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Synapsins are a family of neuron-specific, synaptic vesicle-associated phosphoproteins that have been implicated in the modulation of neurotransmitter release. Synapsins are coded by three distinct genes for synapsin I. II, and III. The synapsin III gene is located on human chromosome 22q12-q13, where a possible schizophrenia susceptibility locus is located. Using the single strand conformation polymorphism method, we searched for variants in 13 exons and the 5'-flanking region of the synapsin III gene in schizophrenia. Three polymorphisms, -631C/G, -271T/C, and E525Q, and one rare variant, -669C >A, were identified. Case-control comparisons of these polymorphisms revealed no significant differences in the allelic and genotypic distributions between schizophrenic and control subjects. The present study did not provide evidence for an association between the synapsin III gene and schizophrenia.

Using positron emission tomography (PET) and [11C]N-methylspiperone (NMSP), we examined 5-HT2 receptors in the cortex of schizophrenic patients in whom we previously observed decreased prefrontal D1 receptor binding. The subjects were 10 neuroleptic-naive schizophrenic patients, 7 schizophrenic patients who were drug-free but had previously been treated with neuroleptics, and 12 normal controls. A non-significant trend towards decreased prefrontal [11C]NMSP binding was observed in the neuroleptic-treated patients, suggesting a possible effect of previous neuroleptic treatment on the alteration in cortical 5-HT2 function. However, the neuroleptic-naive patients showed no noticeable difference in cortical [11C]NMSP binding compared to controls. Our results do not rule out the role of 5-HT2 function as a crucial site of therapeutic activity of schizophrenia, but they do suggest that cortical 5-HT2 receptors might not be primarily involved in the pathophysiology of schizophrenia.

Although amantadine is relatively free of side effects compared with levodopa, the incidence and severity of unwanted effects, such as hallucinations, insomnia and dizziness, markedly increase when the daily dose exceeds 200 mg. A 63-year-old schizophrenic female developed the Pisa syndrome following neuroleptic medication. She was started on a regimen of amantadine, 200 mg per day, on September 4, and the electroencephalogram (EEG) on September 11 was within normal limits. The dosage was increased to 300 mg on September 18 because there was no improvement and no side effects. Two days later a generalised convulsion occurred and an EEG revealed frequent multiple spikes or sharp waves with slow waves. No epileptic seizure has been observed since the amantadine was discontinued. The EEG on September 27 was again within normal limits. To our knowledge, the EEG of a patient with convulsion induced by amantadine has not been described previously. The epileptic mechanisms of amantadine have not been elucidated; however, it may be related to a modulating role of dopamine in the central nervous system.

The benzodiazepine receptor (peripheral) (BZRP) mainly localized on glial cells plays a role in neurosteroid synthesis, and increases with glial proliferation. We have recently reported a significant decrease in the density of BZRP labeled by [3H] PK 11195 in the postmortem brain of chronic schizophrenics, suggesting that dysfunctions of the BZRP are involved in the pathophysiology of schizophrenia. We screened 11 patients with schizophrenia and 10 controls, which were used in a previous postmortem study, for their genomic sequences of the BZRP gene in order to find DNA sequence variations. One novel missense polymorphism (His162Arg) and another previously reported missense mutation (Ala147Thr) were detected. An association study of the identified variations was then performed in an extended Japanese sample of 304 schizophrenic patients and 369 controls. While there was an increased tendency in the frequency of the 162Arg allele of schizophrenics compared to that of the controls (p = 0.0603), no statistically significant association with schizophrenia was observed in the Ala147Thr allele (p = 0.1016). These results do not suggest that the two missense polymorphisms play a major role in the genetic predisposition of schizophrenia in the Japanese sample.

To examine the neurophysiological and cognitive characteristics of language disorder in schizophrenia, the N400 component and late positive component (LPC) of event-related potentials (ERPs) were investigated in medicated schizophrenic patients and health comparison subjects. The subjects were required to indicate whether Japanese sentence completions were semantically congruous or incongruous. The ERPs for the range of 300-500 ms to the incongruous completions contained a more negative component (N400), followed by LPC, which was inversely more positive for the incongruous than congruous condition. The N400 effect and the mean amplitude of the LPC were reduced in the patients. The attenuated N400 effect in schizophrenics mainly originated from an enhanced negativity for the congruous completions, suggesting that the use of context is poor in schizophrenia.

Catechol-O-methyltransferase (COMT) is a key modulator of dopaminergic and noradrenergic neurotransmission. There is a functional polymorphism of the COMT gene, Val108Met in the soluble form of the enzyme (Val158Met in the membrane-bound form). Involvement of the dopaminergic systems in alcoholism has been suggested in mice and humans. We examined associations between this polymorphism and alcoholism in 175 Japanese alcoholics and 354 age- and gender-matched Japanese controls. No significant difference in the allelic distributions in alcoholics and controls and no significant associations between antisocial behaviors in alcoholics and this polymorphism were observed. Therefore, the COMT gene is not likely to play a significant role in alcoholism.

Background: Involvement of the serotoninergic system (S/S) in alcoholism has been suggested in both mice and humans. Previous studies have suggested the S/S genotype of the serotonin transporter gene promoter polymorphism to be associated with severe alcohol dependence marked by severe withdrawal symptoms. It has also been associated with alcoholics who exhibit a dissocial personality disorder., Methods: We examined the polymorphism in 166 Japanese alcoholics who experienced withdrawal seizure or delirium and 290 Japanese controls., Results: The S/S genotype was not increased in the patients. Exploratory analyses showed significantly less frequent S allele and S/S genotype frequencies in the alcoholics with a history of drinking-related arrests than in the controls (p = 0.009 and p = 0.03, respectively), perhaps reflecting previously reported harm avoidance personality traits associated with S/S. Alcoholics with the L allele had a significantly earlier onset of alcohol dependence than those with the S/S genotype (p = 0.01)., Conclusions: The present study failed to provide supportive evidence for an association of the S/S genotype with severe alcoholism marked by physical withdrawal symptoms or with antisocial behaviors among the Japanese. Although our data support involvement of the central serotoninergic system in some types of alcoholism, the potential association findings of this study emerged as only exploratory and, therefore, should be understood as tentative until replicated in other studies.

The human dopamine D4 receptor gene (DRD4) is an important candidate gene for schizophrenia. We identified a novel -521C>T polymorphism in the 5'-promoter region of DRD4. A transient expression method revealed that the T allele of this polymorphism reduces the transcriptional efficiency by 40% compared with the C allele. This polymorphism is of interest because of reported elevation of D4-like sites and DRD4 mRNA in the postmortem schizophrenic brain. The C allele frequency was significantly higher in 252 Japanese schizophrenics (0.48) than in 269 Japanese controls (0.41) (p = 0. 02) [odds ratio = 1.35 (95% confidence interval 1.05 - 1.72)]. Although the association is weak and should be considered tentative until other studies replicate it, this polymorphism provides a tool with the potential to examine whether DRD4 is related to susceptibility to and neuroleptic response in schizophrenia., (Copyright 1999 Academic Press.)

The activity of dopamine-containing neurons in the ventral tegmental area and nucleus accumbens may play a role in alcoholism. Cholecystokinin (CCK) co-exists in a large proportion of A10 dopamine neurons to exert some effect on dopamine-induced behavior. Recently, a C-45T polymorphism was discovered in the Sp1 binding site in the CCK gene promoter region. We investigated an association between the polymorphism and alcoholism in 209 Japanese DSM-III-R alcoholics and 113 Japanese control subjects. The patients and the control subjects had similar allele and genotype frequencies: the T allele frequencies were 0.27 in the patients and 0.28 in the control subjects and the CC, CT, and the TT genotype frequencies 0.53, 0.39, and 0.08 in the alcoholics and 0.53, 0.37, and 0.10 in the control subjects. Frequencies of clinical characteristics of Feighner's criteria for the lifetime diagnosis of alcoholism were not significantly different among the patient groups divided by the genotype. These findings indicate that the polymorphism has no major effect on the etiology of alcoholism.

A deficiency in the serotonergic system has been suggested as a negative reinforcer in alcoholism. Tryptophan hydroxylase (TPH) is critical in the fine-tuning of serotonergic neurotransmission. We observed a significantly high frequency of the A allele of the IVS7+218A>C polymorphism in intron 7 of the TPH gene in Japanese alcoholics with histories of drinking-related antisocial behaviors compared with that of Japanese controls (p = 0.006). However, this polymorphism is intronic, and a study of TPH mRNA did not detect aberrant splice products or polymorphic nucleotides linked to this polymorphism. Therefore, we screened for variations in the promoter and 5'-untranslated region of the gene. Three novel variants/polymorphisms, -1066G>A in the 5' flanking region, IVS1B+23(GTTTT)4-5 in intron 1B, and IVS1C+50T>C in intron 1C, were identified. The -1066G>A and IVS1C+50T>C polymorphisms were in modest linkage disequilibrium with the IVS7+218A>C polymorphism. However, no significant association was found between the three novel polymorphisms and alcoholism. Although our findings reiterate that TPH may play some role in the genetic predisposition to alcoholism, the mechanism remains unknown.

Based on the biochemical analysis of postmortem brains from chronic schizophrenic patients, we found abnormalities of glutamatergic neurons as well as dopaminergic neurons. Glutamate receptors, such as the kainate receptor labeled by 3H-kainate, the N-methyl-D-aspartate (NMDA) receptor by 3H MK801, and the strychnine-insensitive glycine sites in the NMDA receptor by 3H-glycine, increased significantly in various cortical areas of schizophrenic brains. According to the animal experiments and a significant negative correlation between kainate binding values and glutamate concentrations, it is suggested that glutamate receptors increased due to hypoglutamatergic function in the brain of chronic schizophrenia. Hyperdopamine hippothesis of schizophrenia is supported by the correlation between affinity to dopamine receptor and clinical potency of antipsychotic drugs. Measurement of tyrosine hydroxylase activity and dopamine D2 receptor in the schizophrenic brain provided evidence of hyperdopaminergia. Association study of a missense variant in the dopamine D2 receptor gene (Cys311) revealed that the allele frequency of the variant was significantly higher in the schizophrenic patients than the controls. The patients carrying this variant had less severe negative symptoms and better response to antipsychotic drug treatment. Dopamine-induced sequestration of dopamine D2S receptor with Cys variant expressed in CHO cells was shown to a lesser extent than wild-type receptor. This experimental result may be consistent with better responsiveness of the patients with Cys311 to antipsychotic drugs.

The main World Health Organization (WHO) activities of the Tokyo Center are as follows: (1) It performed the research project entitled 'A Bio-Psycho-Social Study on Children with Emotional and Behavioral Problems' in cooperation with the Beijing and Seoul Centers from 1985 to 1987. These results suggested that the deviant behavior of children in the general population had no biological background, but presumably stemmed from psychosocial disadvantages. (2) It has participated in a field trial for the proposed draft for chapter V of the ICD-10 as the Field Trial Coordinating Center in Japan since 1986 and the first Japanese edition of the ICD-10 Classification of Mental and Behavioral Disorders: Clinical Descriptions and Diagnostic Guidelines were published in 1993. (3) It proposed the collaborative project exploratory eye movements in patients with schizophrenia in 1989 and has promoted the project with the cooperation of six centers that included Beijing, Casablanca, Montreal, Munich, Prague and Sapporo. The findings of the present project indicated that exploratory eye movements may be specific to schizophrenia and can be practically used to discriminate schizophrenia without significantly depending on language.

Several antipsychotic agents such as haloperidol and rimcazole are known to bind to sigma receptors with high affinity, and evidence for a potential link between sigma receptors and the etiology of schizophrenia has been reported. The present study was conducted to systematically search for nucleotide variants of the type 1 sigma receptor gene in 48 schizophrenics. Two polymorphisms were found: GC-241-240TT in the 5' flanking region and Gln2Pro. These two polymorphisms were in nearly complete linkage disequilibrium with each other. The Pro2 variant of the Gln2Pro polymorphism changes the endoplasmic reticulum retention signal motif. These polymorphisms were examined in an extended sample of schizophrenics (n = 308) and controls (n = 433) and a significant association between the presence of the TT/Pro2 haplotype and schizophrenia was observed (odds ratio = 1.27, P = 0.04).

We measured adenosine 2a receptors in basal ganglia of 13 schizophrenics and 10 controls, using [3H] CGS21680 as a ligand for the receptor binding assay. There was a significant increase in the specific [3H] CGS21680 binding in the putamen and caudate, but not in the globus pallidus of externa, of the schizophrenic patients, compared to those of controls. These results provide evidence suggesting that adenosine 2a receptors play a role in the pathophysiology of schizophrenia., (Copyright 1998 Elsevier Science B. V.)

Tyrosine hydroxylase is the rate-limiting step in the biosynthesis of catecholamines. To find variants in the tyrosine hydroxylase (TH) gene that are associated with schizophrenia, mood disorders, or alcohol dependence, all of the exons, the exon-intron boundaries, and the 5' promoter region of the TH gene were systematically screened for variants by single-strand conformation polymorphism analysis followed by direct nucleotide sequencing. Source DNAs for sequencing were from 88 Japanese patients comprised of 17 schizophrenics, 21 with mood disorders, and 50 alcoholics. Two novel variants, T-229A and Val468Met, were identified. Case-control comparisons demonstrated that distribution of these two variants were similar in the controls and the three psychiatric groups. Distributions of the previously reported Val81Met polymorphism alleles and the intron 1 TCAT repeat polymorphism alleles were similar in the four subject groups. Our study indicates that the TH gene is not likely to play a major role in the genetic predisposition to schizophrenia, mood disorders, or alcohol dependence.

In our previous studies patients with schizophrenia and their parents had less frequent eye fixations and a more limited area of inspection than normal controls while freely viewing stationary S-shaped figures. The present study attempted to discriminate schizophrenics from non-schizophrenics using exploratory eye movements. Two groups (A and B) were formed, each comprising 30 schizophrenic and 70 non-schizophrenic subjects (10 each of patients with depression, methamphetamine psychosis, alcohol psychosis, anxiety disorder, temporal lobe epilepsy, frontal lobe lesions and healthy normal controls). Discriminant analysis was performed on group A to obtain a discriminant. The validity of applying this discriminant to group B was investigated. By focussing on exploratory eye movements, schizophrenics could be discriminated from non-schizophrenics with a sensitivity of 76.7% and a specificity of 81.4%. These results show that exploratory eye movements are a useful discriminator for schizophrenia.

The authors attempted a replication of earlier studies that detected an association of HLA-DR4 and DR1 with schizophrenia. Japanese patients with schizophrenia (n = 266, DSM-III-R criteria) and Japanese controls (n = 283) were genotyped for DR1 and DR4 alleles using a combination of group-specific polymerase chain reaction (PCR) amplification and PCR-restriction fragment length polymorphism. Significant positive association with HLA-DR1 [odds ratio (OR) = 1.87, corrected p = 0.04] and a negative association with HLA-DR4 (OR = 0.63, corrected p = 0.02) was noted. DR1 and DR4 were independently associated with schizophrenia. The association of the DR1-positive/DR4-negative genotype with schizophrenia was modest (OR = 2.60, 95% confidence intervals = 1.38-4.89, corrected p = 0.008). Thus, these findings support an association of the HLA DRB1 gene locus with schizophrenia in the Japanese population. Since both DR4 and DR1 are positively associated with rheumatoid arthritis, our findings are not simply consistent with the known negative association between schizophrenia and rheumatoid arthritis.

Dopamine D2 receptors have been implicated in the biology of alcohol preference. We examined the -141 C Ins/Del polymorphism in the promoter region of the dopamine D2 receptor gene (DRD2) and the DRD2 TaqI A polymorphisms in 209 Japanese alcoholics and 152 age- and sex-matched Japanese controls. The Ins allele was significantly increased in the alcoholics, compared with the controls (p < 0.002, odds ratio = 1.82). The TaqI A1 allele tended to be more frequent in the alcoholics than in the controls (p < 0.04). Linkage disequilibrium between these two polymorphisms was weak (a maximum delta value = 0.13). The -141 C Ins/Del polymorphism may affect the vulnerability for alcoholism presumably through different expression of DRD2 in the Japanese.

We investigated the relationship between hemodynamic changes in the cortex measured by near-infrared spectroscopy (NIRS) and the polysomnographic changes during sleep. Four healthy male volunteers participated in the study. Near-infrared spectroscopy measuring and polysomnographic recordings were done simultaneously during sleep. In many case, oxy-hemoglobin (oxy-Hb) decreased and deoxy-hemoglobin (deoxy-Hb) increased during the transition from wakefulness to sleep, and oxy-Hb increased toward deep sleep. Oxy-Hb and deoxy-Hb had larger fluctuations during REM sleep than those during non-REM sleep. During REM sleep, oxy-Hb often showed a lower level and deoxy-Hb showed a higher level than those during the preceding and following non-REM sleep.

Background: The association between smoking and depression has been widely investigated. Smoking cessation is known to induce depression to a variable extent, and patients with a history of depression are more likely to experience depressive symptoms. To investigate the hypothesis that nicotine may have an antidepressantlike effect, we used learned helpless rats as an animal model of depression., Methods: Learned helplessness was produced according to our previous method. Learned helpless rats were implanted with nicotine and escape test was performed at 7 and 14 days after the implantation., Results: The number of escape failure in the rats receiving 1.5 mg/kg/day of nicotine was significantly reduced (p < .05) compared to control at day 14. Furthermore, this effect was blocked when the nicotinic receptor antagonist mecamylamine was coadministered., Conclusions: These results suggest that chronic nicotine may act as an antidepressant, probably via nicotinic receptors.

The brain-rich 14-3-3 protein regulates synthesis and excretion of bioamine by activating tyrosine and tryptophan hydroxylases, and by exocytosis of catecholamines and serotonin. In humans, at least eight subunits of the 14-3-3 protein family have been isolated. The 14-3-3 eta chain gene is located at 22q12.1 to q13.1, one of the chromosome regions identified as possibly linked to schizophrenia. We systematically searched for nucleotide variants in the coding region, 5' and 3' untranslated region, and in the exon-intron boundaries of the genomic 14-3-3 eta gene in 24 schizophrenics and 24 controls. Two polymorphic sites were found: one in the 5' untranslated region and one in the 3' untranslated region. However, no variants predicting amino-acid alterations were observed. Similar allelic and genotypic distributions for both polymorphisms were found in 308 schizophrenics and 135 controls.

Serotonergic systems were investigated in the frontal cortex of rats with thioacetamide (TAA)-induced acute hepatic encephalopathy (HE). Extracellular basal levels of 5-HT showed no difference between control and HE animals, whereas the levels of 5-HIAA were significantly increased in HE rats. Unlike basal levels, high K+-evoked 5-HT release was significantly higher in HE rats than controls. Bmax of (+/-)-1-(2,5-dimethoxy-4-[125I] iodophenyl)-2-aminopropane ([125I] DOI) binding, mainly labeling postsynaptic 5-HT2A receptors, was significantly decreased without any change in Kd in HE rats. These results suggest that there is no change in basal 5-HT release in the cortex of rats with TAA-induced HE despite the increase in intraneuronal 5-HT metabolism and in the size of releasable 5-HT pool, and that serotonergic neurotransmission via 5-HT2A receptor is altered in the brain area of rats with HE.

A polymorphism in the 5' region of the serotonin transporter gene modulates its transcription efficiency. Its short allele has been reported to be associated with neurotic traits. The serotonin transporter is the action site of selective serotonin re-uptake inhibitors, widely used in the treatment of panic disorder. We examined an association between the polymorphism and panic disorder in a case-control study consisting of 66 Japanese patients and 150 controls. The short allele was significantly more frequent in the Japanese than in Caucasians. The patients and the controls had similar allele frequencies, indicating no association between the polymorphism and panic disorder in most Japanese patients.

Patients with methylenetetrahydrofolate reductase (MTHFR) deficiency often show psychiatric manifestations. Since a common variant of the MTHFR gene, T677(Ala), responsible for the thermolabile MTHFR with less than 50% specific MTHFR activity, has been reported, we examined whether the T677 allele is associated with psychiatric disorders in an unrelated Japanese population consisting of 297 schizophrenics, 32 patients with major depression, 40 patients with bipolar disorder, and 419 controls. The genotype homozygous for the T677 allele was significantly frequently observed in schizophrenics with an odds ratio of 1.9 (P = 0.0006), and in patients with major depression with an odds ratio of 2.8 (P = 0.005). Our data suggest associations of the MTHFR gene variant with schizophrenia and depression in the Japanese.

An excess dopaminergic activity may be implicated in the etiology of schizophrenia. Our objective was to identify nucleotide variants in the 5' region of the dopamine D2 receptor gene (DRD2) and to clarify their effects on schizophrenia. We identified two polymorphisms, the A-241G and -141C Ins/Del, by examination of 259 bp in the 5'-flanking region and 249 bp of exon 1 of DRD2. Reporter constructs containing the -141C Del allele cloned into a luciferase reporter plasmid drove 21% (Y-79 cells) and 43% (293 cells) expression compared with the -141C Ins allele. In a case-control study, the -141C Del allele frequency was significantly lower in 260 schizophrenic patients than in 312 controls (OR = 0.60, 95%CI 0.44-0.81, P < 0.001). No significant association was found between the A-241G polymorphism and in vitro luciferase activity, or in allele frequency between the patients versus controls. These findings show that the -141C Ins/Del may be a functional polymorphism in the 5'-promoter region of DRD2 and may affect the susceptibility to schizophrenia.

Schizophrenia is believed to involve altered activation of dopamine receptors, and support for this hypothesis comes from the antipsychotic effect of antagonists of the dopamine D2 receptor (D2R). D2R is expressed most highly in the striatum, but most of the recent positron emission tomography (PET) studies have failed to show any change in D2R densities in the striatum of schizophrenics, raising the possibility that other receptors may also be involved. In particular, the dopamine D1 receptor (D1R), which is highly expressed in the prefrontal cortex, has been implicated in the control of working memory, and working memory dysfunction is a prominent feature of schizophrenia. We have therefore used PET to examine the distribution of D1R and D2R in brains of drug-naive or drug-free schizophrenic patients. Although no differences were observed in the striatum relative to control subjects, binding of radioligand to D1R was reduced in the prefrontal cortex of schizophrenics. This reduction was related to the severity of the negative symptoms (for instance, emotional withdrawal) and to poor performance in the Wisconsin Card Sorting Test. We propose that dysfunction of D1R signalling in the prefrontal cortex may contribute to the negative symptoms and cognitive deficits seen in schizophrenia.

We measured the peripheral-type benzodiazepine receptors (PBRs), a marker of gliosis, in 26 brain areas (cerebral cortex, thalamus and extrapyramidal system) of the postmortem brains of 13 chronic schizophrenics and 10 controls, using [3H] PK 11195 as a ligand for the receptor assay. The specific [3H] PK 11195 binding was significantly decreased in three brain areas (superior parietal cortex, primary visual area and putamen) of schizophrenics, although there were no changes in the binding in the other brain areas. Scatchard analysis revealed that there were decreases in both the Bmax and Kd of [3H] PK 11195 binding in the brain areas. These results were almost in accordance with a number of neuropathological studies reporting that there was no change or reduction in glial cells in the brain regions of schizophrenics and suggested that the decreased density of PBRs in the brain may be involved in the pathophysiology of schizophrenia, associated with reduced production of neurosteroids coupled to PBRs.

Because of a potent action of angiotensin converting enzyme (ACE) to degrade substance P (SP) and an association of the insertion/deletion (I/D) polymorphism of the ACE gene with ACE activity, an association between the SP level and the ACE I/D polymorphism were examined using 20 human postmortem brain samples. The results showed a significant association between the polymorphism and SP levels in the basal ganglia and substantia nigra, where both ACE and SP concentrate, and a higher SP level in the subjects with the DD genotype than in those with the II genotype, with an intermediate level in heterozygotes. Associations of the polymorphism with schizophrenia and affective disorders were also investigated in 292 unrelated Japanese schizophrenics, 65 patients with affective disorders, and 579 controls. The D allele was significantly more frequent in the patients with affective disorders than in the controls (p < .02), and the DD genotype was significantly more frequent in the patients with affective disorders than in the controls (p < .002). There is no significant difference in the frequencies of the allele and the genotype between the controls and schizophrenics. These results suggest that the ACE I/D polymorphism is one of the genetic factors for an interindividual variability of brain SP levels, and that the ACE polymorphism may contribute to the susceptibility to affective disorders.

We examined the postnatal development of peripheral-type benzodiazepine receptors (PBRs), labelled with [3H]PK 11195, in rat brain and peripheral tissues. Specific [3H]PK 11195 binding exhibited a heterogeneous patterns of postnatal development in the rat: three patterns of increase, decrease and no change. Hence, the density of the PBRs can be independently regulated in each tissue during postnatal development, and the postnatal alterations in the density might be parallel with the functional activities coupled to the receptors.

Electroencephalography of 12 schizophrenic patients was recorded in a neuroleptic-naive state and after 6.2 +/- 1.1 months of treatment, when they were on medication and in partial remission. Compared with age- and sex-matched controls, the neuroleptic-naive schizophrenics had less alpha 2 power. In the medicated state, alpha 2 power and slow-wave power were reduced as compared with the neuroleptic-naive state. The reduction in alpha 2 power may occur from the early stage of the disease and progress even though the patients are medicated and clinically improved.

We have measured the concentrations of glycine and its potential precursors, serine and threonine, in 20 areas of the postmortem brains of chronic schizophrenics and controls using high-performance liquid chromatography by pre-column derivatization with dimethyl-amino-azobenzene sulphonyl chloride. The regional distribution pattern of glycine in the postmortem brains with and without the disease was more similar to that of serine (r = 0.874, P < 0.0001) than to that of threonine (r = 0.476, P < 0.01). A multiple regression analysis with regressor variables including diagnosis, age at death and interval between death and freezing revealed that there is a significant difference between schizophrenics and controls in the contents of these amino acids in a number of brain areas. The level of glycine in the orbitofrontal cortex of schizophrenics was found to be significantly increased in schizophrenics, with a tendency to an increase in that of serine. The increase in glycine was also significantly high in the off-drug group of schizophrenics who had not taken antipsychotics more than 40 days before death. Prominent decreases in both glycine and serine were observed in the somesthetic cortex of the on-drug schizophrenics. Serine was found to be significantly decreased in the putamen of the off-drug schizophrenics. A marked decrease in threonine was also observed in the supramarginal cortex and posterior portion of the lateral occipitotemporal cortex of the off-drug group of schizophrenics and in the putamen of all schizophrenics. The highly similar distribution pattern of glycine and serine in the postmortem brains supports the close coupling of synthesis and metabolism between these chemicals in human brains. The increased content of glycine in the orbitofrontal cortex, the reduced level of serine in the putamen and the decrease in threonine in the cerebral cortices, which were prominent in the off-drug schizophrenics, may be involved in the pathophysiology of schizophrenia.

We measured [125I] iomazenil binding, labeling the central-type benzodiazepine receptor in 37 discrete rat brain areas following single (7.5 mg/kg, i.p.) and repeated (7.5 mg/kg/day x 14 days, i.p.) treatment with phencyclidine (PCP), a non-competitive antagonist of the N-methyl-D-aspartate(NMDA)-type glutamate receptor, using in vitro quantitative autoradiographic receptor binding assay. Both single and repeated PCP treatment produced heterogeneous changes in the rat brain in a similar manner, the magnitude of change in [125I] iomazenil binding being generally greater in the repeated treatment group than in the single treatment group. A significant increase in [125I] iomazenil binding was observed in the superficial layer (layer I-IV) of the parietal cortex in both of the PCP treatment groups and the CA1 of the hippocampus of the repeated PCP-treated group. There was a significant decrease in [125I] iomazenil binding in the piriform cortex of the repeated PCP-treated group. These results suggest that the blockade of NMDA receptor-mediated glutamatergic neurotransmission by PCP produces the compensational alterations in the central-type benzodiazepine receptor antagonist binding, and that the observed diversity may be due to dissimilar modes of organizations between glutamatergic and the GABA(gamma-aminobutyric acid)-benzodiazepine receptor complex.

1. The authors administered the tetracyclic antidepressant mianserin to aged patients with delirium to examine its efficacy in delirium. 2. The subjects were 62 consecutive aged patients with delirium, diagnosed according to DSM-IV. 3. The patients' symptoms of delirium were assessed once a week over the 4-week study period using the Delirium Rating Scale. 4. It was found that mianserin was effective, especially in treating behavioral and sleep-wake disturbance and that it was almost free from undesirable side-effects. It appears to be particularly useful for elderly patients with delirium, who easily develop extrapyramidal side-effects when given antipsychotic drugs. These properties of mianserin are worthy of further study.

The dopamine D2 receptor gene is a candidate gene for schizophrenia because the potency of certain neuroleptics correlates with their affinity for this receptor. Case-control studies in 291 schizophrenics, 78 patients with affective disorders, and 579 controls on an association of a molecular variant of S311C of the dopamine D2 receptor with psychiatric disorders were conducted. The frequency of individuals with S311C was significantly higher in schizophrenics with the absence of negative symptoms (17.1%, P < 0.00001), but similar in schizophrenics with the presence of negative symptoms (5.7%, P = 0.46) when compared with the controls (4.1%). The frequency of S311C was significantly higher in familial schizophrenics from one local area but not in those from other areas. It was significant that S311C was frequently present in patients with mood-incongruent psychotic affective disorders (33.3%, P < 0.0001), but not in those with other affective disorders. These data suggest that S311C might be one of the genetic factors for symptomatic dimensions of delusions and hallucinations and might be involved in underlying clinical heterogeneity in schizophrenia and affective disorders.

The short (D2S) and long (D2L) isoforms of dopamine D2 receptors were stably expressed in Chinese hamster ovary cells, and dopamine-induced sequestration was examined by measuring the loss of binding of the hydrophilic ligand [3H]sulpiride from the cell surface. Dopamine treatment of Chinese hamster ovary cells expressing D2S for 30 min at 37 degrees caused a 43.8 +/- 3.4% decrease in [3H]sulpiride binding activity measured by incubation of the treated cells with [3H]sulpiride at 4 degrees for 4 hr after the dopamine was washed out. The half-life of the decrease in binding was estimated to be 18.7 +/- 1.6 min, and the concentration of dopamine giving a half-maximal effect (EC50) was estimated to be 180 +/- 90 nM. The decrease was reversible, and the binding activity was recovered by washing out the dopamine and incubating the cells at 37 degrees for 30 min but was not reversible when the cells were incubated at 4 degrees. The binding activity of [3H]spiperone, a hydrophobic ligand, was not affected by the dopamine treatment under the same experimental conditions. These results indicate that approximately one half of the D2S receptors undergo agonist-induced sequestration, probably endocytosis, in a reversible and temperature-dependent manner. Sequestration of D2L receptors was not as apparent as that of D2S receptors; the decrease in [3H]sulpiride binding activity was 21.6 +/- 0.9% and the rate of the decrease was delayed, with a half-life of 33.2 +/- 7.8 min, although effective concentrations of dopamine were similar, with EC50 = 170 +/- 50 nM. A D2S receptor variant containing a missense mutation changing Ser311 in the third intracellular loop to cysteine was found to be sequestered to a significantly lesser extent than with wild-type D2S receptors. This finding was discussed with respect to the report that this variant gene is found more frequently in schizophrenic patients than in control subjects.

Single photon emission computed tomography (SPECT) using 123I-Iomanzenil (IMZ), a tracer which binds specifically to central-type benzodiazepine receptors, was performed in patients with cerebrovascular diseases (CVD) to determine the clinical signicigance of IMZ SPECT studies in evaluating the pathophysiology of CVD. IMZ SPECT images obtained three hours after administration of the tracer were compared with the images of cerebral blood flow (CBF) studies in 206 cases. In regions with decreased CBF, the uptake of IMZ was relatively preserved in patients with cerebral thrombosis in comparison with cerebral embolism, and in those with perforator branch infarction in comparison with cortical infarction. The uptake of IMZ decreased as a function of both the severity of the decrease in the CBF and the duration of illness in regions with a significantly decreased perfusion reserve. These results suggest that decreased IMZ binding in ischemic stroke reflects the neuronal damage caused by the cerebral ischemia. On the other hand, in patients with intracerebral hemorrhage, the cortical uptake of IMZ was relatively well-preserved in regions with decreased CBF, and the decrease in the uptake of IMZ was more profound as a function of the decrease in the CBF, especially in cases of putaminal hemorrhage. These results also suggest that the decreased cortical CBF is a remote effect caused by a neuronal disconnection, and neuronal damage may occur in regions with severely impaired CBF.

Iomazenil (IMZ) is a partial inverse agonist of central-type benzodiazepine receptors (BZR) which binds specifically to BZR with high affinity. A multi-center Phase 3 clinical study was performed to evaluate the clinical usefulness of 123I-IMZ-SPECT in the diagnosis of brain disorders in 169 patients with degenerative neurological diseases and 37 patients with mental disorders such as neurotic, stress-related and somatoform disorders. In dementia, the decrease in activity in late images, obtained three hours after administration of 123I-IMZ, correlated negatively with the dementia score. In Parkinson's disease and spinocerebellar degeneration. 123I-IMZ showed a more profound decrease in uptake in late images than seen in the cerebral blood flow (CBF) images, and this decrease was in proportion to the duration and severity of the illness. In mental disorders, the ratio of the late to early image counts showed a negative correlation with Hamilton's anxiety scale in all regions in the brain cortices. In panic disorders, the ratio of the cerebral count to the cerebellar count in the late images correlated negatively with the severity of the attack in the frontal, temporal and parietal cortices. These results suggest that 123I-IMZ-SPECT enables us to evaluate the neuronal damage in degenerative diseases and the decrease in the BZR binding potential in mental disorders.

A Phase 3 clinical trial of 123I-Iomazenil (IMZ), a tracer which binds specifically to central-type benzodiazepine receptors (BZR), was performed, and the clinical usefulness of IMZ was evaluated in 121 patients with epilepsy (106 cases with partial epilepsy and 15 cases with generalized epilepsy). A regional abnormality in the BZR distribution was detected in late IMZ images in 20 of 24 cases without abnormal MRI and/or X-ray CT findings. Moreover, only 16 of these 20 cases showed abnormal findings in the cerebral blood flow (CBF) images. In partial epilepsy, abnormal regions in late IMZ images agreed or partially agreed with epileptic foci estimated from the clinical symptoms of epileptic seizures, interictal EEG, and MRI and/or X-ray CT findings in 76%, 70% and 96% of the cases detected. These regions also agreed or partially agreed with the estimated epileptic foci in 92% of the cases with foci estimated by combination of those three methods and in 72% of those estimated by ictal EEG. The agreement or partial agreement rates of late IMZ images with each of the other methods were higher than those of CBF images, although the differences were not significant. For surgically-proven epileptic foci without any abnormality in the CBF image, abnormal regions were detected in late IMZ images. These findings suggest that IMZ SPECT is a useful new tool for detecting epileptic foci based on the distribution of BZR in the brain.

This study aimed to replicate positive associations between polymorphisms of the neurotrophin-3 gene and schizophrenia. The reported associations, which were the results of searching for mutations in the locus in schizophrenics under the hypothesis of neurodevelopmental etiology of schizophrenia, are that the states carrying the (CA)23 allele of the CA repeat in the first intron have a 2.56-fold increased risk of schizophrenia and those carrying the allele Glu-63 instead of Gly-63 have a 2.6-fold increased risk of schizophrenia with onset before 25 years and with duration of the illness of more than 10 years. We analyzed these polymorphisms in 80 schizophrenics with onset before 25 years of age and with duration of illness of more than 10 years and 80 age-matched psychosis-free controls. With our sample size, there was a 90% chance of detecting odds ratios observed in initial positive reports. We found similar allele and genotype frequencies of both polymorphisms between the schizophrenic and control groups. We failed to support associations between the polymorphisms of the neurotrophin-3 gene analyzed and schizophrenia.

Iomazenil (IMZ) is a partial inverse agonist of central-type benzodiazepine receptors (BZR) which binds specifically to BZR with high affinity. The safety and clinical effectiveness of 123I-IMZ SPECT in the diagnosis of brain diseases were evaluated in 655 patients with various brain diseases, such as epilepsy, cerebrovascular diseases, degenerative diseases and mental disorders relating to BZR. This was a Phase 3 study conducted as a multicenter trial at 52 collaborating institutions. There was no significant adverse reactions in the clinical symptoms or abnormal laboratory test values. The investigators judged 123I-IMZ SPECT to be effective in 95% of 638 analyzed cases. The injected dose did not correlate with the image quality or the clinical effectiveness of 123I-IMZ SPECT, suggesting that these items depend largely on the characteristics of the apparatus used, the disease or pathology of the patients, rather than the dose. We conclude that 123I-IMZ imaging is safe and provides effective information based on BZR binding which is useful in the diagnosis of various brain diseases.

The effects of chronic treatment with haloperidol on [3H]PK 11195 binding and labelling of the peripheral-type benzodiazepine receptor (PBR) in the rat brain and peripheral tissues were investigated using an in vitro receptor binding technique. The intraperitoneal injection with haloperidol (0.3 or 1.0 mg/kg) for 21 days produced a significant increase in the specific [3H]PK 11195 binding only in the olfactory bulb, but not in the other brain areas or peripheral tissues, while single or subchronic (4 days or 7 days) administration with the drug (0.3 mg/kg, i.p.) failed to increase the binding in the olfactory bulb. Scatchard analysis revealed a significant increase in the maximum number of [3H]PK 11195 binding sites in the olfactory bulb after chronic treatment with haloperidol, showing no change in the affinity of the binding. These results suggest that there is an interaction between PBR and the pharmacological actions of haloperidol in the brain area, and that some compensatory mechanism may be involved in the PBR changes.

In the learned helplessness procedure, rats can be differentiated into two distinct groups. Learned helplessness (LH) rats do not learn to escape a controllable shock while non-learned helplessness (NLH) rats learn this response. This deficit in performance in LH rats lasted for 11 days. In LH rats, pretreatment with acute desipramine (15 mg/kg i.p.) or chronic diazepam (0.95 mg/kg/day p.o. for 7 days) did not produce recovery from this deficit of performance, but pretreatment with chronic desipramine (17.7 mg/kg/day p.o. for 7 days) or chronic mianserin (6.1 mg/kg/day p.o. for 7 days) led to recovery. Before presentation of uncontrollable shock, there was no difference between LH and NLH rats, but 11 days after the shock, head shakes induced by (+/-)-1-(2,5-demethoxy-4-iodophenyl)-2-aminopropane (DOI) in LH rats was significantly more frequent than those in NLH and naive rats without change of [3H]ketanserin binding. The basal corticosterone level was higher in LH rats than in NLH rats. These findings suggest that the learned helplessness model is a reliable animal model of depression accompanied by 5-HT2 receptor hypersensitivity.

OPC-14597 is a new antipsychotic drug with a unique pharmacological profile. In a behavioural study in rats OPC-14597 did not show cataleptogenic activity even at the highest dose (40 mg/kg, i.p.), whereas it antagonized apomorphine-induced stereotypy dose-dependently (0.5-40 mg/kg). In vivo microdialysis showed that extracellular dopamine (DA) in the striatum was decreased significantly after OPC-14597 administration at higher doses of 10 and 40 mg/kg. Similar results were obtained in extracellular dopamine concentration in the frontal cortex, although the changes in DOPAC and HVA concentrations were smaller than those in the striatum. OPC-14597 also antagonized DA increase induced by the DA autoreceptor antagonist (+)-AJ76. These results that OPC-14597 acts either as an antagonist at postsynaptic dopamine receptors or as an agonist at presynaptic dopamine autoreceptors.

Acute immobilization stress induced by taping four limbs, applying tail pinch stress and electric foot shock stress immediately reduced the frequency of head shakes induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((+/-)DOI), a 5-HT2A/C agonist in rats. Immobilization stress due to the use of cylinder restraint and forced swimming did not affect 5-HT2A-mediated behavior. Acute immobilization stress did not affect [3H]ketanserin binding to the 5HT2A receptor in the prefrontal cortex and hippocampus. Presynaptic serotonergic lesions with 5,7-dihydroxytryptamine(5,7-DHT) did not affect the reduction in 5-HT2A-mediated behavior after acute immobilization stress. The decreases in head shake frequency after acute immobilization stress by taping were attenuated by pretreatment with diazepam (2.5 mg/kg IP): This attenuation was reversed by pretreatment with flumazenil (10 mg/kg IP). The reduction in (+/-)DOI-induced 5-HT2A-mediated behavior caused by stress may be related to a change in agonist affinity to the receptor or changes in other neurotransmitter systems or the effect of PI turnover.

To investigate the characteristics of extracellular amino acids released from the striatum, we performed in vivo microdialysis in non-anaesthetised, freely moving rats. Amino acids were determined after precolumn derivatisation with o-phthalaldehyde by high-performance liquid chromatography and fluorescence detection. The omission of Ca2+ in the perfusion medium partially decreased the basal concentration of aspartate and glutamate. This shows that a small fraction of basal concentration of aspartate and glutamate is of neuronal origin. The effect of high K+ and veratrine stimulation was evaluated in the presence or absence of Ca2+ or tetrodotoxin (1 microM). High K+ and veratrine caused a remarkable increase in the aspartate and glutamate efflux. The omission of Ca2+ only partially decreased K(+)-stimulated aspartate and glutamate efflux. Tetrodotoxin completely antagonised veratrine-stimulated aspartate and glutamate efflux. Although glycine and taurine releases were stimulated by high K+ and veratrine, their release was not always antagonised with Ca2+ omission or tetrodotoxin inclusion. Thus, the neuronal origin of stimulated release of glycine and taurine is unclear. Although tetrodotoxin sensitivity and Ca2(+)-dependency are regarded as a basic criterion for classical neurotransmitters in microdialysis experiments, they should not be adapted to the physiological characteristics of the release of amino acids.