuta Ohgi for helpful advice and telling me details for completing a
doctoral degree. I also convey my gratitude to the members in Otsuka pharmaceutical
company who gave me warm and useful messages. I really feel that I want to contribute
to development of a novel drug with them.
On more personal note, I would like to thank my husband Mr. Nozomu Yoshimi,
my father Mr. Akinori Yoshimi, my mother Mrs. Takako Yoshimi, my two sisters Mrs.
Naoko Maeda and Mrs. Masako Abe. Without their love, support and constant
encouragement, this work would not have been possible.