橋本 謙二

Immune dysfunction has been proposed as a mechanism for the pathophysiology of autistic-spectrum disorders. The selectin family of adhesion molecules plays a prominent role in immune/inflammatory responses. We determined the serum levels of three types of soluble-form selectin (sP, sL and sE) in 15 men with high-functioning autism and 22 age-matched healthy controls by enzyme-linked immunosorbent assay. Levels of sP-selectin and sL-selectin were significantly lower in patients than in controls. Furthermore, sP-selectin levels were negatively correlated with impaired social development during early childhood.

Background: The alpha 7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. However, there are currently no suitable positron emission tomography (PET) radioligands for imaging a7 nAChRs in the intact human brain. Here we report the novel PET radioligand [C-11] CHIBA-1001 for in vivo imaging of alpha 7 nAChRs in the non-human primate brain. Methodology/Principal Findings: A receptor binding assay showed that CHIBA-1001 was a highly selective ligand at alpha 7 nAChRs. Using conscious monkeys, we found that the distribution of radioactivity in the monkey brain after intravenous administration of [C-11] CHIBA-1001 was consistent with the regional distribution of alpha 7 nAChRs in the monkey brain. The distribution of radioactivity in the brain regions after intravenous administration of [C-11] CHIBA-1001 was blocked by pretreatment with the selective alpha 7 nAChR agonist SSR180711 (5.0 g/kg). However, the distribution of [C-11] CHIBA-1001 was not altered by pretreatment with the selective alpha 4 beta 2 nAChR agonist A85380 (1.0 mg/kg). Interestingly, the binding of [C-11]CHIBA-1001 in the frontal cortex of the monkey brain was significantly decreased by subchronic administration of the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (0.3 mg/kg, twice a day for 13 days); which is a non-human primate model of schizophrenia. Conclusions/Significance: The present findings suggest that [C-11]CHIBA-1001 could be a novel useful PET ligand for in vivo study of the receptor occupancy and pathophysiology of alpha 7 nAChRs in the intact brain of patients with neuropsychiatric diseases such as schizophrenia and Alzheimer's disease.

Background: Selective serotonin reuptake inhibitors (SSRIs) have been widely used and are a major therapeutic advance in psychopharmacology. However, their pharmacology is quite heterogeneous. The SSRI fluvoxamine, with sigma-1 receptor agonism, is shown to potentiate nerve-growth factor (NGF)-induced neurite outgrowth in PC 12 cells. However, the precise cellular and molecular mechanisms underlying potentiation by fluvoxamine are not fully understood. In this study, we examined the roles of cellular signaling pathways in the potentiation of NGF-induced neurite outgrowth by fluvoxamine and sigma-1 receptor agonists. Methods and Findings: The effects of three SSRIs ( fluvoxamine, sertraline, paroxetine) and three sigma-1 receptor agonists (SA4503, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP), and dehydroepiandrosterone (DHEA)-sulfate) on NGF-induced neurite outgrowth in PC12 cells were examined. Also examined were the effects of the sigma-1 receptor antagonist NE-100, inositol 1,4,5-triphosphate (IP3) receptor antagonist, and specific inhibitors of signaling pathways in the potentiation of NGF-induced neurite outgrowth by selective sigma-1 receptor agonist SA4503. Fluvoxamine ( but not sertraline or paroxetine) and the sigma-1 receptor agonists SA4503, PPBP, and DHEA-sulfate significantly potentiated NGF-induced neurite outgrowth in PC12 cells in a concentration-dependent manner. The potentiation by fluvoxamine and the three sigma-1 receptor agonists was blocked by co-administration of the selective sigma-1 receptor antagonist NE-100, suggesting that sigma-1 receptors play a role in blocking the enhancement of NGF-induced neurite outgrowth. Moreover, the potentiation by SA4503 was blocked by co-administration of the IP3 receptor antagonist xestospongin C. In addition, the specific inhibitors of phospholipase C (PLC-gamma), phosphatidylinositol 3-kinase (PI3K), p38MAPK, c-Jun N-terminal kinase (JNK), and the Ras/Raf/mitogen-activated protein kinase ( MAPK) signaling pathways blocked the potentiation of NGF-induced neurite outgrowth by SA4503. Conclusion: These findings suggest that stimulation of sigma-1 receptors and subsequent interaction with IP3 receptors, PLC-gamma, PI3K, p38MAPK, JNK, and the Ras/Raf/MAPK signaling pathways are involved in the mechanisms of action of sigma-1 receptor agonists such as fluvoxamine and SA4503.

Accumulating evidence suggests that the glycine modulatory site on the NMDA receptor could be potential therapeutic target for cognitive deficits in schizophrenia. The present study was undertaken to examine the effects of the glycine transporter-1 (GlyT-1) inhibitor, (R)-(N-[3-(4'fluorophenyt)-3-(4'-phenylphenoxy)propyl])sarcosine (NFPS), 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-week) administration of NFPS (1.0 and 3.0 mg/kg/day) or D-serine (600 mg/kg/day). However, PCP-induced cognitive deficits were not improved by a single administration of NFPS (3.0 mg/kg). Furthermore, Western blot analysis revealed that levels of GlyT-1 in the hippocampus, but not frontal cortex, of the PCP (10 mg/kg/day for 10 days)-treated mice were significantly higher than those of saline-treated mice. An in vivo microdialysis study revealed that repeated PCP administration significantly decreased the extracellular levels of glycine in the hippocampus, but not frontal cortex, of mice. These findings suggest that repeated PCP administration increased the density of GlyT-1 in the hippocampus of mouse brain, and that the GlyT-1 inhibitor NFPS could ameliorate cognitive deficits in mice after repeated administration of PCR. (C) 2007 Elsevier B.V. and ENCP All rights reserved.

Accumulating evidence suggests that the serotonin 5-HT1A receptor may play a role in the pathophysiology of schizophrenia. The present study was undertaken to examine the effects of perospirone, an atypical antipsychotic drug with 5-HT1A receptor agonism, on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). Subsequent subchronic (14 days) administration of perospirone (1.0, 3.0, or 10 mg/kg) significantly attenuated PCP (10 mg/kg)-induced cognitive deficits in mice, in a dose-dependent manner. The effects of perospirone (10 mg/kg) were significantly antagonized by co-administration of the selective 5-HT1A receptor antagonist WAY100635 (1.0 mg/kg). Furthermore, hypothermia by the 5-HT1A receptor agonist 8-OH DPAT (0.25 mg/kg) was significantly attenuated in mice treated with PCP. Moreover, a receptor binding assay using [H-3]WAY100635 revealed that levels of 5-HT1A receptors in the hippocampus, but not in the frontal cortex, of PCP-treated mice were significantly tower than those of saline-treated mice. These findings suggest that repeated PCP administration alters 5-HT1A receptor function in the mouse brain, and that subsequent subchronic administration of perospirone ameliorates PCP-induced cognitive deficits via 5-HT1A receptors. Therefore, perospirone could be a potential therapy for the cognitive deficits observed in schizophrenic patients. (C) 2007 Elsevier B.V. and ECNP. All rights reserved.

Rationale Several agents that stimulate the glycine site of N-methyl-D-aspartate (NMDA) receptors have been reported to moderately improve both negative symptoms and cognitive dysfunctions in patients with schizophrenia. However, differences in efficacy have also been reported, and further comparative pharmacological studies are still needed. Objectives We aimed to explore the effects of two glycine site agonists of the NMDA receptor, glycine and D-serine, and a partial agonist, D-cycloserine, on prepulse inhibition (PPI) deficits induced by a NMDA receptor antagonist, MK-801, in mice. Furthermore, we performed in vivo microdialysis and additional PPI measurements using a selective glycine site antagonist to verify if the beneficial effects observed after the systemic administration of glycine were due to glycine itself via its activity at the glycine site. Results High doses of glycine (1.6 g/kg) and D-serine (1.8 and 2.7 g/kg) significantly attenuated MK-801-induced PPI deficits. In contrast, D-cycloserine did not show any amelioration of MK-801-induced PPI deficits at doses ranging from 7.5 mg/kg to 60 mg/kg. The selective glycine site antagonist, L-701,324 (10 mg/kg), antagonized the effect of glycine on MK-801-induced PPI deficits. Furthermore, in vivo microdialysis demonstrated that intraperitoneal injection of glycine significantly increased glycine and L-serine levels, but decreased D-serine levels in the prefrontal cortex. The findings of the present study suggest that glycine and D-serine but not D-cycloserine could attenuate PPI deficits associated with NMDA receptor hypofunction via NMDA glycine sites in the brain.

D-Amino acid oxidase (DAAO) catalyzes the oxidation of D-amino acids including D-serine, a full agonist at the glycine site of the NMDA receptor. A series of benzo[d]isoxazol-3-ol derivatives were synthesized and evaluated as DAAO inhibitors. Among them, 5-chlorobenzo[d]isoxazol-3-ol (CBIO) potently inhibited DAAO with an IC(50) in the submicromolar range. Oral administration of CBIO in conjunction with D-serine enhanced the plasma and brain levels of D-serine in rats compared to the oral administration Of D-serine alone.

Background: D-serine is an endogenous coagonist of the N-methyl-D-aspartate subtype glutamate receptor. Genetic association studies have implicated genes coding for enzymes associated with D-serine metabolism in schizophrenia and bipolar disorder. Methods: Protein expression of serine racemase (SR) and its binding partner, protein interacting with C-kinase (PICK1), were examined by Western blotting in brains from wildtype and PICK1 knockout mice. Levels of D-serine in wildtype and PICK1 mice were also examined by an established high-pressure liquid chromatography protocol. Results: Expression of SR and PICK1 proteins was developmentally regulated. Although no change was observed in the level of SR protein, levels of D-serine were selectively decreased in the forebrain of neonatal PICK1 knockout mice, compared with those in wildtype mice. Conclusions: PICK1 may be involved in the regulation of brain D-serine levels and SR in a spatially and temporally specific manner.

Background: Epidemiological studies suggest that radiation exposure may be a potential risk factor for schizophrenia in adult humans. Here, we investigated whether adult irradiation in rats caused behavioral abnormalities relevant to schizophrenia. Methodology/Principal Findings: A total dose of 15-Gy irradiation in six fractionations during 3 weeks was exposed to the forebrain including the subventricular zone (SVZ) and subgranular zone (SGZ) with male rats in the prone position. Behavioral, immunohistochemical, and neurochemical studies were performed three months after fractionated ionizing irradiation. Three months after fractionated ionizing irradiation, the total numbers of BrdU-positive cells in both the SVZ and SGZ zones of irradiated rats were significantly lower than those of control (sham-irradiated) rats. Hyperactivity after administration of the dopaminergic agonist methamphetamine, but not the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine, was significantly enhanced in the irradiated rats although spontaneous locomotion in the irradiated rats was significantly lower than that of controls. Behavioral abnormalities including auditory sensory gating deficits, social interaction deficits, and working memory deficits were observed in the irradiated rats. Conclusion/Significance: The present study suggests that irradiation in adulthood caused behavioral abnormalities relevant to schizophrenia, and that reduction of adult neurogenesis by irradiation may be associated with schizophrenia-like behaviors in rats.

Background: Glutathione (GSH), a major intracellular antioxidant, plays a role in NMDA receptor-mediated neurotransmission, which is involved in the pathophysiology of schizophrenia. In the present study, we aimed to investigate whether GSH levels are altered in the posterior medial frontal cortex of schizophrenic patients. Furthermore, we examined correlations between GSH levels and clinical variables in patients. Methods and Findings: Twenty schizophrenia patients and 16 age-and gender-matched normal controls were enrolled to examine the levels of GSH in the posterior medial frontal cortex by using 3T SIGNA EXCITE H-1-MRS with the spectral editing technique, MEGA-PRESS. Clinical variables of patients were assessed by the Global Assessment of Functioning (GAF), Scale for the Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS), and five cognitive performance tests (Word Fluency Test, Stroop Test, Trail Making Test, Wisconsin Card Sorting Test and Digit Span Distractibility Test). Levels of GSH in the posterior medial frontal cortex of schizophrenic patients were not different from those of normal controls. However, we found a significant negative correlation between GSH levels and the severity of negative symptoms (SANS total score and negative symptom subscore on BPRS) in patients. There were no correlations between brain GSH levels and scores on any cognitive performance test except Trail Making Test part A. Conclusion: These results suggest that GSH levels in the posterior medial frontal cortex may be related to negative symptoms in schizophrenic patients. Therefore, agents that increase GSH levels in the brain could be potential therapeutic drugs for negative symptoms in schizophrenia.

Background: The N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP)-induced cognitive deficits have been used as an animal model for schizophrenia. This study was undertaken to determine whether the antibiotic drug minocycline could improve PCP-induced cognitive deficits in mice. Methods: Saline (10 ml/kg/day, s.c., once daily on day 1-5, 8-12) or PCP (10 mg/kg/day, s.c., once daily on day 1-5, 8-12) were administered to mice for 10 days. Subsequently, vehicle (10 ml/kg/day, i.p.) or minocycline (4.0 or 40 mg/kg/day, i.p.) was injected for 14 consecutive days. One day after the final injection, a novel object recognition test was performed. Results: PCP-induced cognitive deficits in mice were significantly improved by subsequent subchronic (14 days) administration of minocycline (40 mg/kg), but not minocycline (4.0 mg/kg). Conclusions: This study suggests that minocycline could be a potential therapeutic drug for cognitive deficits in schizophrenic patients. (c) 2007 Elsevier Inc. All rights reserved.

Aberrant neuronal development is one of the integrative theories for the etiology of schizophrenia. The plexin A2 (PLXNA2) gene is one of the receptor genes for axonal guidance factors. Recently, four single nucleotide polymorphisms (SNPs), rs841865, rs752016, rs1327175 and rs2498028, from the PLXNA2 genomic interval have been reported to be associated with schizophrenia in samples from European Americans, Latin Americans and Asian Americans. We tested these four SNPs for association with disease in two Asian populations: 1140 case-control Japanese samples and 293 Chinese pedigrees (1163 samples). In the Japanese samples, significant differences in the allelic frequency and genotypic distribution of rs841865 (p=0.019 and 0.020, respectively) were observed between cases and controls. Haplotype analysis also revealed a significant association of the gene with the disease (global p =0.028). In contrast, there was no genetic contribution of PLXNA2 to Chinese schizophrenia, either by linkage analysis or association tests (allelic and haplotypic transmission disequilibrium tests). These findings suggest that PLXNA2 confers a varying genetic risk for schizophrenia among different populations. (C) 2007 Elsevier B.V. All rights reserved.

In practical positron emission tomography (PET) diagnosis, a shortened protocol is preferred for patients with brain disorders. In this study, the applicability of a shortened protocol as an alternative to the 90-min PET scan with [(11)C]SA4503 for quantitative sigma(1) receptor measurement was investigated. Tissue time-activity curves of 288 regions of interest in the brain from 32 [(11)C]SA4503-PET scans of 16 healthy subjects prior to and following administration of a selective serotonin reuptake inhibitor (fluvoxamine or paroxetine) were applied to two algorithms of quantitative analysis; binding potential (BP) was derived from compartmental analysis based on nonlinear estimation, and total distribution volume (tDV) was derived from Logan plot analysis. As a result, although both BP and tDV tended to be underestimated by the shortened method, the estimates from the shortened protocol had good linear relationships with those of the full-length protocol. In conclusion, if approximately 10% differences in the estimated results are acceptable for a specific purpose, then a 60-min measurement protocol is capable of providing reliable results.

Use of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) is an extremely serious and growing problem throughout the world, including Japan. Antipsychotic drugs have been used for psychotic symptoms associated with these abused drugs. However, there are currently no particular pharmacological treatments for the wide range of symptoms associated with these abused drugs. Recently, we reported that the second generation antibiotic drug minocycline can attenuate behavioral abnormalities and neurotoxicity in the brain after administration of methamphetamine or MDMA. In this review, we discuss minocycline as a new potential therapeutic drug for schizophrenia as well as psychosis associated with these abused drugs.

Background: Accumulating evidence suggests that alpha 7 nicotinic receptor (alpha 7 nAChR) agonists could be potential therapeutic drugs for cognitive deficits in schizophrenia. The present study was undertaken to examine the effects of the novel selective alpha 7 nAChR agonist SSR180711 on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). Methods: Saline or PCP (10 mg/kg/day for 10 days) was administered to mice. Subsequently, vehicle, SSR180711 (.3 or 3.0 mg/kg/day), SSR180711 (3.0 mg/kg/day) + the selective alpha 7 nAChR antagonist methyllycaconitine (MLA; 3.0 mg/kg/day), or MLA (3.0 mg/kg/day) was administered IP for 2 consecutive weeks. Twenty-four hours after the final administration, a novel object recognition test was performed. Results: The PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of SSR180711 (3.0 mg/kg). The effects of SSR180711 (3.0 mg/kg) were significantly antagonized by co-administration of MLA (3.0 mg/kg). Furthermore, Western blot analysis and immunohistochemistry revealed that levels of alpha 7 nAChRs in the frontal cortex and hippocampus of the PCP (10 mg/kg/day for 10 days)-treated mice were significantly lower than those of saline-treated mice. Conclusions: These findings suggest that repeated PCP administration significantly decreased the density of alpha 7 nAChRs in the brain and that the alpha 7 nAChR agonist SSR180711 could ameliorate cognitive deficits in mice after repeated administration of PCP. Therefore, alpha 7 nAChR agonists including SSR180711 are potential therapeutic drugs for treating cognitive deficits in schizophrenic patients.

Compounds enhancing N-methyl-D-aspartate (NMDA) glutamate receptor function have been reported to improve cognitive deficits. Since cognitive deficits are considered to be the core symptom of schizophrenia, enhancing NMDA receptor function represents a promising approach to treating, schizophrenia. In the present study, we investigated whether D-serine or a glycine transporter inhibitor N-[3-(4'-fluorophenyl)-3-(4'phenylphenoxy)propyllsarcosine (NFPS), both of which enhance NMDA receptor function, could improve MK-801-induced cognitive deficits in rats, and compared their effects with those of the atypical antipsychotic clozapine and of the typical antipsychotic haloperidol. To assess cognitive function. we used a novel object recognition test in rats that measured spontaneous exploratory activity of a novel object when paired with a familiar object. We then evaluated the effects of the compounds on cognitive deficits induced by treatment with MK-801, the NMDA receptor antagonist. Pretreatment with clozapine (1, 5 mg/kg, i.p.) but not haloperidol (0.03, 0.1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits. Pretreatment with D-serine at 800 mg/ka (i.p.) or NFPS (0.3, 1 ing/k,a, i.p.) significantly improved MK-801-induced cognitive deficits under this test paradigm. These findings suggest that impaired preference for novel objects induced by MK-801 in the novel object recognition test could be a useful animal model for evaluating the efficacy of compounds targeting the cognitive deficits observed in schizophrenic patients. The results also suggest that enhancing NMDA receptor function is an effective way for treating the cognitive deficits associated with schizophrenia. (c) 2007 Elsevier B.V. All rights reserved.

Obsessive-compulsive disorder (OCD) is considered to involve abnormalities in inhibitory processes including gating systems. Auditory P50 inhibition, which is assessed by using a paired auditory stimulus paradigm to record P50 mid-latency evoked potential, is assumed to reflect sensory gating. In the present study, we investigated auditory P50 inhibition in subjects with OCD, and examined the relationship between P50 and clinical variables or neuropsychological performance. Twenty-six subjects with OCD and 26 age- and sex-matched healthy controls received P50 recording and neuropsychological tests. In the OCD subjects, we also evaluated clinical features including OC symptoms and subtypes of the disorder. P50 T/C ratios were significantly higher in OCD subjects than in control subjects (t=2.9, df=50, p=0.006). Compared to the controls, the OCD subjects performed significantly worse on the Symbol Digit Modalities Test (SDMT) and the Trail Making Test (TMT). There were no correlations between P50 T/C ratios and clinical variables or the results of neuropsychological tests. Our findings suggest that sensory gating deficits may be involved in the pathophysiology of OCD in a different way from clinical symptoms and executive attention dysfunction. (c) 2007 Elsevier Inc. All rights reserved.

Reelin, a secretory protease that plays major roles in neurodevelopment and synaptic plasticity, may also play a role in the pathogenesis of schizophrenia. The present study was undertaken to examine whether the expression of two receptors for reelin, very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor type 2 (ApoER2), were abnormal in peripheral blood lymphocytes of schizophrenic patients. In this study, we measured the mRNA levels of V-LDLR and ApoER2 in blood lymphocytes from patients with schizophrenia (drug-naive patients (n = 20) and medicated patients (n = 20)) and age-and gender-matched healthy controls (n = 40) using quantitative real-time RT-PCR. Furthermore, we examined the correlation between mRNA levels and clinical variables in patients. Levels of VLDLR mRNA in drug-naive, unmedicated patients with schizophrenia were significantly lower than those of controls. In contrast, levels of ApoER2 mRNA in drug-naive patients did not differ from those of controls, although the levels of ApoER2 mRNA in medicated patients were significantly lower than those of controls. Interestingly, levels of VLDLR mRNA in drug-naive patients showed significant increases with respect to baseline after six months of antipsychotic treatment, whereas levels of ApoER2 mRNA were significantly lower than baseline after six months of treatment. In all patients, there was a negative correlation between VLDLR mRNA levels and the severity of clinical symptoms. Our findings suggest that peripheral VLDLR mRNA levels may serve as a reliable peripheral biological marker of schizophrenia, and that the reelin-VLDLR/ApoER2 signaling pathway plays a role in the pathophysiology of schizophrenia. (C) 2007 Elsevier B.V. All rights reserved.

Background: Glutamate has been thought to have a role in mental disorders. Because the postmortem interval (PMI) has such a pronounced effect on glutamate and other amino acids, it is important that a study be conducted to examine the effects of PMI on these amino acids in postmortem brains and that the analysis of intergroup differences be adjusted accordingly. We determined the levels of amino acids in postmortem brains from patients with major mental disorders by normalizing the effects of the postmortem interval with equations derived from control studies using rodent and primate postmortem brains. Methods: First, we examined the influence of postmortem intervals on the levels of the amino acids by using rodent brains and derived equations for normalizing the raw data of the amino acids from human brains according to their postmortem intervals. Second, we measured the levels of the amino acids in postmortem human brains, normalized their raw data with the equations, and analyzed the normalized data. Results: Increased levels of glutamate were observed in the frontal cortex from patients with bipolar disorder and major depression. In addition, positive correlations were observed between several pairs of amino acids, including D-serine and glutamate. Conclusions: This study suggests that glutamate plays a role in the pathophysiology of bipolar disorder and major depression.

Background: Accumulating evidence suggests that the immune system plays a role in the pathophysiology of autism, and that the adhesion molecules play an important role in the process of inflammation. This study was undertaken to determine whether serum levels of the adhesion molecules in subjects with high-functioning autism are altered as compared with those of normal controls. Methods: Seventeen male subjects with high-functioning autism and 22 male age-matched unrelated healthy control subjects were enrolled. Serum levels of the soluble forms of platelet-endothelial adhesion molecule (PECAM-1), intracellular adhesion molecule (ICAM-1), and vascular cell adhesion molecule (VCAM-1) were measured. Results: Levels of PECAM-1, but not ICAM-1, in the subjects with autism were significantly lower than those of control subjects. VCAM-I showed a weak trend for a lowered level. There was a negative correlation between serum levels of PECAM-1 and head circumference at birth in the autistic subjects. Conclusions: These results suggest that PECAM-1 plays a role in the pathophysiology of high-functioning autism.

Deficits in prepulse inhibition (PPI) are a biological marker for schizophrenia. To unravel the mechanisms that control PPI, we performed quantitative trait loci (QTL) analysis on 1,010 F2 mice derived by crossing C57BL/6 (B6) animals that show high PPI with C3H/He (C3) animals that show low PPI. We detected six major loci for PPI, six for the acoustic startle response, and four for latency to response peak, some of which were sex-dependent. A promising candidate on the Chromosome 10-QTL was Fabp7 (fatty acid binding protein 7, brain), a gene with functional links to the N-methyl-D-aspartic acid (NMDA) receptor and expression in astrocytes. Fabp7-deficient mice showed decreased PPI and a shortened startle response latency, typical of the QTL's proposed effects. A quantitative complementation test supported Fabp7 as a potential PPI-QTL gene, particularly in male mice. Disruption of Fabp7 attenuated neurogenesis in vivo. Human FABP7 showed altered expression in schizophrenic brains and genetic association with schizophrenia, which were both evident in males when samples were divided by sex. These results suggest that FABP7 plays a novel and crucial role, linking the NMDA, neurodevelopmental, and glial theories of schizophrenia pathology and the PPI endophenotype, with larger or overt effects in males. We also discuss the results from the perspective of fetal programming.

Background: Sigma-1 receptors might be implicated in the pathophysiology of psychiatric diseases, as well as in the mechanisms of action of some selective serotonin reuptake inhibitors (SSRIs). Among the several SSRIs, fluvoxamine has the highest affinity for sigma-1 receptors (Ki = 36 nM), whereas paroxetine shows low affinity (Ki = 1893 nM). The present study was undertaken to examine whether fluvoxamine binds to sigma-1 receptors in living human brain. Methods: A dynamic positron emission tomography (PET) data acquisition using the selective sigma-1 receptor ligand [C-11]SA4503 was performed with arterial blood sampling to evaluate quantitatively the binding of [C-11]SA4503 to sigma-1 receptors in 15 healthy male volunteers. Each subject had two PET scans before and after randomly receiving a single dose of either fluvoxa mine (50,100,150, or 200 mg) or paroxetine (20 mg). The binding potential of [C-11]SA4503 in 9 regions of the brain was calculated by a 2-tissue 3-compartment model. In addition, we examined the effects of functional polymorphisms of the sigma-1 receptor (SIGMARI) gene on the binding potential of [C-11]SA4503. Results: Fluvoxamine bound to sigma-1 receptors in all brain regions in a dose-dependent manner, whereas paroxetine did not bind to sigma-1 receptors. However, there was no association between the SIGMAR1 gene polymorphism GC-241-240TT and binding potential. Conclusions: The study demonstrated that fluvoxamine bound to sigma-1 receptors in living human brain at therapeutic doses. These findings suggest that sigma-1 receptors may play an important role in the mechanism of action of fluvoxamine.

Panic disorder is a common anxiety disorder characterized by sudden and recurrent panic attacks. Previous studies have indicated significant genetic contributions and a susceptibility locus for panic disorder has been mapped to human chromosome 7p15. The receptor for Neuropeptide S (NPS) is located in the same genomic region while NPS is known to produce arousal and anxiolytic-like effects in rodents. Here we report that a coding polymorphism in the Neuropeptide S receptor (NPSR) is associated with panic disorder in male patients of Japanese ancestry. The polymorphism (Asn(107)Ile) results in a gain-of-function of the receptor protein by increasing the agonist sensitivity about tenfold. The allele representing the less active isoform (NPSR Asn(107)) was found under-represented in male panic disorder patients, indicating a potential protective function of the protein. Two unrelated groups of patients diagnosed with schizophrenia or attention-deficit/hyperactivity disorder (ADHD) showed no association of particular NPSR alleles with the disorders. These results provide evidence for a gender-specific effect of NPSR in the pathogenesis of panic disorder. (c) 2007 Elsevier Inc. All rights reserved.

To clarify whether reelin signaling is involved in dopaminergic neurotransmission in the adult mouse brain, we investigated dopamine function in mice lacking reelin (reeler). We found that methamphetamine-induced locomotor activity is significantly attenuated in reeler mice. To elucidate the mechanism of this phenomenon, we first investigated presynaptic dopamine release; however, there were no significant differences in wildtype, heterozygous reeler and homozygous reeler mice. Next, we examined the locomotor response to intra-accumbens injection of dopamine D1 and D2 receptor agonists, and found that lack of reelin signaling results in decreases in both D1 and D2 receptor-mediated dopaminergic functions. In addition, we measured dopamine receptor binding in the striatum, and found that both D1 and D2 classes of dopamine receptors are reduced in reeler mice. Furthermore, we found that the phosphorylation levels of DARPP-32 are also changed by lack of reelin signaling. Finally, to distinguish between a developmental role of reelin or an acute role of reelin in adult mouse, we intraventricularly infused CR-50, a monoclonal antibody against reelin. Interestingly, infusion of CR-50 also significantly reduced methamphetamine-induced hyperlocomotion in wildtype mice, showing that reelin has an acute role in the dopaminergic system. These results indicate that reelin signaling plays a pivotal role in the dopaminergic system in adult mice, especially in postsynaptic levels.

Background: Since several studies have investigated gender-related differences in the onset of disease, response to drug therapy, etc. in schizophrenic patients, we examined the alterations in serum amino acids concentrations in male and female patients separately.Methods: Serum amino acid concentrations in the normal (n=35; male 21 and female 14) and schizophrenic patients (n=32; male 19 and female 13) were determined by HPLC using a pre-column fluorescence derivatization with 4-fluoro-7-nitro-2,1,3-benzoxadiazole.Results: Serum glutamate and serine concentrations were significantly increased in the male schizophrenic patients (p=0.0161 and 0.0257, respectively), while the serum Pro concentration was significantly increased in female schizophrenic patients (p=0.0398). Serum Glu, Ser, and Pro concentrations in the patients did not significantly correlate with the age, age of onset of disease, duration of illness, and chlorpromazine equivalents. Among the amino acids, serum Om concentrations in male and female schizophrenic patients positively correlated with the duration of illness (p < 0.01, r=0.685 and 0.688, respectively).Conclusion: The present data suggest the existence of gender-related differences in the alterations in serum amino acid concentrations in schizophrenic patients; further, serum Orn concentration in both sexes might be influenced by medications. (C) 2007 Elsevier B.V. All rights reserved.

近年，自殺の増加が社会問題になってきており，年間3万人以上の方が，自ら命を絶っている．自殺の原因の一つが，代表的な精神疾患のうつ病であるといわれている．うつ病の治療には，選択的セロトニン再取り込み阻害薬（SSRI）等の抗うつ薬が使用されている．SSRIの急性の薬理作用は前シナプスに存在するセロトニントランスポーターを阻害することにより，シナプス間隙のセロトニン量を増加させることであるが，治療効果の発現には数週間を要することが知られている．一方，SSRIのセロトニン神経系における作用は投与直後に認められることから，セロトニン神経系に直接に作用するだけでなく，細胞内の様々なシグナル伝達系に関わる転写因子制御の分子メカニズムが注目されている．本稿では，うつ病の病態および抗うつ薬の作用メカニズムにおける脳由来神経栄養因子（BDNF）の役割に焦点を当て，最新の知見について解説する． <br>

覚せい剤投与による行動異常および脳内ドパミン神経系の障害に及ぼすミノサイクリンの効果を検討した.雄性Balb/Cマウスを用いた.ミノサイクリンは覚せい剤投与による行動異常を有意に抑制した.さらに,前投与だけでなく後投与でも,覚せい剤の繰り返し投与によるマウス線条体におけるドパミン神経系の障害に対して改善作用を示した.ミノサイクリンは覚せい剤乱用による精神障害および神経障害の予防薬・治療薬として有用であることが示唆された

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.

14歳時発症し,24歳時から長期入院,さらに27歳から解体した言動のため,長期保護室隔離を要するようになった30歳の慢性解体型の治療抵抗性統合失調症の女性例に対して,clozapineの投与を7ヵ月間にわたって,最大1日量600mg/日,400mg/日以上の投与量を20週間継続したが,精神症状の改善を認めなかった.その後,本症例は,電気けいれん療法(ECT)への切り替えにより,著効を示した.わが国でも,clozapineが市販されるようになれば,薬物治療アルゴリズムの中で,ECTより先に難治性統合失調症の治療選択の第一段階として利用され,さらに, clozapineの無効例には,clozapineを維持したまま,ECTを行うという治療選択が議論されていくであろう(著者抄録)

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.

GABA is the main inhibitory neurotransmitter in the adult brain, which causes Cl- influx into the cell via GABAA receptors. The direction of Cl- inflow is dependent on the Cl- gradient across the membrane. Cation-Cl- cotransporters have been considered to play pivotal roles in controlling intracellular Cl- concentration ([Cl-]i) of neurons hence, they modulate the GABAergic function. To elucidate how these cotransporters are distributed in the trigeminal nuclei, we investigated the expressions of K+-Cl - cotransporters (KCC1 and KCC2) and Na+-K +-2Cl- cotransporter (NKCC1) mRNAs by using in situ hybridization histochemistry. KCC2 mRNA was expressed in the motor trigeminal nucleus (Mo5), the principal trigeminal nucleus (Pr5), and the spinal trigeminal nucleus (Sp5), but not in the trigeminal ganglion (TG) and the mesencephalic trigeminal nucleus (Me5). On the other hand, KCC1 and NKCC1 mRNAs were expressed in all the trigeminal nuclei. The resting [Cl-]i of Me5 neurons was significantly higher than that of Mo5 neurons. Thus, in primary sensory neurons such as the TG and the Me5, [Cl-]i would be higher than those in the other trigeminal nuclei because of the lack of KCC2 mRNA expression. Since Me5 neurons, but not Mo5 neurons, responded to GABA by depolarization, GABA would have differential physiological functions among trigeminal nuclei and TG. © 2004 Elsevier B.V. All rights reserved.