Ichiro Sora

Publications (145)455.67 Total impact

• Article: Evidence for shared genetic risk between methamphetamine-induced psychosis and schizophrenia.

  Masashi Ikeda, Yuko Okahisa, Branko Aleksic, Mujun Won, Naoki Kondo, Nobuya Naruse, Kumi Aoyama-Uehara, Ichiro Sora, Masaomi Iyo, Ryota Hashimoto, Yoshiya Kawamura, Nao Nishida, Taku Miyagawa, Masatoshi Takeda, Tsukasa Sasaki, Katsushi Tokunaga, Norio Ozaki, Hiroshi Ujike, Nakao Iwata
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  ABSTRACT: Methamphetamine (METH) use can provoke psychotic reactions requiring immediate treatment, namely METH-induced psychosis. Although the distinction between METH-induced and primary psychosis is important for understanding their clinical courses, we do not have clear diagnostic procedure by their symptoms. Not only are there similarities between the clinical features of METH-induced psychosis and schizophrenia, but there is also epidemiological evidence of a shared genetic risk between 'METH-related' disorders and schizophrenia, which makes the differentiation of these two conditions difficult. In this study, we conducted genome-wide association studies (GWAS) targeting METH-dependent patients. The METH sample group, used in the METH-dependence GWAS, included 236 METH-dependent patients and 864 healthy controls. We also included a 'within-case' comparison between 194 METH-induced psychosis patients and 42 METH-dependent patients without psychosis in a METH-induced psychosis GWAS. To investigate the shared genetic components between METH dependence, METH-induced psychosis and schizophrenia, data from our previous schizophrenia GWAS (total N=1108) was re-analyzed. In the SNP-based analysis, none of the SNPs showed genome-wide significance in either dataset. By performing a polygenic component analysis, however, we found that a large number of 'risk' alleles for METH-induced psychosis are overrepresented in individuals with schizophrenia (Pbest=0.0090). Conversely, we did not detect enrichment either between METH dependence and METH-induced psychosis or between METH dependence and schizophrenia. The results support previous epidemiological and neurobiological evidence for a relationship between METH-induced psychosis and schizophrenia. These also suggest that the overlap between genes scored as positive in these datasets can have higher probability as susceptibility genes for psychosis.Neuropsychopharmacology accepted article preview online, 17 April 2013; doi:10.1038/npp.2013.94.
  Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2013; · 6.99 Impact Factor
• Article: Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery: Validation of the Japanese version.

  Yasuhiro Kaneda, Tetsuro Ohmori, Yuko Okahisa, Tomiki Sumiyoshi, Shenghong Pu, Yoshinori Ueoka, Manabu Takaki, Kazuyuki Nakagome, Ichiro Sora
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  ABSTRACT: This preliminary study was performed to test the reliability and validity of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB), developed by the National Institute of Mental Health MATRICS initiative, as an assessment tool in a Japanese-language version (MCCB-J). The subjects for the present study were 37 patients with schizophrenia. Each subject gave written informed consent to participate in the research. In order to examine the validity of the MCCB-J, the correlation between the MCCB-J and the Japanese-language version of the Brief Assessment of Cognition in Schizophrenia (BACS) was determined. Cronbach's alpha for the MCCB-J was 0.72. The MCCB-J composite score was significantly correlated with all subtests of the MCCB-J. There was a significant correlation between the MCCB-J and the BACS composite score. This preliminary study indicates that the MCCB-J has good psychometric properties and validity.
  Psychiatry and Clinical Neurosciences 04/2013; 67(3):182-8. · 2.13 Impact Factor
• Article: Exclusive expression of VMAT2 in noradrenergic neurons increases viability of homozygous VMAT2 knockout mice.

  Arihisa Ohara, Yoshiyuki Kasahara, Hideko Yamamoto, Harumi Hata, Hideaki Kobayashi, Yohtaro Numachi, Ichiro Miyoshi, F Scott Hall, George R Uhl, Kazutaka Ikeda, Ichiro Sora
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  ABSTRACT: The vesicular monoamine transporter 2 (VMAT2) translocates monoamine neurotransmitters from the neuronal cytoplasm into synaptic vesicles. Since VMAT2-/- mice die within a few days of birth, it is difficult to analyze the detailed VMAT2 functions using these mice. In this study, we generated human VMAT2 transgenic mice that expressed VMAT2 in noradrenergic neurons with the aim to rescue the lethality of VMAT2 deletion. The expression of human VMAT2 in noradrenergic neurons extended the life of VMAT2-/- mice for up to three weeks, and these mice showed severe growth deficiency compared with VMAT2+/+ mice. These results may indicate that VMAT2 expressed in noradrenergic neurons has crucial roles in survival during the first several weeks after birth, and VMAT2 functions in other monoaminergic systems could be required for further extended survival. Although VMAT2 rescue in noradrenergic neurons did not eliminate the increased morbidity and lethality associated with VMAT2 deletion, the extension of the lifespan in VMAT2 transgenic mice will enable behavioral, pharmacological and pathophysiological studies of VMAT2 function.
  Biochemical and Biophysical Research Communications 02/2013; · 2.48 Impact Factor
• Article: Impaired cliff avoidance reaction in dopamine transporter knockout mice.

  Motoyasu Yamashita, Yasufumi Sakakibara, F Scott Hall, Yohtaro Numachi, Sumiko Yoshida, Hideaki Kobayashi, Osamu Uchiumi, George R Uhl, Yoshiyuki Kasahara, Ichiro Sora
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  ABSTRACT: RATIONALE: Impulsivity is a key feature of disorders that include attention-deficit/hyperactivity disorder (ADHD). The cliff avoidance reaction (CAR) assesses maladaptive impulsive rodent behavior. Dopamine transporter knockout (DAT-KO) mice display features of ADHD and are candidates in which to test other impulsive phenotypes. OBJECTIVES: Impulsivity of DAT-KO mice was assessed in the CAR paradigm. For comparison, attentional deficits were also assessed in prepulse inhibition (PPI) in which DAT-KO mice have been shown to exhibit impaired sensorimotor gating. RESULTS: DAT-KO mice exhibited a profound CAR impairment compared to wild-type (WT) mice. As expected, DAT-KO mice showed PPI deficits compared to WT mice. Furthermore, the DAT-KO mice with the most impaired CAR exhibited the most severe PPI deficits. Treatment with methylphenidate or nisoxetine ameliorated CAR impairments in DAT-KO mice. CONCLUSION: These results suggest that DAT-KO mice exhibit impulsive CAR behavior that correlates with their PPI deficits. Blockade of monoamine transporters, especially the norepinephrine transporter (NET) in the prefrontal cortex (PFC), may contribute to pharmacological improvement of impulsivity in these mice.
  Psychopharmacologia 02/2013; · 4.08 Impact Factor
• Article: Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine.

  Osamu Uchiumi, Yoshiyuki Kasahara, Asami Fukui, F Scott Hall, George R Uhl, Ichiro Sora
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  ABSTRACT: Dopamine transporter knockout (DAT KO) mice exhibit elevated extracellular dopamine levels in brain regions that include the striatum and the nucleus accumbens, but not the prefrontal cortex. DAT KO mice model some aspects of psychiatric disorders, including schizophrenia. Smoking is more common in patients with schizophrenia, suggesting that nicotine might ameliorate aspects of the behavioral abnormalities and/or treatment side effects seen in these individuals. We report nicotine-induced normalization of effects on locomotion and prepulse inhibition of acoustic startle (PPI) in DAT KO mice that require intact serotonin 5-HT1A systems. First, we observed that the marked hyperactivity displayed by DAT KO mice was reduced by administration of nicotine. This nicotine effect was blocked by pretreatment with the non-specific nicotinic acetylcholine (nACh) receptor antagonist mecamylamine, or the 5-HT1A antagonist WAY100635. Secondly, we examined the effects of nicotine on PPI in DAT KO mice. Treatment with nicotine significantly ameliorated the PPI deficits observed in DAT KO mice. The ameliorating action of nicotine on PPI deficits in DAT KO mice was blocked by mecamylamine, the α(7) nACh receptor antagonist methyllycaconitine or WAY100635, while the α(4)β(2) nACh receptor antagonist dihydro-β-erythroidinehydrobromide (DHβE) produced only a non-significant trend toward attenuation of nicotine effects. Finally, we observed that administration of the 5-HT1A receptor agonist 8-OH-DPAT also ameliorated the deficit in PPI observed in DAT KO mice. This amelioration was antagonized by pretreatment with WAY100635. These data support the idea that nicotine might ameliorate some of the cognitive dysfunctions found in schizophrenia in a 5-HT1A-dependent fashion. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
  Neuropharmacology 07/2012; 64(1):348-56. · 4.81 Impact Factor
• Article: Cortico-subcortical neuromodulation involved in the amelioration of prepulse inhibition deficits in dopamine transporter knockout mice.

  Yosefu Arime, Yoshiyuki Kasahara, F Scott Hall, George R Uhl, Ichiro Sora
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  ABSTRACT: Prepulse inhibition (PPI) deficits are among the most reproducible phenotypic markers found in schizophrenic patients. We recently reported that nisoxetine, a selective norepinephrine transporter (NET) inhibitor, reversed the PPI deficits that have been identified in dopamine transporter (DAT) knockout (KO) mice. However, the mechanisms underlying nisoxetine-induced PPI recovery in DAT KO mice were unclear in previous experiments. To clarify these mechanisms, PPI was tested after microinjections of nisoxetine into the medial prefrontal cortex (mPFc) or nucleus accumbens (NAc) in wildtype (WT) and DAT KO mice. c-Fos immunohistochemistry provided an indicator of neural activation. Multiple-fluorescent-labeling procedures and the retrograde tracer fluorogold were employed to identify nisoxetine-activated neurons and circuits. Systemic nisoxetine activated the mPFc, the NAc shell, the basolateral amygdala, and the subiculum. Infusions of nisoxetine into the mPFc reversed PPI deficits in DAT KO mice, but produced no changes in WT mice, while infusion of nisoxetine into the NAc had no effect on PPI in both WT and DAT KO mice. Experiments using multiple-fluorescent labeling/fluorogold revealed that nisoxetine activates presumed glutamatergic pyramidal cells that project from the mPFc to the NAc. Activated glutamatergic projections from the mPFc to the NAc appear to have substantial roles in the ability of a NET inhibitor to normalize PPI deficits in DAT KO. Thus, this data suggest that selective NET inhibitors such as nisoxetine might improve information processing deficits in schizophrenia via regulation of cortico-subcortical neuromodulation.
  Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2012; 37(11):2522-30. · 6.99 Impact Factor
• Article: Active behaviours produced by antidepressants and opioids in the mouse tail suspension test.

  Esther Berrocoso, Kazutaka Ikeda, Ichiro Sora, George R Uhl, Pilar Sánchez-Blázquez, Juan Antonio Mico
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  ABSTRACT: Most classical preclinical tests to predict antidepressant activity were initially developed to detect compounds that influenced noradrenergic and/or serotonergic activity, in accordance with the monoaminergic hypothesis of depression. However, central opioid systems are also known to influence the pathophysiology of depression. While the tail suspension test (TST) is very sensitive to several types of antidepressant, the traditional form of scoring the TST does not distinguish between different modes of action. The present study was designed to compare the behavioural effects of classical noradrenergic and/or serotonergic antidepressants in the TST with those of opioids. We developed a sampling technique to differentiate between behaviours in the TST, namely, curling, swinging and immobility. Antidepressants that inhibit noradrenaline and/or serotonin re-uptake (imipramine, venlafaxine, duloxetine, desipramine and citalopram) decreased the immobility of mice, increasing their swinging but with no effect on their curling behaviour. No differences were observed between antidepressants that act on noradrenergic or serotoninergic transmission. While opioid compounds also decreased the immobility of the mice [morphine, codeine, levorphanol, (-)-methadone, (±)-tramadol and (+)-tramadol], they selectively increased curling behaviour. Blocking opioid receptors with naloxone prevented the antidepressant-like effect of codeine, and μ-opioid receptor knockout decreased normal curling behaviour and blocked (±)-tramadol-induced curling, further demonstrating the reliability and validity of this approach. These results show that at least two behaviourally distinct processes occur in the TST, highlighting the antidepressant-like effects of opioids evident in this test. Furthermore, our data suggest that swinging and curling behaviours are mediated by enhanced monoamine and opioid neurotransmission, respectively.
  The International Journal of Neuropsychopharmacology 01/2012; · 4.58 Impact Factor
• Article: μ-opioid receptor-mediated alterations of allergen-induced immune responses of bronchial lymph node cells in a murine model of stress asthma.

  Kaori Okuyama, Soichiro Ide, Shinobu Sakurada, Kazumasu Sasaki, Ichiro Sora, Gen Tamura, Yuichi Ohkawara, Motoaki Takayanagi, Isao Ohno
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  ABSTRACT: Psychological stress has a recognized association with asthma symptoms. Using a murine model of allergic asthma, we recently demonstrated the involvement of μ-opioid receptors (MORs) in the central nervous system in the stress-induced exacerbation of airway inflammation. However, the involvement of MORs on neurons and immunological alterations in the stress asthma model remain unclear. MOR-knockout (MORKO) mice that express MORs only on noradrenergic and adrenergic neurons (MORKO/Tg mice) were produced and characterized for stress responses. Sensitized mice inhaled antigen and were then subjected to restraint stress. After a second antigen inhalation, bronchoalveolar lavage cells were counted. Before the second inhalation, bronchial lymph node (BLN) cells and splenocytes from stressed and non-stressed mice were cultured with antigen, and cytokine levels and the proportions of T cell subsets were measured. Stress-induced worsening of allergic airway inflammation was observed in wild-type and MORKO/Tg mice but not MORKO mice. In wild-type stressed mice, IFN-γ/IL-4 ratios in cell culture supernatants and the proportion of regulatory T cells in BLN cell populations were significantly lower than those in non-stressed mice. These differences in BLN cells were not observed between the stressed and non-stressed MORKO mice. Restraint stress had no effect on cytokine production or T cell subsets in splenocytes. Restraint stress aggravated allergic airway inflammation in association with alterations in local immunity characterized by greater Th2-associated cytokine production and a reduced development of regulatory T cells, mediated by MORs.
  Allergology International 12/2011; 61(2):245-58.
• Article: [Neuronal development of the hyperdopaminergic animal model].

  Yoshiyuki Kasahara, Yosefu Arime, Yumiko Kubo, Asami Fukui, Ichiro Sora
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  ABSTRACT: Dopamine transporter knockout (DAT KO) mice exhibited hyperdopaminergic tone in the nucleus accumbens and striatum, whereas they showed normal levels of extracellular dopamine in the prefrontal cortex. DAT KO mice showed numerous behavioral alterations that can be linked to abnormal dopaminergic function, including hyperlocomotion, deficits of prepulse inhibition (1PI) and impairment of working memory. PPI deficits were also shown in schizophrenic patients and hyperlocomotion was observed in AD/HD patients; therefore DAT KO mice had face validity for these psychiatric disorders. Impairment of neuronal development such as brain volume loss and decrease in spine density was reported especially in the prefrontal cortex of schizophrenia and AD/HD patients. We therefore investigated the neuronal development of DAT KO mice. Our results indicated that DAT KO mice had deficits of neuronal development in the prefrontal cortex similar to schizophrenia and AD/HD patients at least in part. These findings suggest that DAT KO mice are one of the useful models to investigate the impairment of neuronal development observed in psychiatric disorders including schizophrenia and AD/HD.
  Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology 11/2011; 31(5-6):195-9.
• Article: No significant association between SIRT1 gene and methamphetamine-induced psychosis in the Japanese population.

  Taro Kishi, Yasuhisa Fukuo, Tomo Okochi, Tsuyoshi Kitajima, Hiroshi Ujike, Toshiya Inada, Mitsuhiko Yamada, Naohisa Uchimura, Ichiro Sora, Masaomi Iyo, Norio Ozaki, Christoph U Correll, Nakao Iwata
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  ABSTRACT: We previously showed that the sirtuin 1 gene (SIRT1 gene), one of the clock genes, was associated with schizophrenia in a Japanese patient population. Because the symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia and because not every METH user develops psychosis, it is conceivable that METH-induced psychosis and schizophrenia have common susceptibility genes. Therefore, we conducted an analysis of the association of SIRT1 gene with METH-induced psychosis, hypothesizing a significant relationship. This paper presents a case-control study of the SIRT1 gene in 515 Japanese individuals (197 with METH-induced psychosis and 318 age-matched and sex-matched controls) with four tagging single nucleotide polymorphisms (rs12778366, rs2273773, rs4746720, and rs10997875), selected a priori using the HapMap database. rs10997875 (located in the 3' flanking region) was associated with METH-induced psychosis (unadjusted p(genotype)  = 0.0203). However, these results became non-significant after Bonferroni correction (corrected p(genotype)  = 0.0812). In the all-marker haplotype analysis, the SIRT1 gene was not associated with METH-induced psychosis (p = 0.146). Our findings suggest that SIRT1 gene does not contribute to the development of METH-induced psychosis in the Japanese population. However, a replication study using larger samples should be conducted to obtain conclusive results.
  Human Psychopharmacology Clinical and Experimental 08/2011; 26(7):445-50. · 2.48 Impact Factor
• Article: Association analysis of the GDNF gene with methamphetamine use disorder in a Japanese population.

  Tomoko Yoshimura, Hinako Usui, Nagahide Takahashi, Akira Yoshimi, Shinichi Saito, Branko Aleksic, Hiroshi Ujike, Toshiya Inada, Mitsuhiko Yamada, Naohisa Uchimura, Nakao Iwata, Ichiro Sora, Masaomi Iyo, Norio Ozaki
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  ABSTRACT: Methamphetamine (MAP) dependence is a highly heritable and aberrant dopaminergic signaling that has been implicated in the disease. Glial cell line-derived neurotrophic factor (GDNF), which plays an important role in the survival of dopaminergic neurons, may be involved in this disorder. In this study, we examined the association between GDNF and MAP dependence using a Japanese population-based sample. We selected eight single nucleotide polymorphisms (SNPs) in the GDNF locus for the association analysis. When patients with MAP dependence were divided into two subgroups consisting of multi-substance and MAP-only users, we detected a significant association between these two groups and the tagging SNP, rs2910704 (after Bonferroni's correction; allele P=0.034). Thus, GDNF is likely to be related to the severity of MAP use in the Japanese population.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 07/2011; 35(5):1268-72. · 3.25 Impact Factor
• Article: Decreased response to social defeat stress in μ-opioid-receptor knockout mice.

  Hiroshi Komatsu, Arihisa Ohara, Kazumasu Sasaki, Hiromi Abe, Hisaki Hattori, F Scott Hall, George R Uhl, Ichiro Sora
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  ABSTRACT: Substantial evidence exists that opioid systems are involved in stress response and that changes in opioid systems in response to stressors affect both reward and analgesia. Reportedly, mice suffering chronic social defeat stress subsequently show aversion to social contact with unfamiliar mice. To further examine the role of opioid systems in stress response, the behavioral and neurochemical effects of chronic social defeat stress (psychosocial stress) were evaluated in μ-opioid-receptor knockout (MOR-KO) mice. Aversion to social contact was induced by chronic social defeat stress in wild-type mice but was reduced in MOR-KO mice. Moreover, basal expression of brain-derived neurotrophic factor (BDNF) mRNA in MOR-KO mice hippocampi was significantly lower than in wild-type mice. Psychosocial stress significantly decreased BDNF mRNA expression in wild-type mice but did not affect BDNF expression in MOR-KO mice; no difference in basal levels of plasma corticosterone was observed. These results suggest that the μ-opioid receptor is involved in the behavioral sequelae of psychosocial stress and consequent regulation of BDNF expression in the hippocampus, and may play an important role in psychiatric disorders for which stress is an important predisposing or precipitating factor, such as depression, posttraumatic stress disorder, and social anxiety disorder.
  Pharmacology Biochemistry and Behavior 06/2011; 99(4):676-82. · 2.53 Impact Factor
• Article: Lack of association between translin-associated factor X gene (TSNAX) and methamphetamine dependence in the Japanese population.

  Taro Kishi, Tomo Okochi, Tsuyoshi Kitajima, Hiroshi Ujike, Toshiya Inada, Mitsuhiko Yamada, Naohisa Uchimura, Ichiro Sora, Masaomi Iyo, Norio Ozaki, Christoph U Correll, Nakao Iwata
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  ABSTRACT: Recently, we detected that the prokineticin 2 receptor gene was associated with not only major depressive disorder (MDD) but also methamphetamine dependence. Therefore, it is possible that mood disorders and drug addiction have shared susceptibility genes. The translin-associated factor X gene (TSNAX)/disrupted-in-schizophrenia-1 gene (DISC1) has been associated with psychiatric disorders, including schizophrenia, MDD and bipolar disorder. TSNAX is located immediately upstream of DISC1 and has been shown to undergo intergenic splicing with DISC1. Based on this evidence, we hypothesized that TSNAX might be a good candidate gene for methamphetamine dependence. We conducted a case-control study of Japanese individuals (215 with methamphetamine dependence and 318 age- and sex-matched controls) with three tagging SNPs (rs1630250, rs766288 and rs6662926) selected by HapMap database. rs1630250 was associated in males with methamphetamine dependence in the allele analysis (P-value: 0.0253). However, these results did not remain significant after Bonferroni correction to adjust for multiple comparisons (corrected P-value: 0.152). Our findings suggest that TSNAX does not play a role in methamphetamine dependence in the Japanese population. A replication study using larger samples needs to be conducted to obtain conclusive results.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 06/2011; 35(7):1618-22. · 3.25 Impact Factor
• Article: Effect of chronic lithium treatment on gene expression profile in mouse microglia and brain dendritic cells.

  Zhiqian Yu, Chiaki Ono, Ichiro Sora, Hiroaki Tomita
  Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology 04/2011; 31(2):101-2.
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  Available from: Taro Kishi

  Article: Lack of association between prokineticin 2 gene and Japanese methamphetamine dependence.

  Taro Kishi, Tsuyoshi Kitajima, Tomoko Tsunoka, Takenori Okumura, Kunihiro Kawashima, Tomo Okochi, Yoshio Yamanouchi, Yoko Kinoshita, Hiroshi Ujike, Toshiya Inada, Mitsuhiko Yamada, Naohisa Uchimura, Ichiro Sora, Masaomi Iyo, Norio Ozaki, Nakao Iwata
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  ABSTRACT: Disruption of circadian rhythms may be involved in the pathophysiology of psychiatric disorders, including drug addiction. Recently, we detected the significant association between prokineticin 2 receptor gene (PROKR2) and Japanese methamphetamine dependence patients. Also, prokineticin 2 (PK2) gene deficient mice showed reduced physiological and behavioral parameters, including circadian locomotor activity, circulating glucocorticoid, glucose levels and the expression of peripheral clock genes compared with WT mice. These evidences indicate that PK2 gene (PROK2) is a good candidate gene for the pathogenesis of methamphetamine dependence. To evaluate the association between PROK2 and methamphetamine dependence, we conducted a case-control study of Japanese samples (215 methamphetamine dependence and 232 controls) with four tagging SNPs selected by HapMap database. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). We did not detect an association between PROK2 and Japanese methamphetamine dependence patients in allele/genotype-wise analysis, or the haplotype analysis. Our findings suggest that PROK2 does not play a major role in the pathophysiology of methamphetamine dependence in the Japanese population.
  DNA research: an international journal for rapid publication of reports on genes and genomes 03/2011; 9(1):133-6. · 1.73 Impact Factor
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  Available from: Taro Kishi

  Article: Association Analysis of Nuclear Receptor Rev-erb Alpha Gene (NR1D1) and Japanese Methamphetamine Dependence.

  Taro Kishi, Tsuyoshi Kitajima, Kunihiro Kawashima, Tomo Okochi, Yoshio Yamanouchi, Yoko Kinoshita, Hiroshi Ujike, Toshiya Inada, Mitsuhiko Yamada, Naohisa Uchimura, Ichiro Sora, Masaomi Iyo, Norio Ozaki, Nakao Iwata
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  ABSTRACT: Several investigations suggested abnormalities in circadian rhythms are related to the pathophysiology of psychiatric disorders, including drug addiction. Recently, orphan nuclear receptor rev-erb alpha and glycogen synthase kinase-3 β (GSK-3β) were shown to be important circadian components. In addition, the orphan nuclear receptor rev-erb alpha is a key negative feedback regulator of the circadian clock. These evidences indicate that rev-erb alpha gene (NR1D1) is a good candidate gene for the pathogenesis of methamphetamine dependence. To evaluate the association between NR1D1 and methamphetamine dependence, we conducted a case-control study of Japanese samples (215 methamphetamine dependence and 232 controls) with three tagging SNPs selected by HapMap database. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). We did not detect an association between NR1D1 and Japanese methamphetamine dependence patients in allele/genotype-wise analysis, or the haplotype analysis. Our findings suggest that NR1D1 does not play a major role in the pathophysiology of methamphetamine dependence in the Japanese population.
  DNA research: an international journal for rapid publication of reports on genes and genomes 03/2011; 9(1):129-32. · 1.73 Impact Factor
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  Available from: Taro Kishi

  Article: Genetic Association Analysis of NOS1 and Methamphetamine-Induced Psychosis Among Japanese.

  Takenori Okumura, Tomo Okochi, Taro Kishi, Masashi Ikeda, Tsuyoshi Kitajima, Yoko Kinoshita, Kunihiro Kawashima, Tomoko Tsunoka, Yasuhisa Fukuo, Toshiya Inada, Mitsuhiko Yamada, Naohisa Uchimura, Masaomi Iyo, Ichiro Sora, Norio Ozaki, Hiroshi Ujike, Nakao Iwata
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  ABSTRACT: The neuronal nitric oxide synthase gene (NOS1) is located at 12q24, a susceptibility region for schizophrenia, and produces nitric oxide (NO). NO has been reported to play important roles as a gaseous neurotransmitter in brain. NO is a second messenger for the N-methyl-D aspartate (NMDA) receptor and is related to the dopaminergic system. Because the symptomatology of methamphetamine (METH) use disorder patients with psychosis is similar to that of patients with schizophrenia, NOS1 is a good candidate gene for METH-induced psychosis. Therefore, we conducted a case-control association study between NOS1 and METH-induced psychosis with Japanese subjects (183 with METH-induced psychosis patients and 519 controls). We selected seven SNPs (rs41279104, rs3782221, rs3782219, rs561712, rs3782206, rs6490121, rs2682826) in NOS1 from previous reports. Written informed consent was obtained from each subject. This study was approved by the Ethics Committee at Fujita Health University School of Medicine and each participating institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). No significant association was found between NOS1 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, we suggest that NOS1 might not contribute to the risk of METH-induced psychosis in the Japanese population.
  DNA research: an international journal for rapid publication of reports on genes and genomes 03/2011; 9(1):155-9. · 1.73 Impact Factor
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  Available from: Taro Kishi

  Article: No Association Between GRM3 and Japanese Methamphetamine-Induced Psychosis.

  Tomoko Tsunoka, Taro Kishi, Masashi Ikeda, Tsuyoshi Kitajima, Yoshio Yamanouchi, Yoko Kinoshita, Kunihiro Kawashima, Tomo Okochi, Takenori Okumura, Toshiya Inada, Hiroshi Ujike, Mitsuhiko Yamada, Naohisa Uchimura, Ichiro Sora, Masaomi Iyo, Norio Ozaki, Nakao Iwata
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  ABSTRACT: Several investigations have suggested that abnormalities in glutamate neural transmission play a role in the pathophysiology of psychiatric disorders, including schizophrenia. The metabotropic glutamate 3 receptor (mGluR3) gene was reported to be associated with schizophrenia, and paranoid type schizophrenia has symptoms that are similar to those of methamphetamine-induced psychosis. This suggests that mGluR3 gene (GRM3) is a good candidate gene for the pathogenesis of methamphetamine-induced psychosis. To evaluate the association between GRM3 and methamphetamine-induced psychosis, we conducted a case-control study of Japanese samples (181 methamphetamine-induced psychosis and 232 controls). We selected one functional SNP (rs6465084), reported to be associated with prefrontal brain functioning, for an association analysis. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). We did not detect an association between rs6465084 in GRM3 and Japanese methamphetamine-induced psychosis. Our findings suggest that rs6465084 in GRM3 does not play a major role in the pathophysiology of methamphetamine-induced psychosis in the Japanese population. However, because we did not perform an association analysis based on linkage disequilibrium (LD) or a mutation scan of GRM3, a replication study using a larger sample and based on LD may be required for conclusive results.
  DNA research: an international journal for rapid publication of reports on genes and genomes 03/2011; 9(1):160-2. · 1.73 Impact Factor
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  Available from: PubMed Central

  Article: Quantitative Detection of µ Opioid Receptor: Western Blot Analyses Using µ Opioid Receptor Knockout Mice.

  Shinya Kasai, Hideko Yamamoto, Etsuko Kamegaya, George R Uhl, Ichiro Sora, Masahiko Watanabe, Kazutaka Ikeda
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  ABSTRACT: Increasing evidence suggests that µ opioid receptor (MOP) expression is altered during the development of and withdrawal from substance dependence. Although anti-MOP antibodies have been hypothesized to be useful for estimating MOP expression levels, inconsistent MOP molecular weights (MWs) have been reported in studies using anti-MOP antibodies. In the present study, we generated a new anti-MOP antibody (N38) against the 1-38 amino acid sequence of the mouse MOP N-terminus and conducted Western blot analysis with wildtype and MOP knockout brain lysates to determine the MWs of intrinsic MOP. The N38 antibody detected migrating bands with relative MWs of 60-67 kDa in the plasma membrane fraction isolated from wildtype brain, but not from the MOP knockout brain. These migrating bands exhibited semi-linear density in the range of 3-30 µg membrane proteins/lane. The N38 antibody may be useful for quantitatively detecting MOP.
  DNA research: an international journal for rapid publication of reports on genes and genomes 03/2011; 9(1):219-22. · 1.73 Impact Factor
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  Available from: Hideaki Kobayashi

  Article: Association analysis of the tryptophan hydroxylase 2 gene polymorphisms in patients with methamphetamine dependence/psychosis.

  Hideaki Kobayashi, Hiroshi Ujike, Nakao Iwata, Toshiya Inada, Mitsuhiko Yamada, Yoshimoto Sekine, Naohisa Uchimura, Masaomi Iyo, Norio Ozaki, Masanari Itokawa, Ichiro Sora
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  ABSTRACT: There is a growing evidence that serotoninergic systems modulate dopaminergic neurotransmission. We analyzed the association between the variations in the brain tryptophan hydroxylase 2 (TPH2) gene, a rate limiting enzyme for serotonin biosynthesis, and methamphetamine (METH) dependence/psychosis in a Japanese population. We found ten single nucleotide polymorphisms (SNPs) and two polynucleotide polymorphisms in TPH2 gene exons and exon-intron boundaries. A total of 162 patients and 243 controls were used for the association analysis between these polymorphisms and METH dependence/psychosis. No significant differences were observed in either genotypic or allelic frequencies between METH dependent/psychotic patients and controls. A global test of differentiation among samples based on haplotype frequencies showed no significant association. With respect to latency of psychosis, prognosis of psychosis, and spontaneous relapse, we found no significant association with these SNPs. These results suggest that the TPH2 gene variants may not be a factor in vulnerability to METH dependence/psychosis.
  DNA research: an international journal for rapid publication of reports on genes and genomes 03/2011; 9(1):176-82. · 1.73 Impact Factor