橋本 謙二

Background: The precise mechanisms underlying the pathophysiology of autism are currently unknown. Given the key role of brain-derived neurotrophic factor (BDNF) in brain development, we hypothesized that BDNF may play a role in the pathophysiology of autism. In this study, we studied whether serum levels of BDNF are altered in patients with autism. Methods: We measured serum levels of BDNF in 18 adult male patients with autism and 18 age-matched healthy male control subjects. Results: The serum levels of BDNF in patients with autism (25.6 +/- 2.15 ng/ml (mean +/- S.D.)) were significantly (z=-4.42, p < 0.001) lower than those of normal controls (61.6 +/- 10.9 ng/ml (mean S.D.)). Nevertheless, we found no correlations between BDNF levels and clinical variables in autistic patients. Conclusions: This study suggests that reduced BDNF levels may play a role in the pathophysiology of autism. (c) 2006 Elsevier Inc. All rights reserved.

We examined the effects of tropisetron, a 5-hydroxytryptamine (5-HT3) receptor antagonist and alpha 7 nicotinic receptor agonist, on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (2 weeks) administration of tropisetron, but not ondansetron. Effects of tropisetron were significantly antagonized by co-administration of the alpha 7 nicotinic receptor antagonist methyllycaconitine, suggesting the role of 0 nicotinic receptors in the active mechanisms of tropisetron. These findings suggest that tropisetron could be a potential therapeutic drug for cognitive deficits in schizophrenic patients. (c) 2006 Elsevier B.V. All rights reserved.

Accumulating evidence has suggested that brain-derived neurotrophic factor (BDNF) plays a role in eating behaviours, and that BDNF-heterozygous (+/-) mice exhibit abnormal behaviours (e.g. obesity, anxiety and aggression). The present study was undertaken to determine whether or not dietary restriction (DR) alters the behaviours in BDNF+/- mice, as DR has been shown to exert a number of beneficial effects on the brain. Eight-week-old male wild-type (+/+) and BDNF+/- mice were divided into two groups, ad libitum (AL) diet group and DR group, for 16 weeks. After carrying out a behavioural evaluation, we determined the BDNF mRNA levels, as well as mRNA levels for subtypes (5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C) of the 5-HT receptor and 5-HT transporter (5-HTT), protein levels of BDNF and concentrations of 5-HT and 5-HIAA in the hypothalamus, hippocampus and frontal cortex. DR significantly ameliorated behaviours including obesity, anxiety and aggression in BDNF+/- mice. The concentrations of 5-HT and 5-HIAA in the frontal cortex, and 5-HT in the hippocampus, of BDNF+/- mice were significantly lower than those of wild-type mice. Interestingly, DR significantly increased the levels of 5-HT and 5-HIAA in the frontal cortex of BDNF+/- mice. These findings suggest that DR may alter the behaviours in BDNF+/- mice, and that the 5-HT system may be implicated in the beneficial effects of DR on these behaviours.

Background: Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family. Several lines of evidence indicate that BDNF plays a role in the pathophysiology of eating disorders (ED). We found that serum BDNF levels in patients with ED were significantly lower than in normal controls. The aim of this longitudinal study was to compare serum BDNF levels in patients with anorexia nervosa (AN) before (n = 13, initial mean body mass index (BMI) = 14.2 kg/m(2) +/- 0.7) and after partial recovery (mean BMI = 16.2 kg/m(2) +/- 1.7, mean weight gain 5.0 kg +/- 2.0), with age-matched normal control subjects (n = 17, mean BMI = 20.4 kg/m(2) +/- 1.5). Methods: Eating related psychopathology and depressive symptoms were evaluated before and after partial weight recovery, using the Eating Disorder Inventory-2 (EDI-2) and the 17-item Hamilton Depression Rating Scale (HDRS). Serum BDNF levels were measured using a sandwich enzyme-linked immunosorbent assay. Results: Serum BDNF levels with the AN patients (14.5 +/- 4.4 ng/ml) were significantly (p < 0.01) lower than in control subjects (22.1 +/- 8.9 ng/ml). There were no significant differences in serum BDNF levels between the patients with AN before (14.5 +/- 4.4 ng/ml) and after (17.2 +/- 6.9 ng/ml) partial weight recovery. In all subjects, there was a positive correlation (r = 0.5, p < 0.01) between the baseline BDNF levels and the EDI-2 scores (n = 30). Furthermore, in all subjects there was a positive correlation (r = 0.4, p < 0.05) between the BDNF levels and the BMI. Conclusions: Serum BDNF levels did not change after partial weight recovery in AN patients. Our results suggest that an alteration of the serum BDNF in AN patients is not due to changes in body weight. Thus, other possible mechanisms that could be related to low serum BDNF levels in AN patients should be evaluated. (c) 2006 Elsevier Inc. All rights reserved.

The repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) produces neurotoxicity in the 5-hydroxytryptamine (5-HT) and dopamine systems of the brain. In this study, we investigated the effects of minocycline, a second-generation tetracycline derivative, on MDMA-induced neurotoxicity in the 5-HT and dopaminergic systems of the mouse brain. The repeated administration of MDMA (10 mg/kgx3, 3-h intervals, s.c.) significantly decreased the contents of 5-HT and its major metabolite 5-hydroxyindole acetic acid (5-HIAA) in the frontal cortex and hippocampus, and the density of the 5-HT transporter (5-HTT) in the frontal cortex, hippocampus and striatum. The repeated administration of MDMA (10 mg/kg x 3, 3-h intervals, s.c.) significantly decreased the contents of the dopamine and the density of the dopamine transporter (DAT) in the striatum, but not the frontal cortex. Furthermore, pretreatment and the subsequent administration of minocycline (40 mg/kg, i.p.) significantly attenuated the reduction of 5-HT and dopamine as well as the density of 5-HTT and DAT in the mouse brain by the repeated administration of MDMA. Moreover, pretreatment and the subsequent administration of minocycline (40 mg/kg) significantly attenuated the increase of activated microglia in the hippocampus and striatum after the repeated administration of MDMA. Our findings suggest that minocycline protects the neurotoxicity of the 5-HT and dopamine systems in the mouse brain after the administration of MDMA. (c) 2006 Elsevier B.V All rights reserved.

Recent studies have suggested that the alpha 7 nicotinic acetylcholine receptors play important roles in learning and memory. Herein, we describe our research of the structure-activity relationships (SAR) in a series of (S)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin]-2'-ones bearing various bicyclic moieties to discover novel alpha 7 receptor agonists. Through a number of SAR studies on the series, we have found out that inhibition of CYP 2D6 isozyme, which was a primary obstacle for the previously identified compound, was avoidable by the introduction of bicyclic moieties. Chemical optimization of the series led to the identification of a novel and potent alpha 7 nicotinic acetylcholine receptor partial agonist 23. This compound not only possessed high binding affinity (K-i) 3 nmol/L) toward the alpha 7 receptor but also showed agonistic activity even at a concentration of 0.1 mu mol/L. In addition, compound 23 improved cognition in several rat models, which might suggest the potential of the alpha 7 receptor partial agonist for the treatment of neurological disorders including cognitive dysfunction.

千葉県内の精神科医212人に対して郵送法にて司法精神医学に関する調査を行った。回答者は88名であり,回答率は42%であった。このうち精神鑑定経験者数は38名(43%)であり,刑事精神鑑定(正式鑑定または嘱託鑑定,以下本鑑定)経験者は28名で,簡易鑑定経験者は26名であった。本鑑定経験数は1から50回,簡易鑑定経験数は1から105回であり,両者ともとばらつきが大きく,一部の鑑定人が多数の鑑定をこなしていることが示めされた。国際疾病分類(ICD-10 精神および行動の障害)や精神疾患の診断・統計マニュアル第4版(DSM-IV)に比べ,従来診断法が73%(本鑑定),52%(簡易鑑定)と多かった。措置入院治療は55%の回答者が経験していた。治療目標は幻覚妄想85%,衝動制御65%,服薬遵守50%,反社会的行動46%,病識を持たせることが44%,希死念慮の改善が25%であった。この治療目標の達成度は,それぞれ75%,71%,71%,63%,50%,そして82%であった。治療法としては,薬物療法は100%用いられており,電気ショック療法も21%で用いられていた。精神療法としては洞察的精神療法が25%,行動療法や認知行動療法等の指示的精神療法が38%であった。退院後の処遇として,保健所や訪問看護を用いない,一般外来のみの場合が52%であった。また,刑事鑑定についてトレーニングとしては,鑑定助手(トレーニングを受けた中での割合82%),アドバイス(75%)によるものが多く,系統的な研修の必要性が示唆された。トレーニング受講は全回答者88名中48名(55%)が希望していた。 以上より,精神鑑定における診断方法についての統一化や新しい治療法の導入,そしてそれらについての系統的

We have previously reported that both transferred microglia and microglia-conditioned medium (MCM) potentiated the N-methyl-D-aspatate (NMDA) receptor-mediated synaptic responses in cortical neurons. To elucidate the mechanism underlying the potentiation of NMDA receptor-mediated responses by microglia, we examined the effects of MCM on NMDA-induced inward currents in mechanically dissociated hippocampal CA1 neurons under whole-cell patch recordings. MCM potentiated the amplitude of NMDA-induced currents up to 10-fold in a dose-dependent manner, and this effect of MCM remained even after boiling or cutting off molecules with a molecular mass more than 3 kDa. In the presence of glycine with a concentration sufficient to saturate the NMDA receptor glycine site, MCM failed to further potentiate the NMDA-induced currents. The glycine site antagonist 5, 7-dichrolokynurenic acid, significantly inhibited the effects of MCM. The effect of MCM was still observed even after treatment with D-amino acid oxidase, a D-serine degrading enzyme. On the other hand, MCM had no significant effect on the voltage-dependent Mg2+ blockade of NMDA receptors. Furthermore, MCM enhanced the formation of the long-term potentiation in the Schaffer collateral pathway-CA1 pyramidal cell synapses. Using a high performance liquid chromatography system, we found the levels of both glycine and L-serine in MCM to be significantly higher than those in the control medium. It was also noted that an increased glycine productivity of microglia was observed in the hippocampus in the acute phase of neuronal injury. These observations strongly suggest that glycine is a major causative molecule released from microglia that potentiates the NMDA-induced currents. (c) 2006 Wiley-Liss, Inc.

Background: Maternal viral infection is associated with increased risk for schizophrenia. It is hypothesized that the maternal immune response to viruses may influence fetal brain development and lead to schizophrenia. Methods: To mimic a viral infection, the synthetic double strand RNA polyriboinosinic-polyribocytidilic acid (poly I:C) was administered into pregnant mice. Behavioral evaluations (thigmotaxis, methamphetamine [MAP]-induced hyperactivity, novel-object recognition test [NORT]), sensorimotor gating (prepulse inhibition [PPI]), and biochemical evaluation of the dopaminergic function of the offspring of phospbate-buffered saline (PBS)-treated dams (PBS-mice) and that of poly I:C-treated dams (poly L C-mice) were examined. Results: In juveniles, no difference was found between the poy I:C-mice and PBS-mice. However, in adults, the poly I:C-mice exhibited attenuated thigmotaxis, greater response in MAP-induced (2 mg/kg) hyperlocomotion, deficits in PPI, and cognitive impairment in NORT compared with the PBS-mice. Cognitive impairment in the adult poly I:C-mice could be improved by subchronic administration of clozapine (5.0 mg/kg) but not haloperidol (.1 mg/kg). increased dopamine (DA) turnover and decreased receptor binding of D-2-like receptors, but not D-1-like receptors, in the striatum were found in adult poly I:C-mice. Conclusions: Prenatal poly I:C administration causes maturation-dependent increased subcortical DA function and cognitive impairment in the offspring, indicating a neurodevelopmental animal model of schizophrenia.

D-Serine is an endogenous coagonist that increases the opening of N-methyl-D-aspartate (NMDA)-type glutamate receptor channels. We previously reported a reduction Of D-serine serum levels in schizophrenia, supporting the disease hypothesis of NMDA receptor-mediated hyponeurotransmission. The serum levels Of D-serine are thought to reflect brain D-serine content. It is important to understand whether there is a direct link between the altered D-serine levels and NMDA receptor expression in vivo or whether these are independent processes. Two polymorphisms are known to regulate the expression of NMDA receptor subunit genes: (GT)(n) (rs3219790) in the promoter region of the NR2A subunit gene (GRIN2A) and -200T > G (rs1019385) in the NR2B gene (GRIN2B). These polymorphisms are also reported to be associated with schizophrenia. Therefore, we examined the correlation between these two polymorphisms and D-serine serum levels in mentally healthy controls, schizophrenics and the combined group. We observed no significant genotype-phenotype correlations in any of the sample groups. However, analyses of larger sample numbers and the detection of additional polymorphisms that affect gene expression are needed before we can conclude that NMDA receptor expression and serum levels Of D-serine, if involved in schizophrenia pathophysiology, are independent and additive events. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

D-Serine is an endogenous coagonist that increases the opening of N-methyl-D-aspartate (NMDA)-type glutamate receptor channels. We previously reported a reduction Of D-serine serum levels in schizophrenia, supporting the disease hypothesis of NMDA receptor-mediated hyponeurotransmission. The serum levels Of D-serine are thought to reflect brain D-serine content. It is important to understand whether there is a direct link between the altered D-serine levels and NMDA receptor expression in vivo or whether these are independent processes. Two polymorphisms are known to regulate the expression of NMDA receptor subunit genes: (GT)(n) (rs3219790) in the promoter region of the NR2A subunit gene (GRIN2A) and -200T > G (rs1019385) in the NR2B gene (GRIN2B). These polymorphisms are also reported to be associated with schizophrenia. Therefore, we examined the correlation between these two polymorphisms and D-serine serum levels in mentally healthy controls, schizophrenics and the combined group. We observed no significant genotype-phenotype correlations in any of the sample groups. However, analyses of larger sample numbers and the detection of additional polymorphisms that affect gene expression are needed before we can conclude that NMDA receptor expression and serum levels Of D-serine, if involved in schizophrenia pathophysiology, are independent and additive events. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

A certain type of personality is at risk for developing psychiatric diseases. Several lines of evidence support the interaction between brain angiotensins and central catecholamine systems, and suggest that angiotensin I-converting enzyme (ACE) may be a reasonable candidate gene for psychiatric disorders. The present study examined the possibility that ACE insertion (I)/deletion (D) functional polymorphism might be associated with particular personality traits. Healthy Japanese subjects (N=184) were administered the Temperament and Character Inventory (TCI) and the NEO Personality Inventory Revised version (NEO-PI-R), and their ACE I/D polymorphisms were determined. There was an ethnic difference in the genetic distribution of ACE I/D between Japanese (D=34.5%) and Caucasians (D=55.2%). We found that the scores of novelty seeking (NS) in the Low-ACE group (II genotype) of healthy female subjects were significantly lower than those in the High-ACE group (ID or DD genotype) (p=0.018). Our findings suggested that the ACE I/D polymorphism might be associated with the NS personality trait in females, but not males. Taking into account the effects of multiple comparisons, this result should be interpreted with caution, and needs confirmation in a larger sample. (c) 2005 Elsevier Inc. All rights reserved.

Sigma receptors are classified into sigma, and sigma(2) subtypes. These subtypes display a different tissue distribution and a distinct physiological and pharmacological profile in the central and peripheral nervous system. The characterization of these subtypes and the discovery of new specific sigma receptor ligands demonstrated that sigma receptors are novel targets for the therapeutic treatment of neuropsychiatric diseases (schizophrenia, depression, and cognition), brain ischemia, and cocaine addiction. Furthermore, imaging of sigma, receptors in the human brain using specific PET radioligands has started. In addition, the two sigma receptor subtypes are also expressed on tumor cells, where they could be of prognostic relevance. The ability of sigma2 receptor agonists to inhibit tumor cell proliferation through mechanisms that might involve apoptosis, intracellular Ca2+, and sphingolipids has promoted the development of sigma(2) receptor agonists as novel therapeutic drugs for treating cancer. Consequently, sigma(2) receptor ligands have been demonstrated to be potentially useful tumor imaging ligands. In this article, we focus on the sigma receptor ligands as therapeutic agents and as radiopharmaceuticals.

This study was undertaken to examine the effects of subsequent administration of antipsychotic drugs (clozapine and haloperidol) on cognitive deficits in mice after repeated administration of phencyclidine (PCP). In the novel object recognition test, repeated administration of PCP (10 mg/kg) significantly decreased exploratory preference in the retention test session but not in the training test session. PCP-induced deficits were significantly improved by subsequent subchronic (2 weeks) administration of clozapine (5 mg/kg), but not haloperidol (0.1 mg/kg). These findings suggest that PCP-induced cognitive deficits using the novel object recognition test may be a potential animal model of atypical antipsychotic activity. (c) 2005 Elsevier B.V. All rights reserved.

覚醒剤関連障害の脆弱性を規定するとされる遺伝子多型の中でも最も代表的な遺伝子多型ドーパミン受容体D2(DRD2)遺伝子のtaq I A多型について,疾患との関わりをより明らかにするため,患者-対照群の相関解析を行うとともに,endophenotypeとしてMRIによる脳の形態にも着目し,Voxel-based morphometryによる解析,検討を行った.その結果,覚醒剤精神病とDRD2遺伝子taq IA多型との間に相関があること,覚醒剤精神病では左側頭葉と中脳(被蓋)が健常者に比べて狭小であること,A2/A2遺伝子型の罹患者では,特に中脳(被蓋)と左前頭葉下面(内側眼球回)が狭小であることが示された.以上の結果は,taq IA多型が覚醒剤精神病の発症・重篤化の規程因子であることを明らかにするとともに,左側頭葉と中脳の一部が責任部位である可能性を示唆するものである

Physiological deficits in inhibition of the P50 auditory evoked potential in schizophrenia have been related to diminished expression of alpha 7 nicotinic acetylcholine receptors. Diminished P50 inhibition is correlated with neuropsychological deficits in attention, one of the principal neurocognitive disturbances in schizophrenia. Nicotine administration improves P50 inhibition, presumably by achieving additional activation of these diminished receptors, but its toxicity and marked tachyphytaxis make it an ineffective therapeutic. Nicotine also has weak positive effects on several neurocognitive deficits in schizophrenia, which raises the possibility that the alpha 7 nicotinic receptor is a clinically relevant therapeutic target that should be addressed by less toxic agents. Tropisetron, a drug already approved for clinical use outside the United States as an anti-emetic, is a partial agonist at a7 nicotinic receptors and an antagonist at 5-HT3 receptors. As an initial proof-of-principle study, we determined that a single administration of tropisetron significantly improves P50 inhibition in schizophrenia. These data are consistent with biological activity at a pathophysiological mechanism in schizophrenia and support further trials of this drug as a possible therapeutic for neurocognitive deficits in schizophrenia. (c) 2005 Elsevier B.V. All rights reserved.

Backround: We previously reported a reduction in serum levels of D-Serine, an endogenons co-agonist of the N-methyl-D-aspartate (NMDA) receptor, in schizophrenia, supporting The hypofunction hypothesis is of NMDA neurotransmission in schizophrenia. In this study, we examined the genetic roles of serine racemase (SRR), an enzyme catalyzing the formation of D-serine from L-serine, and D-amino-acid oxidase (DAO) in the susceptibility to schizophrenia and the regulation of serum D-serine levels. Methods: We determined the complete cDNA and genomic structures of SRR? and performed mutation screening. Single nucleotide polymorphisms (SNP) in SRR and DAO were tested for their association with schizophrenia in both case-control control and family-based designs and for correlation with serum levels of D-serine. Results. Genomic analyses revealed that human brain SRR transcripts consist of four isoforms with one major species, which were derived from alternative use of various 5 end exons. Genetic association analysis showed no significant association between SRR/DAO and schizophrenia. We replicated the decreased serum D-Serine levels in schizophrenia in the sample set, but D-Serine levels did not correlate with SRR/DAO genotypes. Conclusions: The SRR/DAO are not likely to be major genetic determinants in the development of schizophrenia or control of serum D-serine levels.

Little is known about biological predictors of treatment response in panic disorder. Our previous studies show that the brain-derived neurotrophic factor (BDNF) may play a role in the pathophysiology of major depressive disorders and eating disorders. Assuming that BDNF may be implicated in the putative common etiologies of depression and anxiety, the authors examined serum BDNF levels of the patients with panic disorder, and its correlation with therapeutic response to group cognitive behavioral therapy (CBT). Group CBT (10 consecutive 1 It weekly sessions) was administered to the patients with panic disorder after consulting the panic outpatient special service. Before treatment, serum concentrations of BDNF and total cholesterol were measured. After treatment, we defined response to therapy as a 40% reduction from baseline on Panic Disorder Severity Scale (PDSS) score as described by Barlow et al. (2000) [Barlow, D.H., Gorman, J.M., Shear, M.K., Woods, S.W., 2000. Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial. JAMA. 283, 2529-2536]. There were 26 good responders and 16 poor responders. 31 age- and sex-matched healthy normal control subjects were also recruited in this study. The serum BDNF levels of the patients with poor response (25.9 ng/ml [S.D. 8.7]) were significantly lower than those of the patients with good response (33.7 ng/ml [S.D. 7.5]). However, there were no significant differences in both groups of the patients, compared to the normal controls (29.1 ng/ml [S.D. 7.1]). No significant differences of other variables including total cholesterol levels before treatment were detected between good responders and poor responders. These results suggested that BDNF might contribute to therapeutic response of panic disorder. A potential link between an increased risk of secondary depression and BDNF remains to be investigated in the future. (C) 2005 Elsevier Inc. All rights reserved.

Several lines of evidence suggest that genetic factors might contribute to susceptibility to panic disorder. Our previous studies show that the brain-derived neurotrophic factor (BDNF) may play a role in the pathophysiology of major depressive disorders and eating disorders. Assuming that BDNF may be implicated in the putative common pathophisiology of depression and anxiety, we analyzed the association of two BDNF gene single nucleotide polymorphisms (SNPs), 132C>T (formerly named C270T) in the noncoding region of exon V and 196G>A (va166met) in the coding region of exon XIIIA, with panic disorder. In this study, 109 patients with panic disorder diagnosed according to the DSM-IV criteria, and 178 control subjects were recruited. There were no significant differences in the frequency of the genotype or allele in these two SNPs between patients and controls [132C>T in exon V: genotype, p=1.0, allele, p=0.59; 196G>A (val66met) in exon XIIIA: genotype, p=0.77, allele,p=0.78]. Furthermore, no significant associations of agoraphobia with the two SNPs were detected. This study suggests that the BDNF gene polymorphisms are not associated with panic disorder in our Japanese population. (C) 2005 Elsevier Inc. All rights reserved.

Several lines of evidence suggest that D-serine, an endogenous agonist of the glycine site on the NMDA receptors, might play a role in the pathophysiology of schizophrenia. The purpose of this study was to determine whether levels of D- and L-serine or D-serine ratio (D-serine/total serine) in cerebrospinal fluid (CSF) were altered in first episode and drug-naive schizophrenic patients. The CSF levels of D- and L-serine in 25 male first episode and drug-naive schizophrenic patients and 17 age-matched male healthy subjects were measured using a column-switching high performance liquid chromatography system. The percentage of D-serine in the total serine of patients was significantly (z=-2.01, p=0.044) lower than that of controls. This study suggests that synthetic or metabolic pathways of D-serine may be abnormal in the brain of drug-naive schizophrenic patients, supporting the NMDA receptor dysfunction hypothesis of schizophrenia. (C) 2005 Elsevier Inc. All rights reserved.

Several lines of evidence suggest that genetic factors contribute to the vulnerability of drug abuse such as methamphetamine (MAP), and that dopamine-quinones produced by administration of MAP may be involved in the mechanism of MAP-related symptoms. The detoxification of quinones is catalyzed by a family of proteins designated as quinone oxidoreductases (NQOs). We analysed the polymorphisms of NQO1 and NQO2 genes to elucidate the association with genetic vulnerability to MAP abuse in Japan. The genotype and allele frequencies for the polymorphism (Pro187Ser) of the NQO1 gene did not differ between each subgroup of patients and controls. In contrast, the genotype frequency for the insertion/deletion (I/D) polymorphism in the promoter region of the NQO2 gene was a significant ( p = 0.038) difference between patients with prolonged-type MAP psychosis and controls. This study suggests that the NQO2 gene polymorphism contributes to the aetiology of MAP-related psychosis in Japanese.

A recent report demonstrated that serum levels of epidermal growth factor (EGF) were significantly decreased in patients with schizophrenia, suggesting that impaired EGF signaling might be associated with the pathophysiology of schizophrenia. Our goal in the present study was to determine whether serum levels of EGF are altered in patients with schizophrenia. We found that serum levels of EGF in drug-naive (n = 15) or medicated patients (n = 25) with schizophrenia did not differ from those of age- and sex-matched normal controls (n = 40). However, we found a significant correlation between serum EGF levels and BPRS scores in the combined groups of patients. Therefore, our results do not support the claim that EGF plays a role in the pathogenesis of schizophrenia, but they suggest that EGF may serve as a state marker, that is, as an index of symptom-linked deficits. (C) 2005 Elsevier Ireland Ltd. All rights reserved.

Several lines of evidence suggest that D-serine, an endogenous agonist of the glycine site on the NMDA receptors, might play a role in the pathophysiology of schizophrenia. The purpose of this study was to determine whether levels of D- and L-serine or D-serine ratio (D-serine/total serine) in cerebrospinal fluid (CSF) were altered in first episode and drug-naive schizophrenic patients. The CSF levels of D- and L-serine in 25 male first episode and drug-naive schizophrenic patients and 17 age-matched male healthy subjects were measured using a column-switching high performance liquid chromatography system. The percentage of D-serine in the total serine of patients was significantly (z=-2.01, p=0.044) lower than that of controls. This study suggests that synthetic or metabolic pathways of D-serine may be abnormal in the brain of drug-naive schizophrenic patients, supporting the NMDA receptor dysfunction hypothesis of schizophrenia. (C) 2005 Elsevier Inc. All rights reserved.

Several lines of evidence suggest that genetic factors contribute to the vulnerability of drug abuse such as methamphetamine (MAP), and that dopamine-quinones produced by administration of MAP may be involved in the mechanism of MAP-related symptoms. The detoxification of quinones is catalyzed by a family of proteins designated as quinone oxidoreductases (NQOs). We analysed the polymorphisms of NQO1 and NQO2 genes to elucidate the association with genetic vulnerability to MAP abuse in Japan. The genotype and allele frequencies for the polymorphism (Pro187Ser) of the NQO1 gene did not differ between each subgroup of patients and controls. In contrast, the genotype frequency for the insertion/deletion (I/D) polymorphism in the promoter region of the NQO2 gene was a significant ( p = 0.038) difference between patients with prolonged-type MAP psychosis and controls. This study suggests that the NQO2 gene polymorphism contributes to the aetiology of MAP-related psychosis in Japanese.

Several lines of evidence suggest that oxidative stress plays a role in the mechanisms of action of methamphetamine (MAP) in the human brain. Given the role of glutathione S-transferases (GSTs) in the protection against oxidative stress, genes encoding the GSTs have been considered as candidates for association studies of MAP abuse. This study was undertaken to investigate the role of the functional polymorphism of GSTP1 gene exon 5 (Ile105Val) in the pathogenesis of MAP abuse. Genotyping for GSTP1 gene polymorphism exon 5 (Ile105Val) in 189 MAP abusers and 199 normal controls was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Association between GSTP1 gene polymorphism and clinical features (prognosis of psychosis (transient-type and prolonged-type), spontaneous relapse (positive and negative), and poly-substance abuse) of MAP abusers was evaluated. Significant differences in the frequency of both alleles (P = 0.026, odds ratio: 1.70, 95% confidence intervals (CI) 1.06-2.72) and genotypes (P = 0.029) between MAP abusers and controls were detected. In particular, a significant difference in both genotype frequency (P = 0.013) and allele frequency (P = 0.014, odds ratio: 1.84, 95% CI 1.13-2.97) between MAP abusers with psychosis (transient-type and prolonged-type) and controls was detected. Our findings suggest that the polymorphism (Ile 105Val) on exon 5 of the GSTP1 gene may contribute to a vulnerability to psychosis associated with MAP abuse in Japanese population. (c) 2005 Wiley-Liss, Inc.

Eating disorders, which include anorexia nervosa (AN) and bulimia nervosa (BN), are disorders characterized by abnormal patterns of weight regulation and eating behaviors, and by disturbances in attitudes and perceptions toward weight and body shape. Brain-derived neurotrophic factor (BDNF) plays a critical role in regulating neural survival, development, function, and plasticity in the brain. Recent findings using heterozygous BDNF (+/-) knock-out (reduced BDNF levels) mice have provided evidence that BDNF plays a role in regulating eating behaviors. Recently, we found that serum levels of BDNF in patients with eating disorders are significantly decreased compared with normal controls. In addition, an association between the BDNF gene polymorphism and eating disorders has been demonstrated. We reviewed the role of BDNF in the pathophysiology of eating disorders and the BDNF gene as a susceptibility gene for eating disorders. Considering the low levels of BDNF in patients with eating disorders, using drugs that increase the BDNF levels and/or BDNF gene therapy are possible novel therapeutic approaches. Providing confirmation that the BDNF gene is the true susceptibility gene for eating disorders could lead to rapid therapeutic progress in treating these disorders. In addition, a more complete understanding of the signal transduction pathway via the p75 neurotrophin receptor (p75(NTR)) and TrkB receptors would provide new perspectives for treating eating disorders. (c) 2005 Elsevier Inc. All rights reserved.

Midkine (MK) is a heparin binding growth factor and promotes growth, survival and migration of various cells including neurons. It is also known to accumulate in senile plaques of patients with Alzheimer's disease (AD). To investigate the involvement of serum MK in the pathophysiology of AD, serum MK levels were determined in patients with AD (n = 36) and age- and sex-matched healthy controls (n = 32), using an enzyme-linked immunosorbent assay (ELISA). The serum MK values of the patients with AD (median 560 and interquartile range (500-755) pg/ml) were significantly (U=278.5, P=0.0003, Mann-Whitney U-test) higher than those of the controls (median 500 and interquartile range (385-520) pg/ml). Moreover, 17 patients (47.2%) had abnormally high values of more than 600 pg/ml, but no controls (0%) did. There was no correlation between serum MK level and the mini mental state examination (MMSE) score in the patients. The demonstration of elevated MK levels in sera of patients with AD may contribute toward an understanding the pathophysiology of this disease, and provide a novel potential therapeutic strategy for decreasing neuronal damages in patients with AD. We found that serum MK levels in patients with AD were increased in comparison with those of normal controls. (c) 2005 Elsevier Inc. All rights reserved.

Several lines of evidence suggest that oxidative stress plays a role in the mechanisms of action of methamphetamine (MAP) in the human brain. Given the role of glutathione S-transferases (GSTs) in the protection against oxidative stress, genes encoding the GSTs have been considered as candidates for association studies of MAP abuse. This study was undertaken to investigate the role of the functional polymorphism of GSTP1 gene exon 5 (Ile105Val) in the pathogenesis of MAP abuse. Genotyping for GSTP1 gene polymorphism exon 5 (Ile105Val) in 189 MAP abusers and 199 normal controls was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Association between GSTP1 gene polymorphism and clinical features (prognosis of psychosis (transient-type and prolonged-type), spontaneous relapse (positive and negative), and poly-substance abuse) of MAP abusers was evaluated. Significant differences in the frequency of both alleles (P = 0.026, odds ratio: 1.70, 95% confidence intervals (CI) 1.06-2.72) and genotypes (P = 0.029) between MAP abusers and controls were detected. In particular, a significant difference in both genotype frequency (P = 0.013) and allele frequency (P = 0.014, odds ratio: 1.84, 95% CI 1.13-2.97) between MAP abusers with psychosis (transient-type and prolonged-type) and controls was detected. Our findings suggest that the polymorphism (Ile 105Val) on exon 5 of the GSTP1 gene may contribute to a vulnerability to psychosis associated with MAP abuse in Japanese population. (c) 2005 Wiley-Liss, Inc.

Recent advances in molecular biology suggest that neuronal nicotinic acetylcholine receptors play important roles in the central nervous system (CNS). Of these receptors, the 0 group has recently attracted interest for its CNS-related actions and is looked to as a potential new class of pharmacological targets for cognition, schizophrenia, sensory gating, and anxiety. In the course of a research program aimed at the discovery of alpha 7 receptor agonists with high affinity, subtype selectivity, and good pharmacokinetic profile, we discovered (R)-3'(5-chlorothiophen-2-yl)spiro-l-azabicyclo[2.2.2]octane-3,5'-[1',3'loxazolidin-2'-one (25). Compound 25 has potent binding affinity (K-i = 9 nmol/L) and good selectivity toward the other nicotinic subtypes (alpha A beta 2 and a1 beta 2 gamma delta) and has been found in pharmacokinetic evaluation to have good oral bioavailability and brain permeability.

Repeated use of methamphetamine (MAP) is known to cause neurotoxicity in the dopaminergic neurons of the striatum. Recently, we reported that FK506, a calcineurin inhibitor and immunosuppressive agent, could attenuate acute behavioral changes and the development of sensitization after administration of MAP. In this study, we investigated the effects of FK506 on the neurotoxicity in the dopaminergic neurons induced by repeated administration of MAP. BALB/c mice were injected subcutaneously (s.c.) with vehicle (10 ml/kg) or MAP (4 mg/kg) four times every 2 h. Vehicle (10 ml/kg) or FK506 (0.1, 0.3, 1 or 3 mg/kg i.p.) was administered 15 min before the first MAP administration. Three days later, we assessed the contents of dopamine (DA) and its major metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the mouse striatum using high-performance liquid chromatography (HPLC). We also examined the immunohistochemistry of dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the mouse brain. Repeated administration of MAP decreased significantly the contents of DA and DOPAC in the mouse striatum, and pretreatment with FK506 inhibited significantly the reduction of DA and DOPAC in the mouse brain by repeated administration of MAP. Furthermore, repeated administration of MAP decreased significantly the immunoreactivity of DAT and TH in the striatum as compared to controls. Pretreatment with FK506 (3 mg/kg) attenuated significantly the reduction of DAT and TH immunoreactivity after repeated administration of MAP. These results suggest that FK506 shows protective effects on the MAP-induced neurotoxicity in the dopaminergic neurons of the mouse striatum. (c) 2004 Elsevier Ltd. All rights reserved.