Sumiko Yoshida

Reliability and validity of the Japanese version of the World Health Organization-Five Well-Being Index in the context of detecting depression in diabetic patients.

Abstract  The present study had two aims. The first was to evaluate the reliability and the validity of the Japanese version of the World Health Organization (WHO)‐Five Well‐Being Index (WHO‐5‐J) as a brief well‐being scale. The second was to examine the discriminatory validity of this test as a screening tool for current depressive episodes in diabetic patients. A sample of 129 diabetic patients completed the WHO‐5‐J. Of these, 65 were also interviewed by psychiatrists to assess whether they had any current depressive episodes according to DSM‐IV. The internal consistency was evaluated using Cronbach’s alpha, the Loevinger coefficient of homogeneity, and factor analysis. The external concurrent validity was evaluated by correlations with the external scales potentially related to subjective well‐being. Discriminatory validity was evaluated using receiver operating characteristic (ROC) analysis. Cronbach’s alpha and the Loevinger coefficient were estimated to be 0.89 and 0.65, respectively. A factor analysis identified only one factor. The WHO‐5‐J was significantly correlated with a number of major diabetic complications, depression, anxiety, and subjective quality of life. ROC analysis showed that the WHO‐5‐J can be used to detect a current depressive episode (area under curve: 0.92; 95% confidence interval: 0.85–0.98). A cut‐off of <13 yielded the best sensitivity/specificity trade‐off: sensitivity, 100%; specificity, 78%. The WHO‐5‐J was thus found to have a sufficient reliability and validity, indicating that it is a useful instrument for detecting current depressive episodes in diabetic patients.

Methamphetamine alters expression of DNA methyltransferase 1 mRNA in rat brain.

Methamphetamine, a potent and indirect dopaminergic agonist, also increases glucocorticoid hormone secretion. Glucocorticoid hormones facilitate behavioral effects of methamphetamine in rodents. Several reports suggest that glucocorticoid hormones modulate expression of DNA (cytosine-5-)-methyltransferase 1 (Dnmt1). Dnmt1 was originally recognized as being involved in DNA replication, but a recent study found high levels of Dnmt1 in rodent brains, suggesting a neuron-specific unknown function of Dnmt1. In the present study, we found subchronic methamphetamine treatment (4 mg/kg, i.p., once daily for 21 days) to induce different patterns of Dnmt1 mRNA expression in the nucleus caudatus and nucleus accumbens of two inbred rat strains, Fischer 344/N (increased Dnmt1) and Lewis/N (decreased Dnmt1). These patterns paralleled methamphetamine-induced striatal glucocorticoid receptor mRNA in these two rat strains in our previous study. Because Fischer rats have a hyperresponsive negative feedback in their hypothalamic-pituitary-adrenocortical (HPA) axis and thus a shorter duration corticosterone response to subchronic methamphetamine treatment, they were resistant to sensitizing effects of methamphetamine and their glucocorticoid receptor mRNA levels were upregulated. Lewis rats which have a hyporesponsive feedback in their HPA axis and a longer duration of corticosterone secretion with subchronic methamphetamine were prone to methamphetamine sensitization and their striatal glucocorticoid receptor mRNA levels were downregulated. Our present data suggest that methamphetamine results in differential DNA methylation as well as gene expression in the nucleus caudatus and nucleus accumbens of F344 and Lewis rats. Methamphetamine-induced differences in gene expression might be related to the contrasting susceptibilities of these rats to behavioral and neurochemical effects of methamphetamine.

Psychostimulant Alters Expression of DNA Methyltransferase mRNA in the Rat Brain

Abstract: Methamphetamine (MAP), the most frequently abused substance in Japan, causes severe drug dependence and psychosis, similar to schizophrenia. It is suggested that long‐term alterations in gene expression is related to MAP‐induced brain dysfunction, including dependence and psychosis. DNA (cytosine‐5) methyltransferase (Dnmt), a methylating enzyme of cytosine residues on CpG‐dinucleotides, plays an important role in X chromosome inactivation, genomic imprinting, and gene expression. Reelin is an extracellular matrix protein secreted by GABAergic interneurons. Heterozygous reeler mice that exhibit a 50% downregulation of reelin expression replicate the dendritic spine and GABAergic defects described in schizophrenia. DNA methylation plays an important role in the epigenetic modification of reelin expression. We previously found that MAP could alter expression of Dnmt1 mRNA in the rat brain. In this study, we examined the brain mRNA for Dnmt2 and reelin in MAP‐treated Wistar rats. Acute MAP (4 mg/kg) treatment significantly decreased Dnmt2 mRNA by 27% to 39% in hippocampus dentate gyrus, CA1, and CA3 24 h after treatment, and significantly decreased reelin mRNA by 28% in frontal cortex 3 h after treatment. These results suggest that (1) MAP can alter DNA methylation as well as expression of genes in these brain regions, and (2) decrease in reelin mRNA in the frontal cortex is similar to heterozygous reeler mice, which might be related to schizophrenia‐like psychotic symptoms of MAP psychosis.

Visual event‐related potential in mild dementia of the Alzheimer's type

Abstract Visual event‐related potentials (ERP) and behavioral measures were recorded during a geometrical‐figure discrimination task to examine sensory processing in 10 patients with mild dementia of the Alzheimers type (DAT) and 10 age‐matched controls. No difference existed between the groups in P1, N1, and P2 potentials, which reflects the early stage of sensory processing, as well as in NA potential, which reflects pattern recognition. The patients showed reduced amplitude of P3 potential, retarded reaction time, and increased behavioral errors compared to controls. These findings suggest that the patients with mild DAT were intact in early sensory processing including pattern recognition but were selectively compromised in higher‐level processing, including integration of information and memory matching, which may influence behavioral deviation.

Lack of repetition priming effect on visual event-related potentials in schizophrenia.

BACKGROUND The present study was designed to assess, using event-related potentials, whether aberrant semantic processing reported in schizophrenia results from primary semantic overactivation or contextual dysregulation. METHODS The visual event-related brain potentials were compared between 9 schizophrenic subjects and 16 normal control subjects performing two kinds of semantic categorization tasks with different nontarget stimuli: 1) nontargets comprising words, pseudowords, and unpronounceable foreign letters and 2) nontargets comprising initial presenting words, immediate repetition words, and delayed repetition words. RESULTS Schizophrenic subjects showed no evidence suggestive of a greater negative potential associated with words and pseudowords, but they did show a lack of amplitude change associated with immediately repeated words relative to that in control subjects. CONCLUSIONS These results suggest that aberrant semantic activation in schizophrenia results mainly from a failure to utilize information from preceding words or context, and could explain the increased N400 to the congruent or related words recently reported in this disease.

Impaired cliff avoidance reaction in dopamine transporter knockout mice

RationaleImpulsivity is a key feature of disorders that include attention-deficit/hyperactivity disorder (ADHD). The cliff avoidance reaction (CAR) assesses maladaptive impulsive rodent behavior. Dopamine transporter knockout (DAT-KO) mice display features of ADHD and are candidates in which to test other impulsive phenotypes.ObjectivesImpulsivity of DAT-KO mice was assessed in the CAR paradigm. For comparison, attentional deficits were also assessed in prepulse inhibition (PPI) in which DAT-KO mice have been shown to exhibit impaired sensorimotor gating.ResultsDAT-KO mice exhibited a profound CAR impairment compared to wild-type (WT) mice. As expected, DAT-KO mice showed PPI deficits compared to WT mice. Furthermore, the DAT-KO mice with the most impaired CAR exhibited the most severe PPI deficits. Treatment with methylphenidate or nisoxetine ameliorated CAR impairments in DAT-KO mice.ConclusionThese results suggest that DAT-KO mice exhibit impulsive CAR behavior that correlates with their PPI deficits. Blockade of monoamine transporters, especially the norepinephrine transporter (NET) in the prefrontal cortex (PFC), may contribute to pharmacological improvement of impulsivity in these mice.

Methamphetamine differentially regulates hippocampal glucocorticoid and mineralocorticoid receptor mRNAs in Fischer and Lewis rats.

Fischer 344 (F344) and Lewis (LEW) rats differ in physiological regulation of the limbic-hypothalamo-pituitary-adrenal (LHPA) axis, such that F344 rats exhibit greater LHPA axis responses to a variety of stimuli. Furthermore, LHPA axis activity has been implicated in the development of sensitization to abused drugs, and F344 rats exhibit greater behavioral sensitization to psychostimulants. Accordingly, we hypothesized that there may be some overlap between the neurobiological mechanisms that underlie these strain differences in LHPA axis activity and in behavioral sensitization to psychostimulants. We examined the effects of acute and repeated methamphetamine (4 mg/kg) treatments on the regulation of hippocampal glucocorticoid receptors (GR mRNA) and mineralocorticoid receptors (MR mRNA) in F344 and LEW rats. Our results showed that acute treatment with methamphetamine (MAP) does not alter the level of expression of GR or MR mRNA in both strains. However, repeated treatments with MAP decreased the expression of hippocampal GR, but not MR mRNA specifically in F344 rats. The same repeated treatments had no effect on either GR or MR mRNA in LEW rats. This selective MAP regulation of the level of expression of hippocampal GR mRNA in F344 suggests that these receptors may play a role in the development of behavioral sensitization to MAP in this strain. The lack of alteration in hippocampal GR mRNA in LEW rats suggests that plasticity of hippocampal GR may not be critical for the development of behavioral sensitization to MAP in this strain.

Electroconvulsive shock increases serotonin transporter in the rat frontal cortex

The antidepressive action of electroconvulsive shock (ECS) is thought to involve the alteration in serotonin (5-HT) neurotransmission, including the increase in 5-HT release and uptake. In our previous study, 5-HT transporter (5-HTT) mRNA expression was decreased after single and repetitive ECS in rat raphe nucleus. In the present study, we investigated the effects of single and repetitive ECS on the protein levels of 5-HTT in the frontal cortex, hippocampus and raphe nucleus of rat brain using quantitative Western blot analysis. Single ECS did not alter 5-HTT protein expression in any brain regions examined. Repetitive ECS stably increased 5-HTT protein in the frontal cortex, but not in the hippocampus and raphe nucleus. Because ECS is known to facilitate the release of neurotransmitters, our results suggest that the increased 5-HTT protein expression in the frontal cortex might be a compensatory change against the enhanced 5-HT release by ECS in presynaptic terminals.

Delayed visual NA potential in remitted schizophrenia: a new vulnerability marker for psychotic relapse under low-dose medication

BACKGROUND Lasting cognitive dysfunction throughout remission has been regarded as a biological vulnerability in schizophrenia, which may produce psychotic relapses with characteristic symptoms. Our hypothesis was that an abnormality in event-related potentials (ERPs) may be a neurophysiological marker of vulnerability to psychotic relapse in remitted schizophrenia. We conducted a 2-year follow-up study after evaluating ERP abnormalities to find a new ERP marker for schizophrenic relapse. METHODS Visual ERPs were recorded from outpatients with remitted schizophrenia under maintenance pharmacotherapy (n = 44) and normal controls (n = 20) during a letter discrimination task. Based on the prospective study, the patients were divided into a relapse group (n = 20) and a nonrelapse group (n = 24). ERP findings that related to psychotic relapse within 2 years were analyzed. RESULTS Compared with controls, the relapsers showed ERP abnormalities in the NA, N2, and P3 components, and the nonrelapsers in the P3 component. The peak latency of the NA potential was delayed significantly in the relapse group relative to the nonrelapse group, and predicted a psychotic relapse with about 90% probability. CONCLUSIONS The delayed NA, which reflects early perceptual disorganization, may be a promising neurophysiological predictor of psychotic relapse in remitted schizophrenia under maintenance pharmacotherapy.

Impairment of cliff avoidance reaction induced by subchronic methamphetamine administration and restraint stress: comparison between two inbred strains of rats

1. The effects of subchronic methamphetamine (MAP) treatment and restraint stress on the behavioral sensitization in stereotypy (stereotypy sensitization) and cliff avoidance reaction (CAR) were examined in two inbred strains of male rats; Fischer 344/N (F344), and Lewis/N (LEW). 2. In experiment 1, the animals received 4 mg/kg/day MAP for 30 days. LEW rats developed stereotypy sensitization earlier than F344 rats. However, both strains plateaued at the same stereotypy rating score. Furthermore, F344 rats were susceptible to CAR impairment as a result of MAP treatment, whereas LEW rats were not. 3. In experiment 2, the animals were exposed to daily restraint stress of 2hr for 4 weeks. MAP was administered (4mg/kg) 7 days after the last treatment day. Repeated restraint stress induced almost the same degree of stereotypy sensitization in both strains. F344 rats were susceptible to CAR impairment induced by repeated stress, whereas LEW rats were not. 4. The effects of psychostimulant and stressors appear to be similar not only with respect to stereotypy sensitization but also CAR impairment. Differences in MAP- or stress-induced CAR impairment between the two inbred strains may be genetically linked and may be involved in the development of psychotic behavior.