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P1-C1

Differential role of deltaFosB and delta2deltaFosB in response to stress and drugs of abuse

OHNISHI YOSHINORI, OHNISHI YOKO, Nestler Eric J. 

Department of Neuroscience, Mount Sinai School of Medicine, New York, NY. USA    

The fosB gene produces two distinct mRNAs by alternative splicing. They encode FosB and deltaFosB, respectively. The latter presents two distinct proteins in the brain, one is deltaFosB, C-terminal truncated form of FosB, and the other is deltaFosB, N-terminal truncated form of deltaFosB. We have reported that deltaFosB accumulates in a region-specific manner in brain after chronic exposure to several types of stress, seizures, or drugs of abuse, and that deltaFosB, acting in the nucleus accumbens (NAc), enhances drug reward and promotes antidepressant-like responses. However, in most cases, these activities were observed under conditions when both deltaFosB and delta2deltaFosB accumulate. This is because endogenous and transgenic expressing mRNA constructs of deltaFosB may permit delta2deltaFosB expression and accumulation due to its extraordinary stability similar to deltaFosB.The goal of the present study was to determine whether the previously reported activities of deltaFosB are dependent on deltaFosB per se or also on delta2deltaFosB. To accomplish this goal, we injected adeno-associated virus expressing several types of fosB isotype and mutant into NAc, and did a broad behavioral battery. The data show that only deltaFosB has obvious antidepressant and pro-addictive effects, suggesting that delta2deltaFosB does not complement deltaFosB action. We are now studying the molecular mechanisms underlying these effects.


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P1-C2

Screening and Identifi cation of protein binding partners of deltaFosB using yeast two hybrid system

OHNISHI YOKO, OHNISHI YOSHINORI, Nestler Eric J.

Department of Neuroscience, Mount Sinai School of Medicine, New York, NY. USA

The fosB gene, a member of the AP-1 transcription factor family, has unique properties. it is transcribed into two mature mRNAs encoding FosB and a C-terminal truncated form, deltaFosB. AP-1 complexes consist of Fos family (c-fos, fosB, fra-1, fra-2) and Jun family (c-jun, junB, junD) proteins. Jun proteins are the main component of AP-1 complexes, and activate transcription of target genes as homodimers or as heterodimer with Fos family proteins. On the other hand, Fos family proteins exhibit variable effects on AP-1 transactivity. c-Fos and FosB enhance the transactivity of Jun, while deltaFosB is less active in many cases and, in some cases, can antagonize AP-1 mediated transcription.Our laboratory has focused on deltaFosB function in brain, and have shown that deltaFosB accumulates after prolonged exposure to stress, drugs of abuse, or other stimuli due to its unusual stability. We have shown further than deltaFosB is a key regulatory of drug and stress responses. To elucidate the functions of deltaFosB and other FosB products, we performed yeast two hybrid screening with several fragments of FosB. We identified 8 candidate binding partners with delta2deltaFosB (N-terminal deletion of deltaFosB). Binding of deltaFosB or FosB to several of these candidates has been confirmed in cell culture and in brain, and we have done further behavioral analysis with HSV expression system. Together, this work promises to provide new insight into the mechanisms by which deltaFosB and other FosB gene products regulate brain function and mediate complex behavioral plasticity.

 

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P1-DⅠ5

No alterations of brain GABA after 6 months of treatment with atypical antipsychotic drugs in early-stage fi rst-episode schizophrenia

Goto Naoki 1, Yoshimura Reiji 1, Kakeda Shingo 2, Moriya Junji 2, Hori Hikaru 1, Hayashi Kenji 1, Sugita Atsuko 1, Nakano Wakako 1, Katsuki Asuka 1, Nishimura Joji 2, Korogi Yukunori 2, Nakamura Jun 1

1 Department of psychiatry, University of Occupational and Environmental Health,Kitakyushu,Japan,
2 Department of Radiology,University of Occupational and Environmental Health,Kitakyushu,Japan

GABAergic dysfunction is generally considered to play an important role in the pathophysiology of schizophrenia.We investigated the effects of atypical antipsychotic drugs on GABA concentrations in early-stage,firstepisode schizophrenia patients.Sixteen (8 males,8females;age30 11years old)patients were followed up for six months.We also included 18 sexand age-matched healthy control subjects.The patients psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS)All patients were treated with atypical antipsychotic drugs (5 patients with risperidone,5 patients with olanzapine,4 patients with aripiprazole,and 2 patients with quetiapine).All subjects were examined by 1H-MRS using a 3T MR system with a standard quadrature head coil. The PANSS scores decreased 6 months after treatment of the patients with atypical antipsychotic drugs.In all three regions measured (frontal lobe,left basal ganglia,and parieto-occipital lobe),no differences in GABA concentrations were observed in a comparison of pre-treatment levels and those six months after treatment.These results suggest that relatively short-term treatment with atypical antipsychotic drugs may not affect GABAergic neurotransmission;however,it is also possible that such treatment prevents further reductions in brain GABA levels in people with earlystage, first-episode schizophrenia.This study was approved by the Ethics Committee of the University of Occupational and Environmental Health. All participants gave written consent to participate in the study.


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P1-DⅠ6

Evaluation of factors affecting Continuous Performance Test Identical Pairs Version (CPT-IP) score of schizophrenic patients in a Japanese clinical Sample

KOIDE TAKAYOSHI 1,Aleksic Branko 1,Kikuchi Tsutomu 1,2, Banno Masahiro 1,Kohmura Kunihiro 1,Adachi Yasunori 1,Kawano Naoko 1, Iidaka Tetsuya 1,Ozaki Norio 1

1 Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
2 Matsuzaki Hospital

Objectives: Cognitive impairment in schizophrenia strongly relates to social outcome and is a good candidate for endophenotypes. When we accurately measure drug efficacy or effects of genes or variants relevant to schizophrenia on cognitive impairment, clinical factors that can affect scores on cognitive tests, such as age and severity of symptoms, should be considered. To elucidate the effect of clinical factors, we conducted multiple regression analysis using scores of the Continuous Performance Test Identical Pairs Version (CPT-IP), which is often used to measure attention/vigilance in schizophrenia.Methods: We conducted the CPTIP (4-4 digit) and examined clinical information (sex, age, education, onset age, duration of illness, chlorpromazine equivalent dose, and Positive and Negative Symptom Scale [PANSS] scores) in a large Japanese population (cases=126, controls=138). Multiple regression analysis was used to evaluate the effect of clinical factors.Results: Age, chlorpromazine equivalent dose, and PANSS negative symptom score were associated with mean d' score in patients. These three clinical factors explained about 28% of the variance in mean d' score.Conclusions: Age, chlorpromazine equivalent dose, and PANSS negative symptom score may affect mean d' score in CPT-IP. We should consider the effect of these clinical factors when we interpret CPT-IP results.

 

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P1-DⅡ2

Association study of Fat-mass and obesity-associated (FTO) gene and body mass index in a Japanese schizophrenia and healthy Japanese population

WATANABE SHINYA, Iga Junichi, Nakataki Masahito, Numata Shusuke, Kikuchi Kumiko, Ohmori Tetsuro

Department of Psychiatry, University of Tokushima School of Medicine, Tokushima, Japan

[Objective] Fat-mass and obesity-associated (FTO) was a gene of unknown function, although genetic variations within the FTO gene have been repeatedly shown to be associated with the risk for obesity in many healthy populations including Japanese population. Meanwhile, patients with schizophrenia have an increased risk for obesity compared to the healthy population. The aim of this study is to elucidate the relationships among FTO gene polymorphisms and BMI in Japanese patients with schizophrenia and healthy subjects. [Method] Clinical parameters including BMI and atypical antipsychotics were evaluated in 351 hospitalized patients with schizophrenia and 342 healthy subjects. Single nucleotide polymorphism (SNP) within FTO gene (rs9939609) known to be associated with obesity was genotyped. Participants provided written informed consent and the institutional ethics committees approved our studies. [Results] A significant difference in genotype frequency between schizophrenia and healthy subjects was detected (P=0.013). There were no significant differences in age,sex and BMI between schizophrenia and healthy subjects. A significant effect of the rs9939609 polymorphism on BMI was found in healthy subjects but not in patients. [Conclusion] In our investigation, it is suggested that rs9939609 in FTO gene may play roles in the pathophysiology of Japanese schizophrenia and in the regulation of BMI in healthy subjects. No significant associations between BMI and rs9939609 in patients raise a possibility that other factors including food intake and energy consumption may influence BMI.

 

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P1-DⅡ6

The KCNH2 gene is associated with neurocognition and the risk of Schizophrenia

OHI KAZUTAKA1,2,3, Hashimoto Ryota 1,3,4, Yasuda Yuka 1,3, Fukumoto Motoyuki 1,3, Yamamori Hidenaga 1,3,5, Kamino Kouzin 1,2, Morihara Takashi 1, Iwase Masao1, Kazui Hiroaki 1, Takeda Masatoshi 1,4

  1. Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan,
  2. National Hospital Organization, Yamato Mental Medical Center,
  3. Core Research for Evolutionary Science and Technology of Japan Science and Technology Agency,
  4. Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of Medicine
  5. Department of Molecular Neuropsychiatry, Osaka University Graduate School of Medicine
Objectives. A genetic variant (rs3800779; M30) in the KCNH2 gene has been associated with schizophrenia, a lower intelligence quotient (IQ) and processing speed scores, altered brain functions and increased KCNH3-3.1 mRNA levels in the hippocampus. The aims of this study were to investigate whether the KCNH2 polymorphism is associated with schizophrenia-related neurocognitive deficits and to confirm the association between the variant and schizophrenia. Methods. The effects of the risk genotype on IQ and seven neurocognitive batteries were examined by the analysis of covariance in 191 healthy subjects. We performed a meta-analysis of the association between M30 and schizophrenia using five independent ethnic groups (1,720 cases; 2,418 controls). Written informed consent was obtained for all subjects after the procedures had been fully explained. Results. Consistent with the previous study, we provided evidence that subjects with the risk T carriers had significantly lower IQ scores than those with the G/G genotype (p=0.048). Of the seven neurocognitive batteries, subjects with the risk genotype demonstrated lower performances on attention/vigilance (p=0.0079) and working memory (p=0.0066) relative to subjects with the G/G genotype. Meta-analysis demonstrated evidence for an association between M30 and schizophrenia without showing heterogeneity across studies (odds ratio=1.18; p=0.0017). Conclusions. These data suggest that the KCNH2 polymorphism could be associated with schizophrenia-related neuropsychological deficits and the risk of developing schizophrenia.

 

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P1-DⅢ1

RELA Gene is associated with risk for schizophrenia and defi cits in prepulse Inhibition

Hashimoto Ryota 1,2,3,10, Ohi Kazutaka 2,3, Yasuda Yuka 2,3, Fukumoto Motoyuki 2,3, Yamamori Hidenaga 2,3,4, Takahashi Hidetoshi 2,3, Iwase Masao 2, Okochi Tomo 3,5, Kazui Hiroaki 2, Saitoh Osamu 6, Tatsumi Masahiko 7, Iwata Nakao 3,5, Ozaki Norio 8, Kamijima Kunitoshi 9, Kunugi Hiroshi 10, Takeda Masatoshi 1,2

  1. Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka Univ, Kanazawa Univ and Hamamatsu Univ School of Medicine, Osaka, Japan
  2. Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan
  3. CREST (Core Research for Evolutionary Science and Technology), JST (Japan Science and Technology Agency), Saitama, Japan
  4. Department of Molecular Neuropsychiatry, Osaka University Graduate School of Medicine, Osaka, Japan
  5. Fujita Health University School of Medicine, Aichi, Japan
  6. Department of Psychiatry, National Center Hospital, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
  7. Yokohama Shinryo Clinic, Yokohama, Kanagawa, Japan
  8. Department of Psychiatry, Nagoya University Graduate School of Medicine, Aichi, Japan
  9. Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan
  10. Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
The pathogenesis of schizophrenia is thought to involve aberrant immune and inflammatory responses. NF-kB plays important roles in the immune and inflammatory responses. The v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) gene encodes the major component of the NF-kB complex. We genotyped four single nucleotide polymorphisms (SNPs) in the RELA gene and performed a gene-based association analysis using 1224 patients with schizophrenia and 1663 controls. We found significant associations of three SNPs (rs11820062, rs2306365 and rs7119750) with schizophrenia and stronger evidence for association in a multi-marker sliding window haplotype analysis. The association between this gene and schizophrenia was evident in male subjects but not in female subjects, when separately analyzed by gender. In silico genotype-gene expression analysis revealed that these three schizophrenia-associated SNPs might be related to RELA mRNA expression in immortalized B-lymphocytes. In silico analysis also suggested the putative promoter SNP, rs11820062, might disrupts the consensus transcription factor binding sequence of the androgen receptor. The impact of four RELA polymorphisms on prepulse inhibition (PPI) was investigated in 53 patients with schizophrenia. We provided evidence that at risk genotypes of three SNPs were associated with deficits in PPI, however, there was no effect of the one non-risk SNP on PPI. These findings suggest that variants of the RELA gene are associated with risk for schizophrenia and PPI deficits in a Japanese population. Written informed consent was obtained from all subjects after the procedures had been fully explained. This study was approved by the institutions' ethical committees.

 

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P1-DⅢ5

Amino acid neurotransmission in schizophrenia patients and the effects of antipsychotic medication: A proton magnetic resonance spectroscopy study

NAKATAKI MASAHITO 1, KUBO HIROKO 2, IGA JUN-ICHI 2, WATANABE SHINYA 2, SUMITANI SATSUKI 2, HARADA MASAFUMI 3, OHMORI TETSURO 2

  1. Tokushima University Hospital
  2. The University of Tokushima Graduate School, Department of Psychiatry
  3. The University of Tokushima Graduate School, Department of Radiology
Amino acid, like glutamate (Glu) and Gamma-amino butyric acid (GABA), play a major role as a neurotransmitter in the brain cortex. At excitatory synapses, Glu released from neurons is taken up by glial cells and converted to glutamine (Gln), which is cycled back to neurons. GABA, an inhibitory neurotransmitter, is synthesized from glial Gln and contributes to total Gln/Glu neurotransmitter cycling. Multiple lines of evidence suggest that a dysfunction in glutamatergic and GABAergic neurotransmission might be involved in the pathophysiology of schizophrenia. High magnetic field proton magnetic resonance spectroscopy (1H-MRS) provides a reliable measurement of Glu, glutamine (Gln) and GABA in specific regions of the brain.This study measured amino acid concentration in the anterior cingulate cortex (ACC) and in the left basal ganglia (ltBG) in 38 patients with chronic using 3-Tesla MR scanner. All study participants gave written informed consent in accordance with the guidelines of the ethics committee of the University of Tokushima. In the ACC, the GABA concentration was negatively correlated with the dose of the antipsychotics (rs=-0.388, p=0.018). Glu and Gln showed no correlation with the dose of the antipsychotics, whereas the ratio of glutamine to glutamate was positively correlated with the dose of the antipsychotics (rs=0.464, p=0.004).These findings suggest that antipsychotic medication may cause changes in GABA concentration and in the ratio of glutamine to glutamate. This study support the hypothesis that amino acid neurotransmitter play a key role in the pathophysiology of schizophrenia.

 

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P1-DⅥ2

Adjunctive treatment with low-dosage pramipexole for risperidoneinduced hyperprolactinemia and sexual dysfunction in a male patient with schizophrenia

ISHITOBI MAKOTO, KOSAKA HIROTAKA, SHUKUNAMI KEN-ICHI, MURATA TETSUHITO, WADA YUJI

Department of Neuropsychiatry, University of Fukui, Fukui, Japan

Hyperprolactinemia is a frequent and severe side effect of antipsychotic treatment. Adjunctive dopamine D2 receptor (partial) agonist is one of the strategies for treatment of hyperprolactinemia. However, the utility of an adjunctive dopamine D2 (partial) agonist in managing antipsychoticinduced hyperprolactinemia without worsening psychosis in patients with schizophrenia remains controversial. Pramipexole, a preferential dopamine D3 receptor agonist, is currently used for treatment of idiopathic Parkinsons disease. We report the case of a 34-year-old male patient with schizophrenia who showed hyperprolactinemia induced by risperidone (2 mg/day) and ED, each of which was improved successfully without worsening psychosis by adjunctive treatment with low-dosage pramipexole (0.25 mg/day). Pramipexole, a preferential dopamine D3 receptor agonist with an approximately eight-fold preference for D3 receptors and less affinity for D1, D2, and D4, might be advantageous for reducing risks of exacerbating psychosis because of its lower affinity for D2 receptors. In some cases, adjunctive low-dosage pramipexole might be sufficient for early improvement of ED associated with antipsychoticinduced hyperprolactinemia.

 

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P1-KⅠ1

Association analysis between the 1,alpha-Hydroxylase (CYP27B1) gene polymorphisms and late-onset Alzheimer's disease

UTSUNOMIYA KENSUKE 1, SHINKAI TAKAHIRO 1, YAMADA KENJI 1, SAKATA SHINICHI 4,CHEN HSIN-I 2, OHMORI OSAMU 3, NAKAMURA JUN1

  1. Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
  2. Institute of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan
  3. Wakato Hospital, Kitakyushu, Japan
  4. Sagamigaoka Hospital, Sagamihara City, Japan

INTRODUCTION: Vitamin D may help to prevent neurodegeneration because it plays a key role in the expression of neurotrophic factors, the prevention of oxidative stress, calcium homeostasis, detoxification. Recent studies have reported that low levels of serum 25-hydroxyvitaminD (25[OH]D) were associated with an increased risk of substantial cognitive decline and dementia. 1,25-(OH)2D, the natural vitamin D receptor (VDR) ligand is derived from its precursor 25(OH)D by the enzyme 1,alpha(OH)ase encoded by the CYP27B1 gene. METHODS: We examined an association of polymorphisms at vitamin D metabolism enzyme, CYP27B1 in a Japanese sample of late-onset Alzheimer's disease (LOAD) (over 100 LOAD cases and 200 normal controls). RESULTS: Although our preliminary data does not suggest a robust association, analysis with complete data set is currently undergoing to clarify the relationship between CYP27B1 polymorphisms and LOAD. DISCUSSION: Several lines of findings suggest a possible role of in CYP27B1 and Alzheimer's disease (AD) pathogenesis. Further studies on CYP27B1 and other vitamin D pathway genes in AD will be needed.

 

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P2-AⅡ1

The effect of corticosterone to immunoreactive cell lines

NAKATANI YOSHIHIKO, AMANO TAKU, TSUJI MINORU, TAKEDA HIROSHI

Division of Pharmacology, School of Pharmacy, International University of Health and Welfare, Ohtawara, Japan

Corticosterone, which is classified as steroid hormone, is known as one of the glucocorticoids which have broad effects, such as regulation of glucose metabolism, the reaction of immune system and stress response, in many species. In general, it has been known that corticosterone involves to the stress response and is defined as stress hormone. After the hormonereceptor complex is formed in the cytoplasma, that complex translocates from cytoplasma to nucleus and regulates DNA transcription. Tremendous literatures have reported that neuron is vulnerable under the stress condition. However, the effect of corticosterone to the immunoreactive cell still has remained unclear though it is clear that the immune response cells play an important role under the stress condition. In this study, we focused to the microglia and macrophage, which are important for immunoreactions, and investigated the effect of corticosterone to the cell viability using several cell lines. Under the corticosterone existing culture condition, the proliferation of immunoreactive cells (BV-2 and RAW264.7) was suppressed drastically. On the other hand, neural type cell (Neuro2a, SH-SY5Y and RN46A) didn't show any change in cell proliferation. This inhibitory effect to the cell proliferation recovered by the glucocorticoid receptor antagonist, mifepristone, treatment, but not the mineralcorticoid receptor antagonist, spironolactone, treatment. In conclusion, corticosterone may play a key role to immune and stress response of microglia and macrophage via glucocorticoid receptor in the brain.

 

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P2-AⅡ4

Npas4 regulates neurite outgrowth and phosphoryation of synapsin I

Yun Jaesuk1,Taku Nagai1,Yoko Hibi1,Keisuke Kuroda2, Kozo Kaibuchi2,Kiyofumi Yamada 1

  1. Department of Neuropsychopharmacology and Hospital PharmacyGraduate School of Medicine, Nagoya University, Japan
  2. Departmentof Cell Pharmacology, Graduate School of Medicine, Nagoya University,Japan

We have previously reported that the mRNA levels of neuronal PAS domain protein 4 (Npas4), a brain specific basic helix-loophelix transcription factor, are decreased in the hippocampus of mice following a chronic social isolation or restriction stress. A recent study has demonstrated that Npas4 regulates the development of GABAergic inhibitory neurons. In the presents study, treatment with LiCl in Neuro2a cells resulted in an increase in Npas4 mRNA and phosphorylatedsynapsin I protein expression levels, which were associated with the neurite outgrowth. The knock down of Npas4 significantly inhibited the neurite outgrowth of Neuro2a cells induced by LiCl whereas the overexpression of Npas4 gene potentiated it. Overexpression of Npas4 in Neuro2a cells led to increase in the expression level of NeuN and phosphorylated synapsin I respectively. In primary cultured hippocampal neurons, Npas4 overexpression significantly increased in the protein level of phosphorylated synapsin I. These results suggest that Npas4 plays a role in the structural and functional plasticity of neurons.

 

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P2-BⅡ1

Reduced calcium/calmodulin-dependent protein kinase II activity in the hippocampus is associated with impaired cognitive function in 1-metyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice

MORIGUCHI SHIGEKI, YABUKI YASUSHI, FUKUNAGA KOHJI

Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

Parkinson's disease (PD) patients show deficit of cognitive functions during the early stage in PD. The dopaminergic neurotoxin, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced neurodegeneration causes an injury of the basal ganglia and revels PD-like behaviors. Here we demonstrated that deficit in cognitive functions in MPTP-treated mice is associated with reduced calcium/calmodulin-dependent protein kinase II (CaMKII) autophoshorylation and impaired LTP in the hippocampal CA1 region. Mice were injected once a day for 5 days with MPTP (25 mg/kg i.p.). The impaired motor coordination was observed 1to 2 weeks after MPTP treatment as assessed by a rota-rod and a beam-walking tasks. In immunoblot analyses, the protein levels of tyrosine hydroxylase and CaMKII autophoshorylation in the striatum were significantly decreased 1week after MPTP treatment. By contrast, deficits of cognitive function were observed 3 to 4 weeks after MPTP treatment. Impairment of long-term potentiation (LTP) in the hippocampal CA1 region was also impaired in MPTP-treated mice. Concomitant with impaired LTP, CaMKII autophosphorylation was significantly decreased 3 weeks after MPTP treatment in the hippocampal CA1 region. Finally, the reduced CaMKII autophosphorylation was closely associated with reduced GluR1 (Ser-831) phosphorylation in the hippocampal CA1 region of MPTP-treated mice. Taken together, decreased CaMKII activity with concomitant impaired LTP in the hippocampus likely account for the learning disability observed in MPTP-treated mice.

 

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P2-BⅡ2

Difference in the effect of Imipramine and GBR12909 on the Runway method using priming stimulation effect (PSE) of the intracranial selfstimulation (ICSS) behavior

EZUMI SATORU 1, KAWASAKI YOICHI 1, SAGARA HIDENORI 2, KITAMURA YOSHIHISA 3, MATSUNAGA HISASHI 1, GOMITA YUTAKA 4, SENDO TOSHIAKI 1

  1. Department of Pharmacy, Okayama University Hospital, Okayama, Japan
  2. Department of Pharmaceutical Information Science, Matuyama University
  3. Department of Pharmaceutical Care and Health Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
  4. Department of Pharmacology, Shujitsu University
The motivational deficit is one of the general aspects of the depression. Although it has been needed to improve motivation, no effective drug therapy is available because the estimating models for the motivation are insufficient. In our laboratory, it has been demonstrated that the Runway method using PSE of ICSS behavior can be a useful experimental methodology to estimate reward and motivational effects. However, the correlation between in the Runway method and the other affective animal models, such as forced swimming test (FST) is not clear. In the present study, we compared the behavioral effect of GBR12909 with imipramine in the traditional screening method of antidepressants, FST and the Runway method. In the Runway method, electrodes were implanted chronically into the lateral hypothalamic area (LH) in rats. The goal lever for stimulation of LH was set an opposite site of the start box in the apparatus. After training and acquisition of the operant behavior for getting the reward stimulation, the duration of the running time to the goal lever pressing was measured. In the FST, both imipramine (20 mg/kg) and GBR12909 (5mg/kg) shortened the immobility time. However, in the Runway method, imipramine decreased the running speed although GBR12909 increased the running speed under the priming stimulation condition. In addition, the enhancing effect of GBR12909 was inhibited by the haloperidol. These results suggest that the Runway method can be available to assess the motivational aspects in the depression and may reflect the dopaminergic transmission.

 

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P2-GⅥ1

Predicting antipsychotic plasma concentrations before titrating the dose: a population pharmacokinetic study

UCHIDA HIROYUKI1, David Mamo 2,4, Pollock Bruce 2,4, Suzuki Takefumi 1,5, Takeuchi Hiroyoshi 1, Nomura Kensuke 6, Tsunoda Kenichi 3, Watanabe Koichiro 1, Bies Robert 7

  1. Keio University School of Medicine, Department of Neuropsychiatry, Tokyo, Japan
  2. Centre for Addiction and Mental Health, Toronto, Canada
  3. Department of Psychiatry, Minami-hanno Hospital, Saitama, Japan
  4. University of Toronto, Department of Psychiatry, Toronto, Canada
  5. Department of Psychiatry, Inokashira Hospital, Tokyo, Japan
  6. Department of Psychiatry, Shimada Ryoiku Center, Tokyo, Japan
  7. Indiana University School of Medicine, Division of Clinical Pharmacology, Indianapolis, Indiana, US

Background: Due to a high interindividual variability in peripheral pharmacokinetic parameters, robustly predicting antipsychotic plasma concentrations before changing a dose for each individual has been a challenge, which can be overcome with population pharmacokinetic techniques in theory.
Methods: Two plasma samples for the measurement of risperidone and 9-hydroxyrisperidone concentrations were collected at two separate given time points from patients with schizophrenia (DSM-IV). Subsequently, we collected another sample, following a dosage change. A plasma concentration associated with the dosage change was predicted in a blinded fashion, using the two samples collected at the baseline dose, intervals between last dose and blood draw, and subjects' demographic information with a previously established population pharmacokinetic model for risperidone, using NONMEM. Accuracy of the predictions was then evaluated. This study was approved by the institutional review board at each of the participating sites, and prior to study entry subjects provided written informed consent after receiving detailed information about the protocol. All information collected was anonymized.
Results: Fifty-one subjects participated in this study; of these, one subject prematurely withdrew from this study due to a clinical worsening. Thus, the data from 50 subjects were included in the analysis (mean±SD age = 59±15; 39 men; 7 Caucasians and 43 Asians; 34 inpatients). The mean (95% CI) prediction errors and root squared prediction errors (ng/mL) were as low as 0.0 (-1.3-1.4) and 4.8 (3.6-6.0) for risperidone (Fig. 1a) and 1.0 (-1.1-3.0) and 7.1 (5.7-8.4) for 9-hydroxyrisperidone. The observed and predicted concentrations of risperidone and 9-hydroxyrisperidone were highly correlated (r=0.96, p<0.0001 and r=0.92, p<0.0001, respectively). When results of risperidone and 9-hydroxyrisperidone are combined as the active moiety, the mean (95% CI) prediction error and root squared prediction error (ng/mL) for the active moiety were, again, very low at 1.0 (-1.6-3.6) and 7.9 (6.1-9.8); in addition, a highly significant correlation was found between the observed and predicted concentrations of the active moiety (r=0.94, p<0.0001).
Conclusions: Antipsychotic plasma concentrations could be predicted before a dosage change. Taken together with the close relationship among plasma concentration, dopamine D2 receptor occupancy, and clinical effects, these findings suggest that individualized dosing with the measurement of antipsychotic plasma concentrations could become a real potential clinical application.

 

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P2-GⅥ4

The evolution of antipsychotic switch and polypharmacy in natural practice - a longitudinal perspective

TSUTSUMI CHISA 1, TSUTSUMI YUICHIRO 2, IMASAKA YASUSHI 3,4, KIMURA YOSHIE 3,6,WATANABE KOICHIRO 3,5, TOMITA MASAYUKI 5,6, HIRANO JINICHI 3,4,6, MIZUNO YUYA 7, DEN RYOSUKE 1, ISHIDUKI TOMOMI 8, NAKAGAWA ATSUO 5,9, KITAHATA RYOSUKE 10, UCHIDA HIROYUKI 5,6

  1. Department of psychiatry, Komagino Hospital, Tokyo, Japan
  2. Department of psychiatry, Ongata Hospital, Tokyo, Japan
  3. Department of psychiatry, Ohizumi Hospital, Tokyo, Japan
  4. Department of psychiatry, Ohizumi Mental Clinic, Tokyo, Japan
  5. Department of psychiatry, Keio University School of Medicine, Tokyo, Japa
  6. Department of psychiatry, Asakadai Mental Clinic, Saitama, Japan
  7. Department of psychiatry, Kawasaki Municipal Hospital, Kanagawa, Japan
  8. Department of psychiatry, Kawasaki city Rehabilitation Medical Center, Kanagawa, Japan
  9. Department of Clinical Research, The National center of Neurology and Psychiatry Translational Medical Center, Tokyo, Japan
  10. Department of psychiatry, Tokyo Musashino Hospital, Tokyo, Japan

Objective: Most patients with schizophrenia first start with a single antipsychotic, and yet most finally end up 'switching' or using 'polypharmacy'. The objective of this study was to examine the evolution of antipsychotic switch and polypharmacy in the real-world from a longitudinal perspective.
Methods: A systematic review of longitudinal antipsychotic prescriptions in 300 patients with schizophrenia for up to 2 years after their first visit to the psychiatric clinics in Tokyo, Japan between January, 2007 and June, 2008, was conducted. The evolution of switching and polypharmacy was studied, and prescribed doses were compared to suggested dose ranges by the Texas Medication Algorithm Project.
Results: 208 patients started their antipsychotic treatment with monotherapy. 34.1% of the patients gave up monotherapy with an initial antipsychotic to move to antipsychotic switch (27.4%) and/or polypharmacy (17.8%) within 2 years. The main reason for switching was 'ineffectiveness'; interestingly, this happened despite the fact that the monotherapy dose was below the recommended range in 47.7%. In a subgroup of 100 patients who started as antipsychotic-free, 2 year prevalence rates of switching and polypharmacy were 27.0% and 18.0%, respectively, and polypharmacy was resorted to after a median of 1 antipsychotic had been tried for 84 days (median).
Conclusions: These findings raise a concern that physicians may perform an antipsychotic switch without exploring the dose range and resort to antipsychotic polypharmacy without trying an adequate number of antipsychotics.

 

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P2-HⅢ3

Effect of chronic fl uoxetine treatment on dopamine D1 receptor signaling in the hippocampal dentate gyrus

KUROIWA MAHOMI1, SOTOGAKU NAOKI 1, SHUTO TAKAHIDE 1, MIYAKAWA TSUYOSHI 2, NISHI AKINORI 1

  1. Department of Pharmacology, Kurume University School of Medicine, Kurume, Japan
  2. ICMS, Fujita Health University, Toyoake, Japan

Major depression is a psychiatric disorder with high lifetime prevalence. Antidepressants have been widely used to treat major depression, although the mechanisms underlying their therapeutic effects are not fully understood. Recently, a selective serotonin reuptake inhibitor, fluoxetine, is reported to induce the dematuration of mature granule cells in the hippocampal dentate gyrus, in addition to the facilitation of adult neurogenesis. It is also reported that granule cells with features of immature cells show the decreased expression of calbindin, a marker of mature granule cells, and the increased expression of dopamine D1 receptors. In this study, we investigated dopamine D1 receptor signaling by monitoring the phosphorylation of PKA substrates including DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa) in dentate gyrus slices of C57BL/6 mice, which were treated with fluoxetine (15 mg/kg/day) for 14 days. Treatment of slices with a D1 receptor agonist, SKF81297, increased the phosphorylation of DARPP-32 at Thr34 in a dose dependent manner. The effect of SKF81297 (10 μM) was enhanced in fluoxetine-treated mice. The results suggest that the enhancement of D1 receptor signaling in dentate gyrus by chronic fluoxetine treatment may contribute to the therapeutic action of antidepressants.

 

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P2-IⅢ3

SOCS3, a candidate gene for the molecular effects of lithium and pathophysiology of MDD

IGA JUNICHI, KIKUCHI KUMIKO, TAYOSHI SUMIKO, NAKATAKI MASAHITO, WATANABE SHINYA, NUMATA SHUSUKE, OHMORI TETSURO

 Department of Psychiatry, Course of Integrated Brain Sciences, University of Tokushima School of Medicine, Tokushima, Japan

Objectives: To elucidate the association between SOCS3 and molecular effects of lithium and pathophysiology of MDD, we studied the SOCS3 gene expression changes in leukocytes of healthy individuals during lithium administration and MDD patients during antidepressant treatment.Methods: 8 healthy male subjects participated in the first study. Lithium was prescribed for 2 weeks enough to reach therapeutic serum concentration (0.6-1.0mM). Leukocyte counts and serum lithium concentrations were determined at baseline (before medication), 1-week, 2-week medication and post-2-week (2-week after stopping medication). Gene expression profiling was performed at each time point using Agilent G4112F Whole Human Genome arrays and real-time PCR. In the second study, we compared SOCS3 gene expression in the leukocytes between 27 MDD patients and healthy controls. Results: In the first study, leukocyte counts were significantly increased at 2-week compared with baseline and normalized at post-2-week. Pathway analysis based on the genes which were changed more than 2 folds revealed that Interleukin 6 (IL6) pathway including SOCS3 gene was regulated by lithium. We also confirmed that SOCS3 was significantly decreased by lithium using real-time PCR. In the second study, SOCS3 was significantly lower in MDD patients compared to healthy controls and was significantly increased to the control level by antidepressant treatment.Conclusions: Our investigation suggests that SOCS3 may be implicated in the molecular action of lithium and pathophysiology of MDD.

 

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