橋本 謙二

Previous studies have reported the existence of an association between brain-derived neurotrophic factor and major depression. However, the possible role of brain-derived neurotrophic factor in the pathophysiology of major depression after cancer diagnosis has not yet been investigated. Subjects were collected using the Lung Cancer Database project. Using the cut-off scores on the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D), 81 subjects with depression (HADS-D > 10) and 81 subjects without depression (HADS-D < 5) were selected. The two groups were matched for age, sex, clinical stage and performance status. The serum brain-derived neurotrophic factor levels were measured using an enzyme-linked immunosorbent assay method. The serum brain-derived neurotrophic factor levels were not statistically different between the subjects in the depression group [29.1 (13.6) ng/ml; mean (SD)] and the non-depression group [31.4 (10.6) ng/ml] (P = 0.22). In a stratified analysis by gender, however, the mean serum brain-derived neurotrophic factor level in the depression group tended to be lower than that in the non-depression group among women (n = 24 pairs, P = 0.06). Major depression after cancer diagnosis is not associated with serum brain-derived neurotrophic factor levels.

Background: It has recently been hypothesized that hyperglutamatergia in the brain is involved in the pathophysiology of autism. However, there is no conclusive evidence of the validity of this hypothesis. As peripheral glutamate/glutamine levels have been reported to be correlated with those of the central nervous system, the authors examined whether the levels of 25 amino acids, including glutamate and glutamine, in the platelet-poor plasma of drug-naive, male children with high-functioning autism (HFA) would be altered compared with those of normal controls. Methodology/Principal Findings: Plasma levels of 25 amino acids in male children (N = 23) with HFA and normally developed healthy male controls (N = 22) were determined using high-performance liquid chromatography. Multiple testing was allowed for in the analyses. Compared with the normal control group, the HFA group had higher levels of plasma glutamate and lower levels of plasma glutamine. No significant group difference was found in the remaining 23 amino acids. The effect size (Cohen&apos;s d) for glutamate and glutamine was large: 1.13 and 1.36, respectively. Using discriminant analysis with logistic regression, the two values of plasma glutamate and glutamine were shown to well-differentiate the HFA group from the control group; the rate of correct classification was 91%. Conclusions/Significance: The present study suggests that plasma glutamate and glutamine levels can serve as a diagnostic tool for the early detection of autism, especially normal IQ autism. These findings indicate that glutamatergic abnormalities in the brain may be associated with the pathobiology of autism.

Major depressive disorder (MDD) is a common, chronic, recurrent mental illness that affects millions of individuals worldwide. Currently available antidepressants are known to affect the monoaminergic (e.g., serotonin, norepinephrine, and dopamine) systems in the brain. Accumulating evidence suggests that the glutamatergic neurotransmission via the excitatory amino acid glutamate also plays an important role in the neurobiology and treatment of this disease. Clinical studies have demonstrated that the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant patients with MDD, suggesting the role of glutamate in the pathophysiology of treatment-resistant MDD. Furthermore, a number of preclinical studies demonstrated that the agents which act at glutamate receptors such as NMDA receptors, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and metabotropic glutamate receptors (mGluRs) might have antidepressant-like activities in animal models of depression. In this article, the author reviews the role of glutamate in the neuron-glia communication induced by potential antidepressants.

Background: Accumulating epidemiological evidence shows that life event stressors are major vulnerability factors for psychiatric diseases such as major depression. It is also well known that social isolation in male mice results in aggressive behavior. However, it is not known how social isolation-induced aggression affects anxiety and depressive-like behavior in isolated male mice subjected to unpredictable chronic mild stress (CMS), an animal model of depression. Methodology/Principal Findings: C57/B6 male mice were divided into 3 groups; non-stressed controls, in Group I; isolated mice subjected to the CMS protocol in Group II and aggression by physical contact in socially isolated mice subjected to the CMS protocol in Group III. In the sucrose intake test, ingestion of a 1% sucrose solution by mice in Groups II and III was significantly lower than in Group I. Furthermore, intake of this solution in Group III mice was significantly lower than in Group II mice. In the open field test, mice in Group III, showed reduced locomotor activity and reduced entry and retention time in the central zone, compared to Groups I and II mice. Moreover, the distances moved in 1 hour by Group III mice did not differ between night and morning. In the light/black box test, Groups II and III animals spent significantly less time in the light box compared to Group I animals. In the tail suspension test (TST) and forced swimming test (FST), the immobility times of Group II and Group III mice were significantly longer than in Group I mice. In addition, immobility times in the FST were significantly longer in Group III than in Group II mice. Conclusions/Significance: These findings show that social isolation-induced aggression could potentiate anxiety and depressive -like behaviors in isolated male mice subjected to CMS.

Introduction: Glycine transporter 1 (GlyT-1) is an attractive target in positron emission tomography (PET) studies. Here, we report the in vivo evaluation of three carbon-11-labelled non-sarcosine-type GlyT-1 inhibitors - [(11)C]SA1, [(11)C]SA2 and [(11)C]SA3 - as novel PET tracers for GlyT-1. Methods: The regional brain distributions of the three compounds in mice were studied at baseline and under receptor-blockade conditions with co-injection of carrier loading or pretreatment with an excess of selective GlyT-1 inhibitors (ALX-5407 and SSR504734). Metabolic stability was investigated by radio high-performance liquid chromatography. Dynamic PET scans in conscious monkeys were performed with/without selective GlyT-1 inhibitors. Results: The IC(50) values of SA1, SA2 and SA3 were 9.0, 6400 and 39.7 nM, respectively. The regional brain uptakes of [(11)C]SA1 and ([11)C]SA3 in mice were heterogeneous and consistent with the known distribution of GlyT-1. [(11)C]SA2 showed low and homogeneous uptake in the brain. Most radioactivity in the brain was detected in unchanged form, although peripherally these compounds were degraded. Carrier loading decreased the uptake of [(11)C]SA1 in GlyT-1-rich regions. However, similar reductions were not observed with [(11)C]SA3. Pretreatment with ALX-5407 decreased the uptake of [(11)C]SA1 in GlyT-1-rich regions. In the monkey at baseline, regional brain uptake of [(11)C]SA1 was heterogeneous and consistent with the known GlyT-1 distribution. Pretreatment with selective GlyT-1 inhibitors significantly decreased the distribution volume ratio of [(11)C] SA1 in GlyT-1-rich regions. Conclusions: [(11)C]SA1 has the most suitable profile among the three carbon-11-labelled GlyT-1 inhibitors. Lead optimization of [(11)C]SA1 structure will be required to achieve in vivo selective GlyT-1 imaging. (C) 2011 Elsevier Inc. All rights reserved.

Background: The CogState Schizophrenia Battery (CSB), a computerized cognitive battery, covers all the same cognitive domains as the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery but is briefer to conduct. The aim of the present study was to evaluate the criterion and construct validity of the Japanese language version of the CSB (CSB-J) in Japanese patients with schizophrenia. Methodology/Principal Findings: Forty Japanese patients with schizophrenia and 40 Japanese healthy controls with matching age, gender, and premorbid intelligence quotient were enrolled. The CSB-J and the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) were performed once. The structure of the CSB-J was also evaluated by a factor analysis. Similar to the BACS-J, the CSB-J was sensitive to cognitive impairment in Japanese patients with schizophrenia. Furthermore, there was a significant positive correlation between the CSB-J composite score and the BACS-J composite score. A factor analysis showed a three-factor model consisting of memory, speed, and social cognition factors. Conclusions/Significance: This study suggests that the CSB-J is a useful and rapid automatically administered computerized battery for assessing broad cognitive domains in Japanese patients with schizophrenia.

Cilostazol, a type-3 phosphodiesterase (PDE3) inhibitor, has become widely used as an antiplatelet drug worldwide. A recent second Cilostazol Stroke Prevention Study demonstrated that cilostazol is superior to aspirin for prevention of stroke after an ischemic stroke. However, its precise mechanisms of action remain to be determined. Here, we report that cilostazol, but not the PDE3 inhibitors cilostamide and milrinone, significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Furthermore, specific inhibitors for the endoplasmic reticulum protein inositol 1,4,5-triphosphate (IP(3)) receptors and several common signaling pathways (PLC-gamma, PI3K, Akt, p38 MAPK, and c-Jun N-terminal kinase (JNK), and the Ras/Raf/ERK/MAPK) significantly blocked the potentiation of NGF-induced neurite outgrowth by cilostazol. Using a proteomics analysis, we identified that levels of eukaryotic translation elongation factor eEF1A1 protein were significantly increased by treatment with cilostazol, but not cilostamide, in PC12 cells. Moreover, the potentiating effects of cilostazol on NGF-induced neurite outgrowth were significantly antagonized by treatment with eEF1A1 RNAi, but not the negative control of eEF1A1. These findings suggest that eEF1A1 and several common cellular signaling pathways might play a role in the mechanism of cilostazol-induced neurite outgrowth. Therefore, agents that can increase the eEF1A1 protein may have therapeutic relevance in diverse conditions with altered neurite outgrowth.

L-Serine is required for the synthesis of glycine and D-serine, both of which are NMDA receptor coagonists. Although roles for D-serine and glycine have been suggested in schizophrenia, little is known about the role of the L-serine synthesizing cascade in schizophrenia or related psychiatric conditions. Here we report a patient with schizophrenia carrying a balanced chromosomal translocation with the breakpoints localized to 3q13.12 and 9q21.2. We examined this proband and her son with schizotypal personality disorder for chromosomal abnormalities, molecular expression profiles, and serum amino acids. Marked decrease of L-serine and glutamate was observed in the sera of the patient and her son, compared with those in normal controls. Interestingly, expression of PSAT1 gene, which is located next to the breakpoint and encodes one of the enzymes in the L-serine synthesizing cascade, was reduced in both patient and her son. Direct effect of impaired PSAT1 gene expression on decreased serum L-serine level was strongly implicated by rat astrocyte experiments. In summary, we propose an idea that PSAT1 may be implicated in altered serine metabolism and schizophrenia spectrum conditions. (C) 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Minocycline, a tetracycline antibiotic, interacts with brain glutamate and dopamine neurotransmission. In preclinical studies, minocycline attenuated amphetamine-induced acute dopamine release and subsequent behavioral sensitization. The goal of this study was to determine minocycline's effects on the acute physiological, behavioral, and subjective responses to dextroamphetamine (DAMP) in healthy volunteers. Ten healthy volunteers participated in an outpatient double-blind, placebo-controlled, crossover study. Subjects had a 5-day treatment period with either minocycline (200 mg/day) or placebo and then were crossed over for 5 days of the other treatment. After 2 days of taking the study medication, on days 3 and 4, subjects were randomly assigned to double-blind acute challenge with either 20 mg/70 kg DAMP or placebo DAMP (randomly labeled as drug A or B) and then crossed over to the other challenge. On day 5 (experimental session 3), subjects had the opportunity to self-administer either placebo or DAMP capsules by working on a progressive ratio computer task. Minocycline attenuated DAMP-induced subjective rewarding effects but did not change DAMP choice behavior. Minocycline treatment speeded reaction times on a Go No-Go task and reduced plasma cortisol levels. These findings warrant further studies examining the potential use of minocycline for stimulant addiction.

We have found that mutation of D-amino acid oxidase (DAO) diminished formalin-induced tonic pain. The present research further studied the analgesic effects of a series of DAO inhibitors in this model. 5-Chlorobenzo[d]isoxazol-3-ol (CBIO), 4H-thieno[3,2-b]pyrrole-5-carboxylic acid (compound 8), 5-methylpyrazole-3-carboxylic acid (AS057278), sodium benzoate, and 4-nitro-3-pyrazole carboxylic acid (NPCA) inhibited rat spinal cord-derived DAO activity in a concentration-dependent manner, with maximal inhibition of 100% and potency rank of CBIO &gt; compound 8 &gt; AS057278 &gt; sodium benzoate &gt; NPCA. In rats, intrathecal injections of CBIO, compound 8, AS057278, and sodium benzoate but not NPCA specifically prevented formalin-induced tonic pain but not acute nociception, with the same potency order as in the DAO activity assay. The highly potent analgesia of DAO inhibitors was evidenced by CBIO, which prevented 50% pain at 0.06 mu g, approximately 5-fold the potency of morphine. CBIO given after formalin challenge also reversed the established pain state to the same degree as prevention. The antihyperalgesic potencies of these DAO inhibitors were highly correlated to their inhibitions of spinal DAO activity. Maximum inhibition of pain by these compounds was approximately 60%, comparable with that of the N-methyl-D-aspartic acid receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), suggesting that a larger portion of formalin-induced tonic pain is "DAO-sensitive," whereas the remaining 40% of tonic pain and acute nociception is "DAO-insensitive." These findings, combined with our previous DAO gene mutation and induction results, indicate spinal DAO mediates both induction and maintenance of formalin-induced tonic pain and further validate spinal DAO as a novel and efficacious target molecule for the treatment of chronic pain.

Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease. Approximately 20% cases of familial ALS show the mutation in the superoxide dismutase-1 (SOD1) gene. We previously demonstrated that homologue to E6AP carboxyl terminus- (HECT-) type ubiquitin protein E3 ligase (NEDL1) physically bind to mutated SOD1 protein but not wildtype SOD1 and promote the degradation of mutated SOD1 protein through ubiquitin-mediated proteasome pathway. To further understand the role of NEDL1 involved in the pathogenesis of familial ALS, we generated transgenic mice with human NEDL1 cDNA. The transgenic mice with human NEDL1 expression showed motor dysfunctions in rotarod, hanging wire, and footprint pattern examination. Histological studies indicated degeneration of neurons in the lumbar spinal cord and muscle atrophy. The number of activated microglia in the spinal cord of transgenic mice was significantly higher than that of wild-type mice, suggesting that inflammation might be observed in the spinal cord of transgenic mice. In conclusion, these findings suggest that the human NEDL1 transgenic mice might develop ALS-like symptoms, showing signs of motor abnormalities, accompanied with significant reduction in muscle strength.

Glutamate carboxypeptidase II (GCP II) is a glial enzyme responsible for the hydrolysis of N-acetylaspartylglutamate (NAAG) into glutamate and N-acetylaspartate (NAA). Abnormalities in glutamate neurotransmission are implicated in the pathophysiology of schizophrenia. In this study, we examined the effects of a novel, orally active GCP II inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), on the prepulse inhibition (PPI) deficits after administration of the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine. Oral administration of 2-MPPA (10, 30 or 100 mg/kg) significantly attenuated dizocilpine (0.1 mg/kg)-induced PPI deficits in mice, in a dose dependent manner. Furthermore, the efficacy of 2-MPPA on dizocilpine-induced PPI deficits was significantly antagonized by pretreatment with the selective group II metabotropic glutamate receptor (mGluR) antagonist LY341495 (1.0 mg,(kg). In the same model, however, the selective group II mGluR agonist LY354740 (3, 10 or 30 mg/kg) significantly attenuated dizocilpine-induced PPI deficits at only one dose and prepulse intensity. Our findings suggest that GCP II inhibition may be useful therapeutic strategy for schizophrenia. From a mechanistic perspective, while increased NAAG and activation of group II mGluRs may contribute to the therapeutic efficacy of 2-MPPA, it is likely that additional pharmacological activities are also involved. (C) 2010 Elsevier B.V. All rights reserved.

Some patients with major depressive disorder remain resistant to antidepressant medication. A randomized, placebo-controlled, double-blind trial demonstrated that a single subanesthetic dose (0.5 mg/kg) of the N-methyl-D-aspartate receptor antagonist ketamine caused a rapid antidepressant effect within hours in treatment-resistant patients with major depressive disorder. However, the precise cellular mechanisms underlying ketamine's rapid antidepressant actions were unclear, although it is proposed that the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor might be involved in these mechanisms. Recently, Li et al. reported the role of the mammalian target of rapamycin (mTOR) signaling pathway, a ubiquitous protein kinase involved in protein synthesis and synaptic plasticity, in ketamine's rapid antidepressant effects. Here, these findings are put into context and their significance is discussed.

The hypofunction hypothesis of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of schizophrenia suggests that increasing NMDA receptor function via pharmacological manipulation could provide a new therapeutic strategy for schizophrenia. The glycine modulatory site on NMDA receptor complex is the one of the most attractive therapeutic targets for schizophrenia. One means of enhancing NMDA receptor neurotransmission is to increase the availability of the obligatory co-agonist glycine at modulatory site on the NMDA receptors through the inhibition of glycine transporter-1 (GlyT-1) on glial cells. Some clinical studies have demonstrated that the GlyT-1 inhibitor sarcosine (N-methylglycine) shows antipsychotic activity in patients with schizophrenia. Currently, a number of pharmaceutical companies have been developing novel and selective GlyT-1 inhibitors for the treatment of schizophrenia. A recent double blind phase II study demonstrated that the novel GlyT-1 inhibitor RG1678 has a robust and clinically meaningful effect in patients with schizophrenia. In this article, the author reviews the recent findings on the GlyT-1 as a potential therapeutic target of schizophrenia.

Background: There is emerging evidence that antidepressants may be effective in preventing patients with nonspecific and psychotic-like prodromal symptoms, defined as patients at ultra-high risk (UHR) of psychotic disorder, from transitioning to psychosis. However, the mechanism of such an effect is still unknown. Methods: We report the case of a 19-year-old Japanese man determined to be at UHR of psychotic disorder in whom fluvoxamine (one of the antidepressants with sigma-1 receptor agonism) showed preventive effects on psychotic-like prodromal symptoms. Results: Our patient's depressive symptoms were reduced and maintained below remission as a result of treatment with 100 mg/day of fluvoxamine. In addition, it is likely that an additional dose of fluvoxamine (50 mg/day) improved his psychotic-like prodromal symptoms directly, independent of its antidepressive effects. Conclusion: Fluvoxamine, a sigma-1 receptor agonist, may be effective in preventing patients at UHR of psychotic disorder from onset of psychosis via its neuroprotective/neurotropic actions, independent of its antidepressive effects.

Background: Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of major depressive disorder (MDD). Several meta-analyses have shown decreased serum levels of BDNF in adult patients with MDD, but there has been no report on the serum levels of BDNF in pediatric patients with depression. In this study, we investigated whether serum levels of BDNF are altered in pediatric patients with depression. Methods: We measured serum BDNF levels in the following four groups: male pediatric patients with depression (n = 13), female pediatric patients with depression (n = 17), and age-matched normal control subjects (n = 10 for Male, n=12 for Female). Patients were evaluated using the Children's Depression Rating Scale Revised (CDRS-R). Serum levels of BDNF were measured with the sandwich ELISA method. Results: Serum levels (6.97 ± 3.69 ng/mL [mean ± SD]) of BDNF in male pediatric patients with depression were significantly (p=0.019) lower than those (10.67 ± 3.11 ng/mL) in the male control group. However, there was no difference between the female pediatric patients with depression (9.29 ± 4.61 ng/mL) and the female control group (10.21 ± 4.79 ng/mL). Furthermore, there was no correlation between serum levels of BDNF and CDRS-R scores in the pediatric patients with depression. Interestingly, there was a significant negative correlation (r = -0.683, p=0.010) between the serum BDNF levels and the duration of illness in male, but not female, pediatric patients with depression. Conclusions: This study suggests that low BDNF levels may play a role in the pathophysiology of male pediatric patients with depression. © Sasaki et al.

P&gt;Deficits in prepulse inhibition (PPI) are known in mental illnesses, including schizophrenia. NMDA receptor function affects PPI integrity and d-serine and glycine are endogenous co-agonists for the receptor. Our previous quantitative trait loci analysis using C57BL/6 (B6) mice with better PPI performance and C3H/He (C3) with lower PPI score, shows that genes for both d-serine synthesizing enzyme and enzyme for reversible conversion between glycine and l-serine (Srr and Shmt1, respectively) are located in the same PPI-quantitative trait loci peak. Therefore, we set out to determine which gene is likely to explain the PPI difference and whether the gene is potentially relevant to schizophrenia. We first examined brain interstitial fluid levels of the two amino acids using microdialysis. Recovery of d-serine and glycine from the dialysate was higher in B6, compared to C3. Next, we analyzed expression levels and genetic polymorphisms of the two genes. There were promoter polymorphisms in Shmt1, which elicit lower transcriptional activity in B6 compared to C3 conforming to the results of brain expression levels, but no functional genetic variants in Srr. Finally, we evaluated expression levels of the two genes in the postmortem brains of schizophrenia and genetic associations with the disease. The SHMT1 levels were higher in schizophrenic brains compared to controls, but no changes in SRR levels. We detected a nominal association between SHMT1 and schizophrenia. These results suggest that Shmt1 (SHMT1), but not Srr, is likely to be one of the genetic components regulating PPI in mice and possibly relevant to schizophrenia.

Objective: Accumulating evidence suggests that α1 are involved in the mechanisms of action of some antipsychotic drugs. The purpose of this study is to examine the effects of quetiapine, an atypical antipsychotic drug with antagonist activity at α1-adrenoceptors, on prepulse inhibition (PPI) deficits in mice after a single administration of the NMDA receptor antagonist dizocilpine. Methods: Effects of quetiapine on dizocilpine-induced PPI deficits in mice were examined. Furthermore, we examined the role of α1-adrenoceptors in the mechanisms of action of quetiapine. Results: Pretreatment with quetiapine (3, 10, or 30 mg/kg, p.o.) significantly attenuated dizocilpine (0.1 mg/kg, s.c.Hnduced PPI deficits in mice in a dose-dependent manner. Furthermore, dizocilpine-induced PPI deficits were also significantly ameliorated by pretreatment with the selective α1-adrenoceptor antagonist prazosin (1.0 mg/kg, p.o.). Conclusion: These findings suggest that quetiapine ameliorates dizocilpine-induced PPI deficits in mice viaal-adrenoceptor antagonism, and hence, α1-adrenoceptor antagonism may play a prominent role in quetiapine's psychopharmacological effects. Copyright©2010, Korean College of Neuropsychopharmacoiogy.

Background: Minocycline, a second-generation tetracycline antibiotic, has potential activity for the treatment of several neurodegenerative and psychiatric disorders. However, its mechanisms of action remain to be determined. Methodology/Principal Findings: We found that minocycline, but not tetracycline, significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration dependent manner. Furthermore, we found that the endoplasmic reticulum protein inositol 1,4,5-triphosphate (IP3) receptors and several common signaling molecules (PLC-gamma, PI3K, Akt, p38 MAPK, c-Jun N-terminal kinase (JNK), mammalian target of rapamycin (mTOR), and Ras/Raf/ERK/MAPK pathways) might be involved in the active mechanism of minocycline. Moreover, we found that a marked increase of the eukaryotic translation initiation factor eIF4AI protein by minocycline, but not tetracycline, might be involved in the active mechanism for NGF-induced neurite outgrowth. Conclusions/Significance: These findings suggest that eIF4AI might play a role in the novel mechanism of minocycline. Therefore, agents that can increase eIF4AI protein would be novel therapeutic drugs for certain neurodegenerative and psychiatric diseases.

Deficits in prepulse inhibition (PPI) are thought to be a biological trait of mental illnesses, including schizophrenia. It is known that the N-methyl-D-aspartate type glutamate (NMDA) receptor function affects PPI integrity and D-serine and glycine are typical endogenous co-agonists for the receptor. In parallel, we re-visited our prior quantitative trait loci (QTL) analysis study that examined C57BL/6 (B6) mice with high PPI and C3H/He (C3) with low PPI, and noticed that the genes encoding enzymes responsible for the productions of D-serine (serine racemase: Srr) and glycine (serine hydroxymethyltransferase 1: Shmt1) map to the chromosome 11 QTL. Therefore, we set out to examine whether brain interstitial fluid (ISF) levels of the two amino acids are different between the two mouse strains, using in vivo microdialysis. Recovery of D-serine and glycine from the dialysate of the frontal cortex was higher in B6 mice, which performed better in PPI, compared to C3 mice. Next, we analyzed the two genes, Srr and Shmt1. We then identified promoter polymorphisms in Shmt1 which elicit lower transcriptional activity in B6 compared to C3 mice. Human studies revealed higher expression levels of SHMT1 in the frontal cortex of postmortem brains from schizophrenics compared to controls, but no changes in SRR levels. In addition, genetic analysis detected a nominal association between SHMT1 and schizophrenia. These results suggest that Shmt1 (SHMT1) is one of the genetic components regulating PPI in mice and is relevant to schizophrenia susceptibility in humans.

Methamphetamine (METH) use is one of the major public health concerns worldwide. Long-term use of METH induces not only dependence but also psychosis which is associated with METH-induced brain damage, including neuroinflammation produced by activated microglia. We report the case of a female patient whose psychotic symptoms in METH use disorder were successfully improved by anti-inflammatory drug minocycline therapy. Although the precise mechanism(s) underlying the efficacy of minocycline in METH use disorder are currently unclear, minocycline appears to be a good candidate for future investigation clinical trials for medication development in METH using populations. © 2010 Elsevier Inc.

Accumulating evidence suggests that the alpha 7 subtype of nicotinic acetylcholine receptors (nAChRs) plays a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer&apos;s disease. Currently, there are no suitable small molecule radioligands for alpha 7 nAChRs in the brain, although [I-125]alpha-bungarotoxin has been widely used as a radioligand for alpha 7 nAChRs. In the present study, we characterized a new radioligand, 4-[H-3] methylphenyl 2,5-diazabicyclo[3.2.2]nonane-2-carboxylate ([H-3)CHIBA-1001), a derivative of the selective alpha 7 nAChR agonist SSR180711, in brain membranes from rat, monkey, and human. Scatchard analysis revealed an apparent equilibrium dissociation constant (Kd) of 193.4 nM in rat brain membranes at 4 degrees C, and the maximal number of binding sites (Bmax) was 346.2 fmol/mg protein. The order of drugs for the inhibition of [H-3]CHIBA-1001 binding to rat brain membranes is SSR180711&gt;A-844606&gt;MG624&gt;epibatidine&gt;DMAB&gt;A-582941, suggesting a similarity of alpha 7 nAChR pharmacological profiles. In contrast, alpha-bungarotoxin, MLA, and nicotine were found to be very weak. The distribution of [H-3]CHIBA-1001 binding to crude membranes from dissected regions of rat, monkey, and human brain was different from that of [I-125]alpha-bungarotoxin binding, suggesting that [H-3]CHIBA-1001 binding sites may not be identical to [I-125]alpha-bungarotoxin binding in the brain. In summary, [H-3]CHIBA-1001 would be a useful radioligand for alpha 7 nAChRs in the brains of rodents, non-human primates, and humans. (C) 2010 Elsevier B.V. All rights reserved.

CONTEXT: Various factors are involved in the pathogenesis of schizophrenia. Accumulation of advanced glycation end products, including pentosidine, results from carbonyl stress, a state featuring an increase in reactive carbonyl compounds (RCOs) and their attendant protein modifications. Vitamin B(6) is known to detoxify RCOs, including advanced glycation end products. Glyoxalase I (GLO1) is one of the enzymes required for the cellular detoxification of RCOs. OBJECTIVES: To examine whether plasma levels of pentosidine and serum vitamin B(6) are altered in patients with schizophrenia and to evaluate the functionality of GLO1 variations linked to concomitant carbonyl stress. DESIGN: An observational biochemical and genetic analysis study. SETTING: Multiple centers in Japan. PARTICIPANTS: One hundred six individuals (45 schizophrenic patients and 61 control subjects) were recruited for biochemical measurements. Deep resequencing of GLO1 derived from peripheral blood or postmortem brain tissue was performed in 1761 patients with schizophrenia and 1921 control subjects. MAIN OUTCOME MEASURES: Pentosidine and vitamin B(6) concentrations were determined by high-performance liquid chromatographic assay. Protein expression and enzymatic activity were quantified in red blood cells and lymphoblastoid cells using Western blot and spectrophotometric techniques. RESULTS: We found that a subpopulation of individuals with schizophrenia exhibit high plasma pentosidine and low serum pyridoxal (vitamin B(6)) levels. We also detected genetic and functional alterations in GLO1. Marked reductions in enzymatic activity were associated with pentosidine accumulation and vitamin B(6) depletion, except in some healthy subjects. Most patients with schizophrenia who carried the genetic defects exhibited high pentosidine and low vitamin B(6) levels in contrast with control subjects with the genetic defects, suggesting the existence of compensatory mechanisms. CONCLUSIONS: Our findings suggest that GLO1 deficits and carbonyl stress are linked to the development of a certain subtype of schizophrenia. Elevated plasma pentosidine and concomitant low vitamin B(6) levels could be the most cogent and easily measurable biomarkers in schizophrenia and should be helpful for classifying heterogeneous types of schizophrenia on the basis of their biological causes.

Accumulating evidence suggests that the endoplasmic reticulum protein sigma-1 receptors function as "receptor chaperons", and that sigma-1 receptors might be involved in the pathophysiology of neuropsychiatric diseases such as schizophrenia, mood disorders, anxiety disorders, and cognitive deficits. Recent findings suggest that sigma-1 receptors play an important role in the neuronal plasticity in the brain. Recently, we reported that sigma-1 receptor agonists could enhance nerve growth factor-induced neurite outgrowth in cell culture, and that sigma-1 receptor agonists could attenuate phencyclidine-induced cognitive deficits in mice. In this article, the author reviews the role of sigma-1 receptors in the neuronal plasticity and clinical implications of sigma-1 receptors in the treatment for neuropsychiatric diseases.

Cognitive impairment is a primary feature of patients with major depressive disorder (MDD) and is characterised by stress-induced neural atrophy. Via alpha-adrenergic, anti-cholinergic and anti-histaminic activities, several antidepressants can cause significant counter-therapeutic cognitive impairment. Evidence is emerging of the involvement of sigma-1 receptor agonism in the mechanism of action of some antidepressants, notably fluvoxamine. Sigma-1 receptors are abundant in areas affected by depression/stress-induced cerebral atrophy and their ligands have a unique pharmacological profile; they may promote neurogenesis and initiate adaptive neural plasticity as a protection/reaction to stress. Fluvoxamine, as a potent sigma-1 receptor agonist, has shown ameliorating effects in animal models of psychosis, depression, stress, anxiety, obsessive-compulsive disorder (OCD) and aggression and has been shown to improve cognitive impairments. In humans, fluvoxamine may repair central nervous system (CNS) atrophy and restore cognitive function. The current review explores the mechanisms through which sigma-1 receptors can modulate cognitive function and examines how antidepressant therapy with fluvoxamine may help improve cognitive outcomes in patients with depression. Copyright (C) 2010 John Wiley & Sons, Ltd.

Objective: To examine the effects of cilostazol, a selective inhibitor of type III phosphodiesterase (PDE), on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP). Methods: Saline (10 ml/kg/day) or PCP (10 mg/kg/day) were administered subcutaneously to mice for 10 days (once daily on days 1-5 and 8-12). Three days (day 15) after the final administration of saline or PCP, vehicle (0.5% carboxymethylcellulose) or cilostazol (0.3, 3, 10 or 30 mg/kg/day) were administered orally for 14 consecutive days (once daily on days 15-28). The novel object recognition test (NORT) was performed 24 hours (day 29) after the final administration. Results: In the NORT, PCP-induced cognitive deficits in mice were improved significantly by subsequent sub-chronic (14 days) administration of cilostazol (3, 10 or 30 mg/kg/day), but not by the lowest dose of cilostazol (0.3 mg/kg/day). Conclusion: This study suggests that cilostazol ameliorates PCP-induced cognitive deficits in mice. Therefore, it is likely that cilostazol has therapeutic potential for cognitive deficits in schizophrenia. Copyright©2010, Korean College of Neuropsychopharmacology.