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The relationships between the individual (and racial) differences in alcohol metabolism and toxicity, and the genetic polymorphism of alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and cytochrome P-4502E1(CYPIIE1) were reviewed. In recent studies involving DNA analysis, it was found that a deficiency of the ALDH2 isozyme (ALDH2*2) was responsible for the flushing symptoms as well as other vasomotor symptoms caused by a higher acetaldehyde level after alcohol consumption. Deficiency of ALDH2 activity has been found prevalently only among people of Mongoloid origin, and the deficiency of ALDH2 prevents them from developing alcohol dependence due to the unpleasant physical effects of the flushing symptom. It was reported that Mongoloids such as Japanese and Chinese people carry the enzymatically active (ALDH2*1) subunit and/or the inactive (ALDH2*2) one, and that a low proportion of ALDH2 deficiency (ALDH2*2 allele frequency) was found in alcoholics compared with healthy controls. It was also reported that polymorphism of ALDH2 and/or CYP2E1 may be associated with the susceptibility to alcohol-induced liver injury. Concerning blood ethanol elimination kinetics, it was reported that the c2 gene of CYP2E1 and the ALDH2*1 gene may have greater effects on ethanol and acetaldehyde elimination than the other genotypes, when the blood ethanol level is below 20 m M. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about a study which investigates the relationship between Borna disease virus infection and the pathogenesis of schizophrenia.

Examines the prevalence of Borna disease virus (BDV) infections among schizophrenic patients in Japan. Relationships of negative syndromes with schizophrenia and BDV; Proportion of patients with anti-BDV antibody; Correlation between BDV infection and dominant contribution by negative syndromes.

(1) We prepared a questionnaire modified from that of Edwards, G. et al, to investigate the factors influencing drinking behaviors. Responses of the questionnaire were filled out by the alcoholics, their families, and health care professionals in four psychiatric hospitals having intensive alcoholic rehabilitation programmes. Clinical course of them were traced back for at least two years. (2) We examined the relationship between the course of alcoholism and the differences in perceptions among alcoholics, their families, and health care professionals. (3) We obtained sufficient responses from 76 alcoholics. Those were divided into two groups; one is a group of alcoholics with a history of continuous abstinence of over one year (50 cases), and the other is the group of less than one year of recent abstinence period (26 cases). (4) As the overall results from the participants, items on "self-help group" were favorably responded for the improvement of drinking behavior. Families tend to perceive more sensitively into the internal psychological changes of the alcoholics than the health care professionals, whereas the health care professionals tend to make general and common responses regardless of any alcoholics. We, health care professionals should be aware of such a limit to promote more efficient collaborative works with alcoholics and their families. (5) We compared these two groups ("over one year group" vs. "less than one year group") with regard to their demographic and family backgrounds, clinical features, treatment, self-help group attendance, employment, etc. (6) A significant accordance of responses among three groups (alcoholics, family, health care professionals) was found in the "over one year group" than in the "less than one year group". Such a high level of accordance is considered to reflect a favorable family adaptation along with the recovery from alcoholism, deep understanding on the part of health care professionals, progress in the treatment and in the relationship in a self-help group. (7) As regards the "less than one year" group, it includes more single individuals and less frequent attendances to self-help groups. For this group of alcoholics, group therapy in a smaller group, individualistically oriented approaches for their needs including various supportive resources in the society should be addressed.

The effects of maternal deprivation (MD) during early postnatal life on the brain-derived neurotrophic factor (BDNF) level were investigated in the present study. Wistar rats were assigned to either maternal deprivation or mother-reared control (MRC) groups. MD manipulation was achieved by separating rat pups from their mothers for 3h a day during postnatal days (PND) 10-15. At 16, 20, 30, and 60 days of age, the level of BDNF mRNA in the hippocampal formation of each group was determined using real-time PCR analysis. Early postnatal maternal deprivation of rat pups resulted in a significant increase in body weight at 60 days of age. The expression of BDNF mRNA in the hippocampus was significantly decreased at 16 days of age, and increased at 30 and 60 days of age. These data indicate that even a brief period of maternal deprivation during early postnatal life can affect hippocampal BDNF expression.

Several pharmacological studies suggest the possible involvement of sigma(1) receptors in the pathogenesis of schizophrenia. An association has been reported between schizophrenia and two variants (GC-241-240TT and Gln2Pro) in the sigma(1) receptor gene (SIGMAR1). We also previously reported that, along with T-485 A, these two variants alter SIGMAR1 function. To investigate the role of SIGMAR1 in conveying susceptibility to schizophrenia, we performed a case-control study. We initially screened for polymorphisms in the SIGMAR1 coding region using PCR-single strand conformation polymorphism analysis. The distribution of SIGMAR1 polymorphisms was analyzed in 100 schizophrenic and 104 control subjects. A novel G620A variant was detected in exon4. G620A was predicted to alter the amino acid represented by codon 211 from arginine to glutamine. Our case-control study showed no significant association between the T-485 A, GC-241-240TT, Gln2Pro, and G620A (Arg211Gln) variants and schizophrenia and clinical characteristics. These findings suggest that these SIGMAR1 variants may not affect susceptibility to schizophrenia.

There is an increased incidence of schizophrenia-like psychosis in temporal lobe epilepsy (TLE), and several risk factors have been implicated, including the duration of epilepsy and temporal lobe neuropathology. To investigate the biological mechanism of epileptic psychosis, we examined alterations of central dopaminergic systems in the kainate model of TLE. In adult rats, kainate was microinjected into the left amygdala to induce status epilepticus. An indirect dopamine agonist methamphetamine (MAP, 2 mg/kg, i.p.) was administered before and 1 month after the kainate treatment. MAP-induced locomotor activity was significantly enhanced in the kainate group compared with the baseline (pre-kainate) level, which was antagonized by pretreatment with haloperidol. The enhancement of locomotor activity in the kainate group was significantly correlated with the density of hippocampal CA1 neurons. Although the basal extracellular dopamine concentration was significantly lower in the striatum in the kainate group than in the control group (5.5 vs 39.2 fmol/20-min sample), the maximal concentration following MAP administration did not differ between the two groups. These results clearly demonstrate that hypersensitivity of the dopamine systems develops in the chronic phase of the kainate-induced TLE model, which may be responsible for the mechanism of epileptic psychosis., (Copyright 2004 Nature Publishing Group)

Kindling of the ventral tegmental area (VTA), a major source of the mesolimbic dopamine pathway, was examined in rats. We applied two quantitative measurements of dopamine sensitivity before and 2 weeks after VTA kindling (20 times electrical stimulations (100 microA at 1 min intervals) delivered once per day for 14 consecutive days): behavioral responses induced by test VTA stimulation and methamphetamine (MAP)-induced locomotor activity. The total amount of MAP-induced locomotor activity was significantly increased after VTA kindling, while the responses to electrical stimulation were unchanged. These results indicate that repeated activation of the mesolimbic dopamine system can produce a neuroplastic change, which results in dopamine supersensitivity.

Background: Sigma1 receptors are involved in the pathogenesis of drug abuse. Two polymorphisms (GC-241-240TT and Gln2Pro) in the sigma1 receptor gene (SIGMAR1) have been identified. To investigate the role of SIGMAR1 in conveying susceptibility to alcoholism, we performed a functional analysis of polymorphisms in the SIGMAR1 and a case-control study., Methods: We initially screened for polymorphisms in the 5'-upstream region. The effects of the polymorphisms on transcriptional activity were determined using a gene reporter assay. The distribution of SIGMAR1 polymorphisms was analyzed in 307 alcoholic and 302 control subjects., Results: A novel T-485A polymorphism was identified. The transcriptional activity of the A-485 allele and the TT-241-240 allele was significantly reduced compared with that of the T-485 allele and the GC-241-240 allele. The frequencies of the A-485 allele (chi2=5.575, df=1, p=.0205) and the TT-241-240/Pro2 haplotype (chi2=21.464, df=1, p<.0001) were significantly higher in control subjects compared with alcoholic subjects. The T-485A and the GC-241-240TT may be functional polymorphisms, and the A-485 allele and TT-241-240/Pro2 haplotype are possible protective factors for the development of alcoholism.

Exposure of the developing brain to X-irradiation in utero is known to cause various deleterious consequences. We have previously reported the effects of prenatal X-irradiation on the development of the cerebral cortex in rats. We have now extended this study to examine the effects of such X-irradiation on the development of the cerebellum. Wistar rats were exposed to 1.5 Gy X-irradiation either on days 14, 15 or 16 of gestation (E14, E15, E16). Sham-irradiated animals were used as controls. At seven postnatal weeks of age, male rats from each group were deeply anesthetized and killed by intracardiac perfusion with 2.5% glutaraldehyde in 0.1 M phosphate buffer. The unbiased stereological procedure known as the fractionator method was used to estimate the total number of Purkinje cells in the cerebellum of each animal. Body and cerebellar weights from E14 and E15, but not E16 irradiated rats showed significant deficits compared to control animals. Rats irradiated on E16 and control rats had about 285100-304800 Purkinje cells in the cerebellum. There was no significant difference between these values. However, E14 and E15 irradiated animals had about 117500 and 196300 Purkinje cells, respectively. These estimates were significantly different from those observed in both control and E16 irradiated rats. Given that the phase of division of Purkinje cell progenitors is mainly between E14-E15 and the phase of differentiation and migration is between E16-E20, it is concluded that the vulnerable period of the Purkinje cells to X-irradiation closely overlaps the phase of division of progenitors.

Unlabelled: Since delusional disorder is characterized by mono-symptomatic paranoid symptoms, it can be a good clinical model for investigating the dopaminergic mechanism responsible for paranoid symptoms. We examined neuroleptic responses, plasma homovanillic acid (pHVA) and genes of the dopamine receptor (DR) and its synthesizing enzyme (tyrosine hydroxylase: TH) in patients with delusional disorder and compared them with those of schizophrenic patients and healthy controls., Results: (1) A relatively small dose of haloperidol was more effective for delusional disorder than for schizophrenia. (2) The pretreatment level of pHVA was higher in patients with persecution-type, but not in those with jealousy-type delusional disorder, compared with age- and sex-matched controls. This increased pHVA level was decreased eight weeks after successful haloperidol treatment. (3) The genotype frequency of the DRD2 gene Ser311Cys was significantly higher in patients with persecution-type delusional disorder (21%), compared with schizophrenic patients (6%) or controls (6%). (4) Patients homozygous for the DRD3 gene Ser9Ser had higher pretreatment levels of pHVA than those heterozygous for Ser9Gly. (v) A significant positive correlation was found between the polymorphic (TCAT)(n) repeat in the first intron of the TH gene and pretreatment levels of pHVA in delusional disorder. We suggest that delusional disorder, especially the persecution-type, includes a "dopamine psychosis," and that polymorphism of the DRD2, DRD3 and/or TH gene is part of the genetic basis underlying the hyperdopaminergic state that produces paranoid symptoms. Further studies on a large sample size are required.

To characterize the biochemical mechanism of cell death induced by ethanol intoxication, we examined expression of mRNAs of bcl-2 and bax genes in the brain, which are related to apoptosis, by using the reverse transcription-polymerase chain reaction method (RT-PCR). According to ethanol administrations, the expression of bcl-2 mRNA in the cerebral cortex decreased after 1 day and be recovered after 3 days. The expression of bcl-2 mRNA in the cerebellum was not changed soon after 1 day and increased after 3 days. The expression of bax mRNA in the cerebral cortex decreased after 1 day and be recovered after 3 days. The expression of bax mRNA in the cerebellum increased after 1 day and after 3 days. We found that bcl-2 or bax mRNA expressions in the brain were changed after short-term ethanol exposure. These results suggest that bcl-2 or bax may have functional significance about ethanol intoxication.