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The Open Clinical Chemistry Journal, 2009, 2, 7-11 7
Open Access
Improvement of Phencyclidine-Induced Cognitive Deficits in Mice by
Subsequent Subchronic Administration of Fluvoxamine, but not
Sertraline
Tamaki Ishima1, Yuko Fujita1, Mami Kohno1, Shinsui Kunitachi1, Mao Horio1, Yuto Takatsu1, Takahiko Minase1, Yuko Tanibuchi1,2, Hiroko Hagiwara1,2, Masaomi Iyo2 and Kenji Hashimoto1,* 1Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan, and 2Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan Abstract: This study was undertaken to examine the effects of the two selective serotonin reuptake inhibitors (SSRIs: flu-
voxamine and sertraline) with a high affinity at sigma-1 receptors on cognitive deficits in mice after repeated administra-
tion of the N-methyl-D-asparatte (NMDA) receptor antagonist phencyclidine (PCP). In the novel object recognition test
(NORT), PCP (10 mg/kg/day, 10 days)-induced cognitive deficits in mice were significantly improved by subsequent
subchronic (14 days) administration of fluvoxamine (20 mg/kg/day), but not sertraline (10 or 20 mg/kg/day). Western blot
analysis revealed that repeated administration of PCP (10 mg/kg/day, 10 days) caused the reduction of sigma-1 receptors
in the frontal cortex and hippocampus of mouse brain. These findings suggest that repeated administration of PCP caused
the reduction of sigma-1 receptors in the mouse brain, and that sigma-1 receptor agonists such as fluvoxamine may be
useful for treatment of cognitive deficits in schizophrenia.
sigma-1 receptors [26]. Recently, we reported that, in NORT, PCP-induced cognitive deficits could be significantly im- Cognitive deficits in patients with schizophrenia are core proved by subsequent subchronic (14 days) administration of features of the illness, and predict vocational and social dis- sigma-1 receptor agonists (fluvoxamine, SA4503, and dehy- abilities for patients [1]. Multiple lines of evidence suggest droepiandrosterone 3-sulfate (DHEA-S)), and that the effects that a dysfunction in glutamatergic neurotransmission via the of these sigma-1 receptor agonists was significantly antago- N-methyl-D-aspartate (NMDA) receptors might be involved nized by co-administration of the selective sigma-1 receptor in the pathophysiology of schizophrenia [2-11]. The NMDA antagonist NE-100 [13]. These findings suggest that agonis- receptor antagonists such as phencyclidine (PCP) are known tic activity of fluvoxamine at sigma-1 receptors plays a role to induce schizophrenia-like symptoms including cognitive in the active mechanisms of fluvoxamine on PCP-induced deficits and negative symptoms in healthy subjects [2]; con- cognitive deficits in mice [13]. sequently, PCP has been used widely in animal models of cognitive deficits in schizophrenia [2, 12-17]. We reported The present study was undertaken whether another SSRI that, in the novel object recognition test (NORT), PCP- sertraline with high affinity for sigma-1 receptors could im- induced cognitive deficits could be improved by subsequent prove PCP-induced cognitive deficits in mice. Furthermore, subchronic (14 days) administration of clozapine, but not we studied the effects of repeated PCP administration on the haloperidol, suggesting that reversal of PCP-induced cogni- levels of sigma-1 receptors in mouse brain. tive deficits using the NORT may be a potential animal model of atypical antipsychotic activity in relation to amelio- MATERIALS AND METHODS
ration of cognitive deficits in schizophrenia [12]. Accumulating evidence suggests that the endoplasmic Male ICR mice (6 weeks old) weighing 25–30 g were reticulum protein sigma-1 receptors play a role in the patho- purchased from SLC Japan (Hamamatsu, Shizuoka, Japan). physiology of neuropsychiatric diseases such as schizophre- Mice in groups of 4 or 5 were housed in clear polycarbonate nia, anxiety disorders, and depression as well as in the evolu- cages (22.5
33.8
14.0 cm) under a controlled 12/12-h light– tion of cognitive deficits associated with these conditions dark cycle (light from 7:00 AM to 7:00 PM), at 23 ± 1°C and [18-25]. We previously reported that some of selective sero- 55 ± 5% humidity. The mice were given free access to water tonin reuptake inhibitors (SSRIs) possess high to moderate and food pellets. The experimental procedure was approved affinity for sigma-1 receptors [26]. Among the SSRIs, flu- by the Animal Care and Use Committee of Chiba University. voxamine was the most potent (Ki = 36 nM) for sigma-1 receptors, and sertraline was also the potent (Ki = 57 nM) for Materials
*Address correspondence to this author at the Division of Clinical Neuro- PCP hydrochloride was synthesized in our laboratory. science, Chiba University Center for Forensic Mental Health, Chiba 260- Fluvoxamine maleate and sertraline hydrochloride were ob- 8670, Japan; E-mail: [email protected] 2009 Bentham Open
8 The Open Clinical Chemistry Journal, 2009, Volume 2
Ishima et al.
tained from Solvay Seiyaku K.K., (Tokyo, Japan) and To- brane fraction. The pellet was washed twice in buffer and ronto Research Chemicals Inc. (North York, ON, Canada), resuspended in the solution including 0.1 mg/mL aprotinin, respectively. Other drugs were purchased from commercial 0.1 mg/mL pepstatin, 2.5
g/mL phenylmethylsulfonyl fluo- sources. The doses of fluvoxamine (20 mg/kg) and sertraline ride, and 1% Tween 20. Aliquots (50
g protein) of the (10 or 20 mg/kg) had been shown to be effective in vivo as membranes were incubated for 5 min at 95°C with an equal reported previously [13, 27]. volume of 125 mM Tris/HCl, pH 6.8, 20% glycerol, 0.1% bromphenol blue, 10%
-mercaptoethanol, 4% SDS, and Drug Administration
subjected to SDS-PAGE using 10% mini-gels (Mini Protean II; Bio-Rad, Hercules, CA, USA). Proteins were transferred Saline (10 ml/kg) or PCP (10 mg/kg expressed as a hy- onto PVDF membranes using a Trans Blot Mini Cell (Bio- drochloride salt) was administered subcutaneously (s.c.) for Rad, Hercules, CA, USA). For immunodetection, the blots 10 days (once daily on days 1-5, 8-12) as reported previously were blocked for 1-2 h in TBST (50 mM Tris/HCl, pH 7.8, [12-17]. In the subchronic (14 days) administration experi- 0.13 M NaCl, 0.1% Tween 20) containing 5% nonfat dry ment, three days (day 15) after the final administration of milk at room temperature (RT), followed by incubation with saline or PCP, vehicle or drugs was administered i.p. into goat anti-sigma-1 receptor antibody (1:250, Cat. No: SC- mice. This treatment was continued for 14 consecutive days 16203, Santa Cruz Biotechnology, Inc., Santa Cruz, CA, (once daily on days 15-28). The training session of the USA) overnight at 4°C in TBST/5% blocker. The blots were NORT was performed 24 hours after the final administra- washed five times with TBST. Incubation with the secondary tion, and the retention test session was performed 24 hours antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, after the training session as described below. USA) was performed for 1 h at RT. After extensive washing, Novel Object Recognition Test (NORT)
immunoreactivity was detected by ECL plus Western Blot-ting Detection system (GE Healthcare Bioscience, UK). Im- NORT was performed as previously reported [12-17]. ages were captured using a Fuji LAS3000-mini imaging sys- The apparatus for this task consisted of a black open field tem (Fujifilm, Tokyo, Japan), and immunoreactive bands box (50.850.825.4 cm). Before the test, mice were habitu- were quantified.
-Actin immunoreactivity was used to ated in the box for 3 days. During a training session, two monitor equal sample loading. The levels of sigma-1 recep- objects (various objects differing in shape and color but tors in the PCP-treated mice were expressed as a percentage similar in size) were placed in the box 35.5 cm apart (sym- of those of saline-treated mice (control). metrically), and each animal was allowed to explore in the box for 5 minutes. The animals were considered to be ex- Statistical Analysis
ploring the object when the head of the animal was facing Data are expressed as means ± S.E.M. Statistical analysis the object within 2.54 cm of the object or when any part of was performed using Student t-test or one-way analysis of the body, except for the tail, was touching the object. The variance analysis (ANOVA) and the post hoc Bonferroni time that mice spent exploring each object was recorded. test. The p values less than 0.05 were considered statistically After training, mice were immediately returned to their home cages, and the box and objects were cleaned with 75% etha-nol to avoid any possible instinctive odorant cues. Retention tests were carried out at one–day intervals following the re-spective training. During the retention test each mouse was In the NORT, repeated administration of PCP (10 placed back into the same box in which one of the objects mg/kg/day for 10 days) caused significant cognitive deficits used during training was replaced by a novel one. The mice in mice, consistent with previous reports [12-17]. We found were then allowed to explore freely for 5 minutes, and the that PCP-induced cognitive deficits were significantly im- time spent exploring each object was recorded. Throughout proved after subsequent subchronic (14 days) administration the experiments, the objects were used in a counter-balanced of fluvoxamine (20 mg/kg/day), but not sertraline (10 or 20 manner in terms of their physical complexity and emotional mg/kg/day). The effect of fluvoxamine (20 mg/kg) on PCP- neutrality. A preference index, i.e., the ratio of the amount of induced cognitive deficits is consistent with a previous study time spent exploring any one of the two objects (training session) or the novel one (retention test session) over the In the training session, one-way ANOVA revealed that total time spent exploring respective to both objects, was the exploratory preferences of five groups were not signifi- used to measure memory performance. cantly different (F [4, 72] = 1.202, p=0.317) (Fig. 1). How-
ever, one-way ANOVA did reveal significant differences in
Western Blotting
the exploratory preferences of the five groups in the reten- Saline (10 ml/kg/day) or PCP (10 mg/kg/day) was ad- tion test sessions (F [4, 72] = 14.27, p<0.001) (Fig. 1). The
ministered s.c. for 10 days (once daily on days 1-5, 8-12). post hoc Bonferroni test indicated that the exploratory pref- Three days (days 15) after the final administration of saline erence of the PCP plus vehicle-treated group was signifi- or PCP (10 mg/kg/day for 10 days), mice were sacrificed by cantly (p<0.001) lower than that of the PCP plus fluvoxam- decapitation. Then, frontal cortex and hippocampus were ine (20 mg/kg/day)-treated group, but not of groups treated dissected on ice, and stored at -80°C. with PCP plus sertraline (10 or 20 mg/kg/day) (Fig. 1). In
contrast, there was no difference between vehicle-treated
Briefly, brain tissue was homogenized in 10 vol of 5 mM group and PCP plus fluvoxamine (20 mg/kg/day)-treated Tris/HCl (pH 7.4) containing 0.32 M sucrose and centrifuged group although the difference failed to reach statistical sig- for 10 min at 1,000 x g. The resulting supernatant was recen- nificance (p=0.065) (Fig. 1).
trifuged for 10 min at 40,000 x g to obtain the crude mem- Improvement of Phencyclidine-Induced Cognitive Deficits
The Open Clinical Chemistry Journal, 2009, Volume 2 9
Retention test session
Ser (10) Ser (20)
Ser (10) Ser (20)
Fig. (1). Effects of fluvoxamine and sertraline on PCP-induced cognitive deficits in mice. Saline (10 ml/kg/day) or PCP (10 mg/kg/day)
were administered s.c. for 10 days (once daily on days 1-5, 8-12). Three days (day 15) after the final administration of saline or PCP, vehicle
(10 ml/kg/day), fluvoxamine (20 mg/kg/day), or sertraline (10 and 20 mg/kg/day) were administered i.p. into mice. The treatment was con-
tinued for 14 consecutive days (once daily on day 15-28). The training session for the novel object recognition test was performed 24 hrs
(day 29) after the final administration of vehicle or drugs, and the retention test session was performed 24 hrs (day 30) after the training ses-
sion. Values are means ± S.E.M (n=9-24). ***p<0.001 as compared with PCP-treated group.
Next we examined whether repeated PCP administration chronic (14 days) administration of fluvoxamine, but not alters the density of sigma-1 receptors in the mouse brain. sertraline. Recently, we reported that, in the NORT, PCP- Western blot analysis revealed that levels of sigma-1 recep- induced cognitive deficits could be significantly improved tors in the frontal cortex (t=4.987, p=0.001) and hippocam- by subsequent subchronic (14 days) administration of flu- pus (t=3.482, p=0.006) of the PCP (10 mg/kg/day for 10 voxamine, and that the effect of fluvoxamine was signifi- days)-treated mice were significantly lower than those of cantly antagonized by co-administration of the selective saline-treated mice (Fig. 2).
sigma-1 receptor antagonist NE-100, suggesting the role of sigma-1 receptor agonism in the mechanism of action of DISCUSSION
fluvoxamine [7]. Unlike to fluvoxamine, sertraline (SSRI with a high affinity at sigma-1 receptors) did not attenuate The major findings of the present study are that repeated the PCP-induced cognitive deficits in mice. The reason un- PCP administration significantly decreased the density of derlying this discrepancy between two SSRIs is currently sigma-1 receptors in mouse brain, and that PCP-induced unclear. One possibility may be due to the difference for cognitive deficits could be improved by subsequent sub- pharmacological actions (agonist or antagonist) of two Fig. (2). Effects of repeated administration of PCP on sigma-1 receptor protein in mouse brain. Saline (10 ml/kg/day) or PCP (10
mg/kg/day) were administered s.c. for 10 days (once daily on days 1-5, 8-12). Three days (days 15) after the last administration of saline or
PCP, mice were sacrificed by decapitation. Western blot analysis using goat anti-sigma-1 receptor antibody was performed as described in
Methods. The levels of sigma-1 receptors in the PCP-treated mice were expressed as a percentage of those of saline-treated mice. Values are
the mean ± S.E.M (n=6). **p<0.01 as compared with saline-treated group (Control).
10 The Open Clinical Chemistry Journal, 2009, Volume 2
Ishima et al.
SSRIs at sigma-1 receptors. Takebayashi et al. [28] reported CONFLICT OF INTEREST
that antidepressants including fluvoxamine significantly Ms. Ishima, Ms. Fujita, Ms. Kohno, Mr. Kunitachi, Ms. could enhance nerve growth factor (NGF)-induced neurite Horio, Mr. Takatsu, Mr. Minase, Ms. Hagiwara and Dr. sprouting in PC12 cells, and that NE-100 blocked the en- Tanibuchi report no competing interests. Dr. Iyo reports re- hancements by these antidepressants, suggesting the role of ceiving the speaker fees from Janssen, Meiji Seika, Asteras, sigma-1 receptor agonism in the mechanism of action of Dainippon-Sumitomo, GlaxoSmithKline, Novartis, Eli Lilly, fluvoxamine [28]. Recently, we found that, unlike to fluvox- Pfizer, and Otsuka. Dr. Hashimoto reports receiving the amine, sertraline did not enhance the NGF-induced neurite speaker fees from Solvay, Meiji Seika, Asteras, Dainippon- sprouting in PC12 cells [29]. These finings suggest that flu- Sumitomo, Eli Lilly, Pfizer, Janssen, and Otsuka. voxamine and sertraline may exert as an agonist and an an-tagonist at sigma-1 receptors, respectively [29]. Taken to- gether, it is likely that the discrepancy of pharmacological action (agonist vs. antagonist) for sigma-1 receptors might Analysis of variance analysis contribute to the discrepancy of these two SSRIs on PCP- DHEA-S = Dehydroepiandsterone-sulfate induced cognitive deficits although a further detailed study is necessary. Nerve growth factor Another possibility may be due to anti-cholinergic effect NMDA = N-methyl-D-aspartate of sertraline. It is known that, unlike to fluvoxamine (Ki = Novel object recognition test 31,200 nM), sertraline binds to muscarinic receptors with a moderate affinity (Ki =427 nM) [23, 30]. Potent anti- cholinergic activity may produce the unpleasant side effects Selective serotonin reuptake inhibitor including cognitive deficits and memory loss [23, 24]. Thus, it is likely that anti-cholinergic activity of sertaline may play REFERENCES
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Received: November 21, 2008 Revised: January 12, 2009 Accepted: January 13, 2009 Ishima et al.; Licensee Bentham Open. This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

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