Michio Toru

Association of dopamine D2 receptor molecular variant with schizophrenia

We have examined a variant of the dopamine D2 receptor gene (Ser311-->Cys) in 156 Japanese schizophrenic patients and 300 controls. The allele frequency of Cys311 was significantly higher in the whole patient group (0.054), among patients with onset before age 25 (0.090), and among those with a family history (0.135) than in the controls (0.018). 3 patients were homozygous for Cys311. The patients with Cys311 showed significantly less severe thought disorder and negative symptoms of schizophrenia than those without Cys311. The Cys311 variant of the D2 receptor may be a genetic risk factor for some types of schizophrenia.

Epileptiform EEG Discharges in Healthy Children: Prevalence, Emotional and Behavioral Correlates, and Genetic Influences

Summary: Epileptiform discharges in 8 electrode waking EEGs at rest and during hyperventilation in 1,057 healthy children aged 6–12 years from an elementary school were studied: Epileptiform discharges, detected in 53 children (5.0%), consisted of centrotemporal spikes (37 cases), generalized spike ahd slow wave complexes (10 cases), occipital spikes (2 cases), frontal spikes (1 case), and a combination of multiple spike and slow wave complexes and focal spikes (2 cases). The occurrence of a positive past history of febrile convulsions was higher in children with epileptiform discharges (18.9%) than in those without epileptiform discharges (9.4%). Using the Rutter scales for teachers and parents, we compared the emotional and behavioral problems of children with epileptiform EEG discharges with those of children without epileptiform discharges. No statistically significant differences were noted, indicating that the emotional and behavioral problems existing are most probably coincidental and not directly related to the epileptiform discharges. A genetic basis for generalized epileptiform discharges was postulated because the occurrence of generalized discharges in siblings of probands with generalized discharges was higher (4 of 9, 44.4%) than the prevalence in all subjects. However, the occurrence of centrotemporat spikes in the siblings of probands with centrotemporal spikes was not higher (2/38, 5.3%) and an autosomaldominant genetic factor for centrotemporal spikes in waking EEGs of healthy children could not be confirmed.

Modulation of [3H]mazindol binding sites in rat striatum by dopaminergic agents

This study was undertaken to examine whether repeated alteration of dopamine turnover influences the function of dopamine uptake sites. In the first experiment, rats were repeatedly injected intraperitoneally with L-3,4-dihydroxyphenylalanine (L-DOPA), alpha-methyl-p-tyrosine or 1-[2-bis(4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl)piperazine (GBR 12909) once daily for 14 days. An increase in the number of [3H]mazindol binding sites in the striatum was seen with L-DOPA and GBR 12909. A decrease was seen with alpha-methyl-p-tyrosine. In the second experiment, the effect of a single treatment with the same drugs was investigated and no change in the number and affinity of [3H]mazindol binding sites was found. These results indicate that the number of dopamine uptake sites is modulated by persistent changes in dopamine turnover, and that repeated treatment with a selective dopamine uptake inhibitor, GBR 12909, increases their number.

Excitatory amino acids: Implications for psychiatric disorders research

The hyperdopaminergic theory of schizophrenia may account for some types of schizophrenia, but schizophrenia with negative symptoms or resulting in a chronic state of deterioration after repeated relapses cannot be explained by this theory. This minireview first discusses the interactions between dopamine and excitatory amino acid (EAA) neurons to produce abnormal behavior. Secondly, it deals with the influence of the psychotropic drugs on EAA, such as the relationship between phencyclidine and the hypoglutamate theory, the involvement of EAA in behavioral sensitization induced by amphetamines, the interactions between antipsychotic, antidepressant and antianxiety drugs and EAA, considering the possibility of developing newer psychotropic drugs related with EAA. Finally, glutamate receptors measured in postmortem schizophrenic brains are tabulated and the bases of the hypoglutamate hypothesis are discussed.

Platelet 3H-paroxetine binding in control subjects and depressed patients: Relationship to serotonin uptake and age

3H-paroxetine is regarded as a better ligand for the serotonin (5-hydroxytryptamine; 5-HT) uptake site than 3H-imipramine. In the present study, platelet 14C-5-HT uptake and 3H-paroxetine binding were simultaneously measured in 12 control subjects. There was a significant positive correlation between the individual Bmax value for 3H-paroxetine binding and the Vmax value for 14C-5-HT uptake. Platelet 3H-paroxetine binding was also determined in 21 drug-free patients who satisfied DSM-III-R criteria for major depression and 21 control subjects. A negative correlation was found between the Bmax values for 3H-paroxetine binding with age in control subjects. There was no change in 3H-paroxetine binding in depressed patients compared with control subjects. Our results indicated that 3H-paroxetine was a good ligand for evaluating 5-HT uptake sites, and the influence of age ought to be taken into consideration in the study of 3H-paroxetine binding. The present study indicated that there was no change in 5-HT uptake sites in platelets from depressed patients.

Involvement of the fimbria fornix in the initiation but not in the expression of methamphetamine-induced sensitization

To put forward our previous finding that the lesion of the fimbria fornix, a hippocampo-accumbal pathway, blocked the development of behavioral sensitization induced by repeated methamphetamine (MAP) administrations, we examined the role of the fimbria fornix in the expression of sensitization in this study. After rats had shown locomotor augmentation following repeated drug injections, they received either the fimbria fornix lesion or a sham operation. Both groups of rats still exhibited a similar sensitized locomotor response to MAP as before the surgeries. In addition, we evaluated dopamine metabolism in the nucleus accumbens of these rats following a challenge injection of MAP after the behavioral study. The data obtained correspond to the results of behavioral experiments in that 3-methoxytyramine, one of the dopamine metabolites, increased significantly after MAP challenge only in the groups of sensitized animals. These findings further support the recent concept that there may exist different neural mechanisms in the initiation and expression of sensitization phenomenon.

A follow-up study of healthy children with epileptiform EEG discharges

Abstract Fifty-two healthy elementary schoolchildren with epileptiform EEGs who were not taking anticonvulsants were followed for an average period of 3 years and 3 months. Thirty-seven had centrotemporal spikes, three had occipital spikes, one had frontal spikes, nine had generalized spike-and-wave complexes, and two had a combination of multiple spike-and-wave complexes and focal spikes. Disappearance of epileptiform discharges was observed in 65% on waking EEGs and in 45% on sleep EEGs. After 5 years, the rate of disappearance was over 80% in waking and sleep EEGs. This study confirms that most epileptiform discharges in healthy children disappear spontaneously during childhood and that age-related development and disappearance occur in healthy children who would otherwise never be subjected to EEG examination. Epileptic seizures occurred in three cases (6%). This low percentage is not considered to be an indication for treating children with epileptiform discharges with anticonvulsants. However, the risk for seizure development may be higher than in the general population. According to the literature, children with multiple spike-wave complexes have a greater tendency to develop seizures. One girl with multiple spike-wave complexes and focal spikes developed generalized tonic-clonic convulsions. Two boys with centrotemporal spikes developed benign childhood epilepsy with centrotemporal spikes (BCECS). This study confirms that some (5%) of healthy children with centrotemporal spikes, the most common epileptiform pattern in healthy children, develop BCECS.

Lower Interhemispheric Coherence in a Case of Agenesis of the Corpus Callosum

Interhemispheric coherence and relative power were compared in a patient with total agenesis of the corpus callosum and age and sex matched controls. The patient showed lower interhemispheric coherence than normal controls in F3-F4, C3-C4, and in P3-P4 especially in the higher theta, lower alpha, and beta bands. Differences in relative power were much less marked. These results seem to reflect that interhemispheric connection is degraded because of callosal agenesis.

Quantitative magnetic resonance imaging in patients with temporal lobe epilepsy

Abstract Quantitative brain changes on magnetic-resonance-weighted imaging (MRI) were studied in 30 patients with temporal lobe epilepsy (TLE) who showed negative findings on computed tomography and no visible abnormality on MRI, and 20 healthy controls in order to detect changes not visible by standard imaging. The patients with TLE showed a significant decrease in size and a significant increase in T1 values of the mesial temporal area in both hemispheres compared to controls who had normal values bilaterally. Patients with a current or past history of organic delusional disorder (ICD-10) resembling schizophrenia showed a significant increase in the size of the third ventricle. The data suggest that (a) there are atrophic changes in the mesial temporal areas of patients with TLE, reflecting an increased water content in these areas, (b) TLE patients often have bilateral atrophic changes in the mesial temporal areas, even if there is only unilateral abnormality of EEG, and (c) TLE patients with schizophrenia-like organic symptoms may have some structural changes around the third ventricle, including limbic system structures. Further research needs to clarify the exact structures involved and the factors responsible for these abnormalities.

Effect of a single injection of psychoactive drugs on CCK mRNA in rat brain

The acute and long-term effects of a single injection of psychoactive drugs, methamphetamine or phencyclidine, were investigated by Northern blot to assess alterations in the cholecystokinin (CCK) mRNA in three areas of the rat brain. In the frontal cortex, there were no significant changes in CCK mRNA after the drug injection. In contrast, decreases in CCK mRNA were observed in the posterior cortex and the hippocampus from 30 min to 48 h after the drug treatment. The data suggest that CCK gene expression has different sensitivity to these psychoactive drugs within the cortices.