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Views:2215
ID 1299
Language Japanese
Title 特定領域「神経グリア回路網」A-03-5-公募
ニューロン・グリア間におけるD型セリンの分子機構解明
Last Modified Date Mar 31, 2010 22:21:19
Created Date Mar 31, 2010 22:21:19
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Item Description 著者:橋本 謙二

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N-Methyl-D-aspartate (NMDA)受容体を介するグルタミン酸神経伝達の異常は、統合失調症などの精神疾患の病態に関与していることが示唆されている。NMDA受容体のグリシン調節部位に作用するD型セリンは脳内に存在する酵素セリンラセマ−ゼ(SRR)によってL型セリンより合成されることが知られている。以前我々は、統合失調症の患者では、血液中D型セリン濃度が健常者と比較して有意に減少していることを報告し、統合失調症の病態におけるNMDA受容体機能低下仮説を支持する結果を報告した(Arch Gen Psychiatry 2003)。またカロリンスカ研究所との共同研究として、初発で未治療の統合失調症患者の脳脊髄液中の全セリン濃度に対するD型セリン濃度の割合が健常者と比較して有意に減少していること(Prog Neuropsychopharmacol Biol Psychiatry 2005)、およびグルタミン/グルタミン酸濃度比が健常者と比較して有意に増加していることを報告した(BMC Psychiatry 2005)。これらの結果は、統合失調症の発症時、脳ではD型セリンの合成・分解に係る過程やグリア−ニューロン間におけるグルタミン/グルタミン酸サイクルが異常になっている可能性を示唆している。すなわち、統合失調症の病態にグリアの異常が関与している可能性を強く示唆している(Curr Psychiatry Rev 2005)。

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N-Methyl-D-aspartate (NMDA)受容体を介するグルタミン酸神経伝達の異常は、統合失調症などの精神疾患の病態に関与していることが示唆されている。NMDA受容体のグリシン調節部位に作用するD型セリンは脳内に存在する酵素セリンラセマ−ゼ(SRR)によってL型セリンより合成されることが知られている。以前我々は、統合失調症の患者では、血液中D型セリン濃度が健常者と比較して有意に減少していることを報告し、統合失調症の病態におけるNMDA受容体機能低下仮説を支持する結果を報告した(Arch Gen Psychiatry 2003)。またカロリンスカ研究所との共同研究として、初発で未治療の統合失調症患者の脳脊髄液中の全セリン濃度に対するD型セリン濃度の割合が健常者と比較して有意に減少していること(Prog Neuropsychopharmacol Biol Psychiatry 2005)、およびグルタミン/グルタミン酸濃度比が健常者と比較して有意に増加していることを報告した(BMC Psychiatry 2005)。これらの結果は、統合失調症の発症時、脳ではD型セリンの合成・分解に係る過程やグリア−ニューロン間におけるグルタミン/グルタミン酸サイクルが異常になっている可能性を示唆している。すなわち、統合失調症の病態にグリアの異常が関与している可能性を強く示唆している(Curr Psychiatry Rev 2005)。

次に、ヒトSRR遺伝子について統合失調症との関連研究を行なった。5’-RACE解析により、SRRには4種類の5’非翻訳エクソン(Exon 1a-1d)が存在することを明らかにし、それらエクソンの選択的使用によって4種類のmRNA(Isoforms a-d)が生成されることを見いだした。また脳においては、Isoform bが主である事が判った。これらゲノム情報に基づきSRR遺伝子の変異・多型検索を実施した結果、exon 1b近傍に2個のSNPとintron 5および3’非翻訳部位に1個ずつ頻度の低いSNPを見つけた。本研究では頻度の高い2個のSNP(exon 1b近傍の2個のSNP)について解析を行なった結果、両群で差はなかった(Biol Psychiatry 2005)。
一方、死後脳を用いた研究は、統合失調症などの精神疾患の病態研究に不可欠であるが、脳内のアミノ酸濃度は、死亡から脳摘出して凍結するまでの時間(PMI: postmortem interval)などによって大きく影響することが知られている。今回、マウス脳を用いて脳内アミノ酸濃度とPMIとの関係を調べ、次にマウスで求めた補正式を米国スタンレイ財団より提供された死後脳(コントロ−ル、統合失調症、双極性障害、うつ病各15例)に当てはめ、各サンプルの死亡時期におけるアミノ酸(グルタミン酸、グルタミン、グリシン、D型セリン、L型セリン)濃度を測定した。その結果、D型セリン、L型セリン、グルタミン、グリシンについては4群で有意な差は無かったが、グルタミン酸に関しては、双極性障害、うつ病群において高値を示した(Biol Psychiatry 2007)。近年、治療抵抗性のうつ病患者を対象とした臨床試験研究より、NMDA受容体拮抗薬ケタミンに即効性の抗うつ作用があることが報告されており、うつ病の病態にグルタミン酸が重要な役割を果たしている可能性が指摘されている。今回の私たちの研究成果は、このケタミンの臨床効果を支持する結果であると思われる。

統合失調症を対象とした臨床試験研究より、NMDA受容体のグリシン調節部位の内在性アゴニストであるグリシンやD型セリンに治療効果があることが報告されている。しかしながら、体内動態や脳移行性等の問題により、多量のグリシンやD型セリンを服用する必要がある。我々は NMDA受容体拮抗薬の投与で引き起こされる統合失調症のモデル動物(プレパルス抑制障害モデル)を用いて、選択的なD型アミノ酸酸化酵素(D型セリンを分解する酵素)阻害剤を併用することにより、D型セリンの投与量を大幅に軽減することを見出した。また、NMDA受容体近傍の細胞外グリシン濃度は、グリア細胞に存在するグリシン・トランスポ−タ−(GlyT-1)によって制御されている。私たちは、NMDA受容体拮抗薬の投与で引き起こされる統合失調症のモデル動物(認知機能障害モデル)において、海馬におけるGlyT-1が増加しており、GlyT-1阻害薬が認知機能障害に有効であることを見出し、統合失調症の新規治療薬として有望であることを報告した(Eur Neuropsychopharmacol 2008)。またD型セリン合成酵素SRRと相互作用するPICK1遺伝子欠損マウスの発達期の脳では、全セリン濃度に対するD型セリンの割合が有意に減少していることを見出し、PICK1遺伝子が脳内D型セリン合成に関わっていることを報告した(Biol Psychiatry 2007)。さらに、ヒトPICK1遺伝子多型が覚せい剤精神病の発症に関わっていることを報告した(Am J Psychiatry 2007)。

以上の結果より、D型セリンおよびグリシンはNMDA受容体の内在性調節因子として、統合失調症などの精神疾患の病態に関与している可能性があり、グリア細胞は精神神経疾患の新しい治療ターゲットとして期待されている。

【文献】
1) Minabe Y, Hashimoto K, Shirayama Y, Ashby CR*. The effect of the acute and chronic administration of the putative atypical antipsychotic drug Y-931 (8-fluoro-12-4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3b][1,5]benzodiazepine maleate) on spontaneously active rat midbrain dopamine neurons: an in vivo electrophysiological study. Synapse 51: 19-26 (2004).
2) Minabe Y, Shirayama Y, Hashimoto K, Routledge C, Hagan JJ, Ashby CR*. The effect of the acute and chronic administration of the selective 5-HT6 receptor antagonist SB-271046 on the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study. Synapse 52: 20-28 (2004).
3) Hashimoto K*, Fukushima T, Shimizu E, Okada S, Komatsu N, Okamura N, Koike K, Koizumi H, Kumakiri C, Imai K, Iyo M. Possible role of D-serine in the pathophysiology of Alzheimer’s disease. Prog. Neuropharmacol. Biol. Psychiatry 28: 385-388 (2004).
4) Fujisaki M*, Hashimoto K, Iyo M, Chiba T. Role of amygdalo-hippocampal transition area in the fear expression: evaluation by behavior and immediate early gene expression. Neuroscience 124: 247-260 (2004).
5) Okamura N, Hashimoto K*, Shimizu E, Kumakiri C, Komatsu N, Iyo M. Adenosine A1 receptor agonists block the neuropathological changes in rat retrosplenial cortex after administration of the NMDA receptor antagonist dizocilpine. Neuropsychopharmacol. 29: 544-550 (2004).
6) Koizumi H, Hashimoto K*, Kumakiri C, Shimizu E, Sekine Y, Ozaki N, Inada T, Harano M, Komiyama T, Yamada M, Sora I, Ujike H, Takei N, Iyo M. Association between the glutathione S-transferase M1 gene deletion and female methamphetamine abusers. Am. J. Med. Genet. 126B: 43-45 (2004).
7) Shimizu E*, Hashimoto K, Iyo M. Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: the possibility to explain ethnic mental traits. Am. J. Med. Genet. 126B: 122-123 (2004).
8) Koike K, Hashimoto K*, Okamura N, Ohgake S, Shimizu E, Koizumi H, Komatsu N, Iyo M. Decrease of cell proliferation in the dentate gyrus of hippocampus of alpha-7 nicotinic receptor heterozygous mice. Prog. Neuropharmacol. Biol. Psychiatry 28: 517-520 (2004).
9) Koizumi H, Hashimoto K*, Itoh K, Nakazato M, Shimizu E, Ohgake S, Koike K, Okamura N, Matsushita S, Suzuki K, Murayama M, Higuchi S, Iyo M. Association between the brain-derived neurotrophic factor 196G/A polymorphism and eating disorders. Am. J. Med. Genet. 127B: 125-127 (2004).
10) Yanahashi S, Hashimoto K*, Hattori K, Yuasa S, Iyo M. Role of NMDA receptor subtypes in the induction of catalepsy and increase in Fos protein expression after administration of haloperidol. Brain Res. 1011: 84-93 (2004).
11) Shimizu E*, Hashimoto K, Kobayashi K, Mitsumori M, Ohgake S, Koizumi H, Okamura N, Koike K, Kumakiri C, Nakazato M, Komatsu N, Iyo M. Lack of association between angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) gene functional polymorphism and panic disorder. Neurosci. Lett. 363: 81-83 (2004).
12) Tatsumi R*, Seio K, Fujio M, Katayama J, Horikawa T, Hashimoto K, Tanaka H. (+)-3-[2-(Benzo[b]thiephen-2-yl)-2-oxoethyl]-1-azabicyclo[2.2.2]-octane as potent agonists for the α7 nicotinic acetylcholine receptor. Bioorg. Med. Chem. Lett. 14: 3781-3784 (2004).
13) Fukami G, Hashimoto K*, Koike K, Okamura N, Shimizu E, Iyo M. Effect of antioxidant N-acetyl-L-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine. Brain Res. 1016: 90-95 (2004).
14) Hashimoto K*, Tsukada H, Nishiyama S, Fukumoto D, Kakiuchi T, Shimizu E, Iyo M. Protective effects of N-acetyl-L-cysteine on the reduction of dopamine transporters in striatum of monkeys treated with methamphetamine. Neuropsychopharmacol. 29: 2018-2023 (2004).
15) Shimizu E*, Otsuka A, Hashimoto K, Iyo M. Blepharospasm associated with olanzapine: a case report. Eur. Psychiatry 19: 389 (2004).
16) Kubota O, Hattori K, Hashimoto K, Yagi T, Sato T, Iyo M, Yuasa S*. Auditory-conditioned-fear-dependent c-Fos expression is altered in the emotion-related brain structures of Fyn-deficient mice. Mol. Brain Res. 130: 149-160 (2004).
17) Nakazato M*, Hashimoto K, Shiina A, Koizumi H, Mitsumori M, Imai M, Shimizu E, Iyo M. No changes in serum ghrelin levels in female patients with bulimia nervosa. Prog. Neuropsychopharmacol. Biol. Psychiatry 28: 1181-1184 (2004).
18) Itoh K, Hashimoto K*, Shimizu E, Sekine Y, Ozaki N, Inada T, Harano M, Iwata N, Komiyama T, Yamada M, Sora I, Nakata K, Ujike H, Iyo M. Association study of the brain-derived neurotrophic factor gene polymorphisms and methamphetamine abusers in Japan. Am. J. Med. Genet. 132B: 70-73 (2005).
19) Okamoto H*, Shimizu E, Ozawa K, Hashimoto K, Iyo M. Lithium augmentation in milnacipran-refractory depression for the prevention of relapse following electroconvulsive therapy. Aust. N.Z. J. Psychiatry 39: 108 (2005).
20) Hashimoto K*, Engberg G, Shimizu E, Nordin C, Lindstrom LH, Iyo M. Elevated glutamine/glutamate ratio in cerebrospinal fluid of first episode and drug naive schizophrenic patients. BMC Psychiatry 5, 6 (2005).
21) Koike K, Hashimoto K*, Fukami G, Okamura N, Zhang L, Ohgake S, Koizumi H, Matsuzawa D, Kawamura N, Shimizu E, Iyo M. The immunophilin ligand FK506 protects against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum. Neuropharmacology 48: 391-397 (2005).
22) Tatsumi R*, Fujio M, Satoh H, Katayama J, Takanashi S, Hashimoto K, Tanaka H. Discovery of the α7 nicotinic acetylcholine receptor agonists. (R)-3’-(chlorothiophen-2-yl)spiro-1-azabicyclo[2.2.2]octane-3,5’-[1’,3’]-oxazolidin-2’-one as a novel, potent, selective, and orally bioavailable ligand. J. Med. Chem. 48: 2678-2686 (2005).
23) Hashimoto T, Hashimoto K*, Matsuzawa D, Shimizu E, Sekine Y, Inada T, Ozaki N, Iwata N, Harano M, Komiyama T, Yamada M, Sora I, Ujike H, Iyo M. A functional glutathione-S-transferase P1 polymorphism is associated with methamphetamine-induced psychosis in Japanese population. Am. J. Med. Genet. 135B: 5-9 (2005).
24) Koizumi H, Hashimoto K*, Shimizu E, Iyo M, Mashimo Y, Hata A. Further analysis of microsatellite in the BDNF gene. Am. J. Med. Genet. 135B: 103 (2005).
25) Salama RH, Muramatsu H, Shimizu E*, Hashimoto K, Ohgake S, Watanabe H, Komatsu N, Okamura N, Koike K, Shinoda N, Okada S, Iyo M, Muramatsu T. Increased midkine levels in sera from patients with Alzheimer's disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 29: 611-616 (2005).
26) Koike K, Hashimoto K*, Takai N, Shimizu E, Komatsu N, Watanabe H, Nakazato M, Okamura N, Stevens KE, Freedman R, Iyo M. Tropisetron improves deficits in auditory P50 suppression in schizophrenia. Schizophrenia Res. 76: 67-72 (2005).
27) #Yamada K, #Ohnishi T, #Hashimoto K, Ohba H, Iwayama-Shigeno Y, Takao H, Toyota T, Minabe Y, Nakamura K, Shimizu E, Itokawa M, Mori N, Iyo M, Yoshikawa T*. Identification of multiple serine racemase (SRR) mRNA isoforms and genetic analyses of SRR and DAO in schizophrenia and D-serine levels. Biol. Psychiatry 57: 1493-1503 (2005). (#equal contribution)
28) Kobayashi K, Shimizu E*, Hashimoto K, Koizumi H, Ohgake S, Okamura N, Koike K, Matsuzawa D, Nakazato M, Iyo M. Serum brain-derived neurotrophic factor (BDNF) levels in patients with panic disorder: as a biological predictor of response to group cognitive behavioural therapy. Prog. Neuropsychopharmacol. Biol. Psychiatry 29: 658-663 (2005).
29) Shimizu E*, Hashimoto K, Itoh K, Kobayashi K, Mitsumori M, Koizumi H, Ohgake S, Okamura N, Koike K, Matsuzawa D, Kumakiri C, Nakazato M, Komatsu N, Iyo M. No association of the brain-derived neurotrophic factor (BDNF) gene polymorphisms with panic disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 29: 708-712 (2005).
30) Hashimoto K*, Engberg G, Shimizu E, Nordin C, Lindstrom LH, Iyo M. Reduced D-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog. Neuropsychopharmacol. Biol. Psychiatry 29: 767-769 (2005).
31) Matsuzawa D, Hashimoto K*, Shimizu E, Fujisaki M, Iyo M. Functional polymorphism of the glutathione peroxidase 1 gene is associated with personality traits in healthy subjects. Neuropsychobiology 52: 68-70 (2005).
32) Ohgake S, Hashimoto K*, Shimizu E, Koizumi H, Okamura N, Koike K, Matsuzawa D, Sekine Y, Inada T, Ozaki N, Iwata N, Harano M, Komiyama T, Yamada M, Sora I, Ujike H, Shirayama Y, Iyo M. Functional polymorphism of the NQO2 gene is associated with methamphetamine psychosis. Addiction Biol. 10: 145-148 (2005).
33) Hashimoto K*, Shimizu E, Komatsu N, Watanabe H, Shinoda N, Nakazato M, Kumakiri C, Okada S, Takei N, Iyo M. No changes in serum epidermal growth factor levels in patients with schizophrenia. Psychiatry Res. 135: 257-260 (2005).
34) Hashimoto K*, Fujita Y, Shimizu E, Iyo M. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of clozapine, but not haloperidol. Eur. J. Pharmacol. 519: 114-117 (2005).
35) Yamamoto T*, Sakakibara R, Hashimoto K, Nakazawa K, Uchiyama T, Liu Z, Ito T, Hattori T. Striatal dopamine level increases in the urinary storage phase in cats: An in vivo microdialysis study. Neuroscience 135: 299-303 (2005).
36) Hashimoto K*, Iyo M, Freedman R, Stevens KE. Tropisetron improves deficient inhibitory auditory processing in DBA/2 mice: role of α7 nicotinic acetylcholine receptors. Psychopharmacol. 183: 13-19 (2005).
37) Hashimoto K*. Neonatal signs following exposure to SSRIs. Hum. Psychopharmacol. 20: 522 (2005).
38) Shimizu E*, Hashimoto K, Ohgake S, Koizumi H, Okamura N, Koike K, Fujisaki M, Iyo M. Association between angiotensin I-converting enzyme insertion/deletion gene functional polymorphism and novelty seeking personality in healthy females. Prog. Neuropsychopharmacol. Biol. Psychiatry 30: 99-103 (2006).
39) Iwayama Y, Hashimoto K, Nakajima M, Toyota T, Yamada K, Shimizu E, Itokawa M, Hoshika A, Iyo M, Yoshikawa T*. Analysis of correlation between serum D-serine levels and functional promoter polymorphisms of GRIN2A and GRIN2B genes. Neurosci. Lett. 394: 101-104 (2006).
40) Hayashi Y, Ishibashi H, Hashimoto K, Nakanishi H*. Potentiation of the NMDA receptor-mediated responses through the activation of the glycine site by microglia secreting soluble factors. Glia 53: 660-668 (2006).
41) Ozawa K*, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M. Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia. Biol. Psychiatry 59: 546-554 (2006).
42) Hashimoto K, Ishiwata K*. Sigma receptor ligands: Possible applications as therapeutic drugs and as radiopharmaceuticals. Curr. Pharm. Des. 12: 3857-3876 (2006).
43) Zhang L, Kitaichi K, Fujimoto Y, Nakayama H, Shimizu E, Iyo M, Hashimoto K*. Protective effects of minocycline on behavioral changes and neurotoxicity in mice after administration of methamphetamine. Prog. Neuropsychopharmacol. Biol. Psychiatry 30: 1381-1393 (2006).
44) Nakazato M*, Hashimoto K, Yoshimura K, Hashimoto T, Shimizu E, Iyo M. No change between the serum brain-derived neurotrophic factor in female patients with anorexia nervosa before and after partial weight recovery. Prog. Neuropsychopharmacol. Biol. Psychiatry 30: 1117-1121 (2006).
45) Tatsumi R*, Fujio M, Takanashi S, Numata A, Katayama J, Satoh H, Shiigi Y, Maeda J, Kuriyama M, Horikawa T, Murozono T, Hashimoto K, Tanaka H. (R)-3’-(3-Methylbenzo[b]thiophen-5-yl)spiro[1-azabicyclo[2,2,2]octane-3,5’-oxazolidin]-2’-one,a novel and potent α7 nicotinic acetylcholine receptor partial agonist displays cognitive enhancing properties. J. Med. Chem. 49: 4374-4383 (2006).
46) Zhang L, Shirayama Y, Shimizu E, Iyo M, Hashimoto K*. Protective effects of minocycline on 3,4-methylenedioxymethamphetamine-induced neurotoxicity in serotonergic and dopaminergic neurons of mouse brain. Eur. J. Pharmacol. 544: 1-9 (2006).
47) Shinohe A, Hashimoto K*, Nakamura K, Tsujii M, Iwata Y, Tsuchiya KJ, Sekine Y, Suda S, Suzuki K, Sugihara G, Matsuzaki H, Minabe Y, Sugiyama T, Kawai M, Iyo M, Takei N, Mori N. Increased serum levels of glutamate in adult patients with autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 30: 1472-1477 (2006).
48) Hashimoto K*, Iwata Y, Nakamura K, Tsujii M, Tsuchiya KJ, Sekine Y, Suzuki K, Minabe Y, Takei N, Iyo M, Mori N. Reduced serum levels of brain-derived neurotrophic factor in adult male patients with autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 30: 1529-1531 (2006).
49) Koizumi H, Hashimoto K*, Iyo M. Dietary restriction changes behaviors in brain-derived neurotrophic factor heterozygous mice: role of serotonergic system. Eur. J. Neurosci. 24: 2335-2344 (2006).
50) Hashimoto K*, Fujita Y, Ishima T, Hagiwara H, Iyo M. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of tropisetron: Role of α7 nicotinic receptors. Eur. J. Pharmacol. 553: 191-195 (2006).
51) Shimizu E*, Hashimoto K, Ochi S, Fukami G, Fujisaki M, Okamura N, Koike K, Watanabe H, Nakazato M, Shinoda N, Komatsu N, Morita F, Iyo M. Posterior cingulate metabolite changes may reflect cognitive deficits in schizophrenia, more than the left and right medial temporal lobes: a proton magnetic resonance spectroscopy investigation. J. Psychiatry Res. 41: 49-56 (2007).
52) Nakajima M, Hattori E, Yamada K, Iwayama Y, Toyota T, Iwata Y, Tsuchiya KJ, Sugihara G, Hashimoto K, Watanabe H, Iyo M, Hoshika A, Yoshikawa T*. Association and synergistic interaction between promoter variants of the DRD4 gene in Japanese schizophrenics. J. Hum. Genet. 52: 86-91 (2007).
53) Okada K, Hashimoto K*, Iwata Y, Nakamura K, Tsujii M, Tsuchiya KJ, Sekine Y, Suda S, Suzuki K, Sugihara G, Matsuzaki H, Minabe Y, Sugiyama T, Kawai M, Takei N, Mori N. Decreased serum levels of transforming growth factor-β1 in adult patients with autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 31: 187-190 (2007).
54) Shimizu E*, Watanabe H, Kojima T, Hagiwara H, Fujisaki M, Miyatake R, Hashimoto K, Iyo M. Combined intoxication with methylone and 5-MeO-MIPT. Prog. Neuropsychopharmacol. Biol. Psychiatry 31: 288-291 (2007).
55) Fukushima T*, Mitsuhashi S, Tomiya M, Iyo M, Hashimoto K, Toyo'oka T. Determination of kynurenic acid in human serum and its correlation with the concentration of certain amino acids. Clin. Chim. Acta. 377: 174-178 (2007).
56) Sugihara G, Hashimoto K*, Iwata Y, Nakamura K, Tsujii M, Tsuchiya KJ, Sekine Y, Suda S, Suzuki K, Matsuzaki H, Minabe Y, Sugiyama T, Kawai M, Takei N, Mori N. Decreased serum levels of hepatocyte growth factor in adult patients with autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 31: 412-415 (2007).
57) Fukushima T*, Mitsuhashi S, Tomiya M, Kawai J, Hashimoto K, Toyo'oka T. Determination of rat brain kynurenic acid by column-switching HPLC with fluorescence detection. Biomed. Chromatogr. 21: 514-519 (2007).
58) Hashimoto K*, Fujita Y, Iyo M. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of fluvoxamine: Role of sigma-1 receptors. Neuropsychopharmacol. 32: 514-521 (2007).
59) Hashimoto K*, Tsukada H, Nishiyama S, Fukumoto D, Kakiuchi T, Iyo M. Protective effects of minocycline on the reduction of dopamine transporters in the striatum after administration of methamphetamine: A PET study in conscious monkeys. Biol. Psychiatry 61: 577-581 (2007)
60) Tomiya M, Fukushima T*, Watanabe H, Fukami G, Fujisaki M, Iyo M, Hashimoto K, Mitsuhashi S, Toyo'oka T. Alterations in serum amino acid concentrations in male and female schizophrenic patients. Clin. Chim. Acta. 380: 186-190 (2007).
61) Matsuzaki H, Minabe Y, Nakamura K, Suzuki K, Iwata Y, Sekine Y, Tsuchiya KJ, Sugihara G, Suda S, Takei N, Nakahara D, Hashimoto K, Nairn AC, Mori N, Sato K*. Disruption of Reelin signaling attenuates methamphetamine-induced hyperlocomotion. Eur. J. Neurosci. 25: 3376-3384 (2007).
62) Matsuzawa D, Hashimoto K*, Miyatake R, Shirayama Y, Shimizu E, Maeda K, Suzuki Y, Mashimo Y, Sekine Y, Inada T, Ozaki N, Iwata N, Harano M, Komiyama T, Yamada M, Sora I, Ujike H, Hata A, Sawa A, Iyo M. Identification of functional polymorphisms in the promoter region of the human PICK1 gene and their association with methamphetamine psychosis. Am. J. Psychiatry 164: 1105-1114 (2007).
63) Suzuki K, Hashimoto K*, Iwata Y, Nakamura K, Tsujii M, Tsuchiya KJ, Sekine Y, Suda S, Sugihara G, Matsuzaki H, Minabe Y, Sugiyama T, Kawai M, Takei N, Mori N. Decreased serum levels of epidermal growth factor in adult patients with autism. Biol. Psychiatry 62: 267-269 (2007).
64) Zhang L, Shirayama Y, Iyo M, Hashimoto K*. Minocycline attenuates hyperlocomotion and prepulse inhibition deficits in mice after administration of the NMDA receptor antagonist dizocilpine. Neuropsychopharmacology 32: 2004-2010 (2007)
65) Hashimoto K*. (2007) Glycine transporter-1 inhibitors as novel therapeutic drugs for schizophrenia. CNS Agents Med. Chem. 7: 177-182.
66) Okamura N, Hashimoto K, Iyo M, Shimizu E, Dempfle A, Friedel S, Reinscheid RK*. Gender-specific association of a functional coding polymorphism in the neuropeptide S receptor gene with panic disorder but not with schizophrenia or attention-deficit/hyperactivity disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 31: 1444-1448 (2007).
67) Ishikawa M, Ishiwata K, Ishii K, Kimura Y, Sakata M, Naganawa M, Oda K, Miyatake R, Fujisaki M, Shimizu E, Shirayama Y, Iyo M, Hashimoto K*. High occupancy of sigma-1 receptors in the human brain after single oral administration of fluvoxamine: A PET study using [11C]SA4503. Biol. Psychiatry 62: 878-883 (2007).
68) Tsuchiya K, Hashimoto K*, Iwata Y, Tsujii M, Sekine Y, Sugihara G, Matsuzaki H, Suda S, Kawai M, Nakamura K, Minabe Y, Yagi A, Iyo M, Takei N, Mori N. Decreased serum levels of PECAM-1 in subjects with high-functioning autism: a negative correlation with head circumference at birth. Biol. Psychiatry 62: 1056-1058 (2007).
69) Watanabe A, Toyota T, Owada Y, Hayashi T, Owayama Y, Matsumata M, Ishitsuka Y, Nakaya A, Maekawa M, Ohnishi T, Arai R, Sakurai K, Yamada K, Kondo H, Hashimoto K, Osumi N, Yoshikawa T*. Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. PLoS Biol. 5: e297 (2007)
70) Hashimoto K*, Sawa A, Iyo M. Increased levels of glutamate in brains from patients with mood disorders. Biol. Psychiatry 62: 1310-1316 (2007).
71) Hashimoto K*, Ishima T, Fujita Y, Matsuo M, Kobashi T, Takahagi M, Tsukada H, Iyo M. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the novel selective α7 nicotinic receptor agonist SSR180711. Biol. Psychiatry 63: 92-97 (2008)
72) Karasawa J, Hashimoto K, Chaki S*. 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 (2008).
73) Suzuki K, Nakamura K, Iwata Y, Sekine Y, Kawai M, Sugihara G, Tsuchiya KJ, Suda S, Matsuzaki H, Takei N, Hashimoto K*, Mori N. Decreased expression for the reelin receptor VLDLR in peripheral lymphocytes of drug naive schizophrenic patients. Schizophrenia Res. 98: 148-156 (2008).
74) Hashimoto T, Shimizu E*, Koike K, Orita Y, Suzuki T, Kanahara N, Fukami G, Miyatake R, Shinoda N, Fujisaki M, Shirayama Y, Hashimoto K, Iyo M. Deficits in auditory P50 inhibition in obsessive-compulsive disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 32: 288-296 (2008).
75) Fujita Y, Ishima T, Kunitachi S, Hagiwara H, Zhang L, Iyo M, Hashimoto K*. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antibiotic drug minocycline. Prog. Neuropsychopharmacol. Biol. Psychiatry 32: 336-339 (2008).
76) Takeshita M, Yamada K, Hattori E, Iwayama Y, Toyota T, Iwata Y, Tsuchiya KJ, Sugihara G, Hashimoto K, Watanabe H, Iyo M, Kikuchi M, Okazaki Y, Yoshikawa T*. Genetic examination of the PLXNA2 gene in Japanese and Chinese schizophrenics. Schizophrenia Res. 99: 359-364 (2008).
77) Sakata M, Kimura Y*, Naganawa M, Ishikawa M, Oda K, Ishii K, Hashimoto K, Chihara K, Ishiwata K. Shortened protocol in practical [11C]SA4503-PET studies for the sigma-1 receptor quantification. Ann. Nucl. Med. 22: 143-146 (2008).
78) Hashimoto K*, Shinohe A, Mori N. Reply to: Hyperglutamatergic hypothesis of autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 32: 912-913 (2008).
79) Matsuzawa D, Obata T, Shirayama Y, Nonaka H, Kanazawa Y, Yoshitome E, Takanashi J, Matsuda T, Shimizu E, Ikehira H, Iyo M, Hashimoto K*. Negative correlation between brain glutathione levels and negative symptoms in schizophrenia: a 3T 1H-MRS study. PLoS ONE 3: e1944 (2008).
80) Hikida T, Mustafa AK, Maeda K, Fujii K, Barrow RK, Saleh M, Oby L, Huganir RL, Snyder SH, Hashimoto K, Sawa A*. Modulation of D-serine levels in brains of mice lacking PICK1. Biol. Psychiatry 63: 997-1000 (2008).
81) Hashimoto K*, Fujita Y, Ishima T, Chaki S, Iyo M. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of glycine transporter-1 inhibitor NFPS and D-serine. Eur. Neuropsychopharmacol. 18: 414-421 (2008).
82) Hagiwara H, Fujita Y, Ishima T, Kunitachi S, Shirayama Y, Iyo M, Hashimoto K*. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antipsychotic drug perospirone: role of serotonin 5-HT1A receptor. Eur. Neuropsychopharmacol. 18: 448-454 (2008).
83) Iyo M*, Shirayama Y, Watanabe H, Fujisaki M, Miyatake R, Fukami G, Shiina A, Nakazato M, Shiraishi T, Ookami T, Hashimoto K. Fluvoxamine as a sigma-1 receptor agonist improved cognitive impairments in a patient with schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 32: 1072-1073 (2008).
84) Iwata Y*, Suzuki K, Wakuda T, Seki N, Thanseem I, Matsuzaki H, Mamiya T, Ueki T, Mikawa S, Sasaki T, Suda S, Yamamoto S, Tsuchiya KJ, Sugihara G, Nakamura K, Sato K, Takei N, Hashimoto K*, Mori N. Irradiation at adulthood as a new model of schizophrenia. PLoS ONE 3: e2283 (2008).
85) Kanahara N, Shimizu E*, Ohgake S, Fujita Y, Kohno M, Hashimoto T, Matsuzawa D, Shirayama Y, Hashimoto K, Iyo M. Glycine and D-serine, but not D-cycloserine, attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801. Psychopharmacology 198: 363-374 (2008).
86) Fujita Y, Ishima T, Horio M, Hagiwara H, Iyo M, Hashimoto K*. Alterations in plasma levels of amino acids after intracerebroventricular administration of L-serine or D-serine in conscious and freely moving rats. The Open. Clin. Chem. J. 1: 22-26 (2008).
87) Ferraris D, Duvall B, Ko YS, Thomas AG, Rojas C, Majer P, Hashimoto K, Tsukamoto T*. Synthesis and biological evaluation of D-amino acid oxidase inhibitors. J. Med. Chem. 51: 3357-3359 (2008) Nishimura T, Ishima T, Iyo M, Hashimoto K*. Potentiation of nerve growth factor-induced neurite outgrowth by fluvoxamine: role of sigma-1 receptors, IP3 receptors and cellular signaling pathways. PLoS ONE 3: e2558 (2008).
88) Hashimoto K*. Editorial: CSF serine enantiomers and glycine in the study of neurologic and psychiatric disorders. Clin. Chemistry 54: 1413-1414 (2008).
89) Ishima T, Nishimura T, Iyo M, Hashimoto K*. Potentiation of nerve growth factor-induced neurite outgrowth in PC12 cells by donepezil: role of sigma-1 receptors and IP3 receptors. Prog. Neuropsychopharmacol. Biol. Psychiatry 32: 1656-1659 (2008).
90) Hashimoto K*. Microglial activation in schizophrenia and minocycline treatment. Prog. Neuropsychopharmacol. Biol. Psychiatry 32: 1758-1759 (2008).
91) Hashimoto K*., Nishiyama S, Ohba H, Matsuo M, Kobashi T, Takahagi M, Iyo M, Kitashoji T, Tsukada H. [11C]CHIBA-1001 as a novel PET ligand for α7 nicotinic receptors in the brain: A PET study in conscious monkeys. PLoS ONE 3: e3231 (2008).
92) Hashimoto K*. Food addictives and hyperactive behaviors in children. Clin. Psychopharmacol. Neurosci. 6: 79 (2008).
93) Hashimoto T, Hashimoto K*, Miyatake R, Matsuzawa D, Sekine Y, Inada T, Ozaki N, Iwata N, Harano M, Komiyama T, Yamada M, Sora I, Ujike H, Iyo M. Association study between polymorphisms in glutathione-related genes and methamphetamine use disorder in a Japanese population. Am. J. Med. Genet. Part B 147B: 1040-1046 (2008).
94) Hashimoto K*. Correspondence: Regarding “N-Acetyl cysteine as a glutathione precursor for schizophrenia – a double-blind, randomized, placebo-controlled trial”. Biol. Psychiatry 64: e1 (2008).
95) Iwata Y, Tsuchiya KJ, Mikawa S, Nakamura K, Takai Y, Suda S, Sekine Y, Suzuki K, Kawai M, Sugihara G, Matsuzaki H, Hashimoto K, Tsujii M, Sugiyama T, Takei N*, Mori N. Serum levels of P-selectin in men with high-functioning autism. Bri. J. Psychiatry 193: 338-339 (2008).
96) Matsuzawa D, Hashimoto K*, Hashimoto T, Shimizu E, Watanabe H, Fujita Y, Iyo M. Association study between the genetic polymorphisms of glutathione-related enzymes and schizophrenia in a Japanese population. Am. J. Med. Genet. Part B in press.
97) Kanahara N, Iyo M, Hashimoto K*. Failure to confirm the association between the PIK4CA gene and schizophrenia in a Japanese population. Am. J. Med. Genet. Part B. in press.
98) Kanahara N, Miyatake R, Sekine Y, Inada T, Ozaki N, Iwata N, Harano M, Komiyama T, Yamada M, Sora I, Ujike H, Iyo M, Hashimoto K*. Association study between the PIK4CA gene and methamphetamine use disorder in a Japanese population. Am. J. Med. Genet. Part B. in press.
99) Nakazato M*, Tchanturia K, Schmidt U, Campbell IV, Treasure J, Collier DA, Hashimoto K, Iyo M. Brain-derived neurotrophic factor (BDNF) and set-shifting in currently ill and recovered anorexia nervosa (AN) patients. Psychol. Med. in press.
100) Matsuoka Y*, Nishi D, Nakajima S, Yonemoto N, Hashimoto K, Noguchi H, Otomo Y, Kim Y. The Tachikawa Cohort of Motor Vehicle Accident Study: Design, Methods, and Baseline characteristics. Soc. Psychiatry Psychiatric Epidemiol. in press.
101) Hashimoto K*. Nausea associated with a nicotinic agonist therapy in schizophrenia. Clin. Psychopharmacol. Neurosci. In press.
102) Hashimoto K*. BDNF and obesity in the WAGR syndrome. Clin. Psychopharmacol. Neurosci. In press.
103) Hashimoto K*. Reply to: Minocycline, schizophrenia and GluR1 glutamate receptors. Prog. Neuropsychopharmacol. Biol. Psychiatry in press.
104) Inoue R, Hashimoto K, Harai T, Mori H*. NMDA- and β-amyloid1-42-induced neurotoxicity is attenuated in serine racemase knockout mice. J. Neurosci. In press.
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