Koichiro Fujimaki

Administration of a cAMP phosphodiesterase 4 inhibitor enhances antidepressant-induction of BDNF mRNA in rat hippocampus

The influence of two selective phosphodiesterase 4 (PDE4) inhibitors, rolipram and Ro 20–1724, on the induction of BDNF mRNA by antidepressant treatment was examined. Coadministration of rolipram or Ro 20–1724 with an antidepressant (either desipramine or Org 4428) for 21 d resulted in a significant induction of BDNF mRNA in hippocampus relative to administration of vehicle. Coadministration of a PDE4 inhibitor with an antidepressant for 7 or 14 d also increased levels of BDNF mRNA. In contrast, acute coadministration did not influence levels of BDNF mRNA. In situ hybridization analysis demonstrated that the induction of BDNF mRNA in response to the repeated coadministration paradigm occurs in the dentate gyrus granule and CA1 and CA3 pyramidal cell layers of hippocampus. These findings demonstrate that coadministration shortens the time required for the upregulation of BDNF mRNA, supporting the possibility that this treatment may provide an effective therapy for major depression.

Suppression of Cell Proliferation by Interferon-Alpha through Interleukin-1 Production in Adult Rat Dentate Gyrus

The therapeutic use of interferon-alpha (IFN-α), a proinflammatory cytokine, is known to cause various neuropsychiatric adverse effects. In particular, depression occurs in 30–45% of patients, frequently interrupting treatment. IFN-α-treated animals also show depression-like behaviors. However, mechanisms underlying the depression caused by IFN-α remain to be defined. Recently, a decrease in adult hippocampal neurogenesis was revealed as a possible neuropathological mechanism of depression. Therefore, we investigated the effect of subchronic IFN-α treatment on neurogenesis in the adult rat dentate gyrus (DG). Immediately after the administration of IFN-α for 1 week, a decrease in the number of 5-bromo-deoxyuridine-labeled proliferating cells was observed in the DG; however, no effect was detected on the expression of mature neuronal phenotype in the newly formed cells 3 weeks later. Also, an increase in the level of interleukin-1beta (IL-1β), a major proinflammatory cytokine, was observed in the hippocampus following the administration of IFN-α. Furthermore, coadministration of an IL-1 receptor antagonist completely blocked the IFN-α-induced suppression of the cell-proliferative activity in the DG. Our results indicate that IFN-α suppresses neurogenesis in the DG, and that IL-1β plays an essential role in the suppression. The decreased cell proliferation caused by IFN-α-induced IL-1β may be responsible, at least in part, for IFN-α-induced depression.

Stimulation of Adenylyl Cyclase and Induction of Brain-Derived Neurotrophic Factor and TrkB mRNA by NKH477, a Novel and Potent Forskolin Derivative

Abstract: The present study was undertaken to examine whether NKH477, a novel and potent water‐soluble forskolin derivative, stimulates adenylyl cyclase and regulates brain‐derived neurotrophic factor (BDNF) and TrkB expression in the rat brain. Administration of NKH477 at a dose of 1.0 mg/kg, but not 0.1 mg/kg, increased levels of cyclic AMP (cAMP) in a time‐dependent manner in frontal cortex and hippocampus. Repeated administration of NKH477 (1.0 mg/kg) for 7 or 14 days also increased levels of cAMP in these two brain regions, indicating that the response does not desensitize with chronic treatment. In addition, administration of NKH477 at the 1 mg/kg dose increased the expression of BDNF and TrkB mRNA in frontal cortex and hippocampus. This effect was observed after single, as well as repeated (7 or 14 days), administration of NKH477. These results demonstrate that NKH477 administration rapidly increases cAMP levels in brain and provides evidence that stimulation of this second messenger system increases the expression of BDNF and TrkB mRNA.

Predictors of quality of life in inpatients with schizophrenia

Shortening hospital stays has become a key focus in psychiatric care in recent years. However, patients with schizophrenia account for about 60% of inpatients in psychiatry departments in Japan. This study was designed to investigate the relationship between quality of life (QOL) and key indicators for long-term hospital stays among schizophrenia inpatients. A further aim was to elucidate the clinical determinants of QOL among long-stay inpatients. The study sample consisted of 217 inpatients with schizophrenia. Age, duration of illness, duration of hospitalization, years of education, body mass index, neurocognitive function, drug-induced extrapyramidal symptoms, involuntary movements, psychiatric symptoms, and dose equivalents of antipsychotics and anticholinergic agents were used as index factors. Pearson linear correlation and regression analyses were performed to examine the associations between QOL and the above-mentioned factors. Negative symptoms, psychological discomfort, and resistance as rated on the Brief Psychiatric Rating Scale (BPRS) were correlated with all subscale scores of the Japanese version of the Schizophrenia Quality of Life Scale (JSQLS). Stepwise regression showed that negative symptoms, psychological discomfort, and resistance predicted the dysfunction of psycho-social activity score and the dysfunction of motivation and energy score on the JSQLS. This study shows that active treatment for negative symptoms, psychological discomfort, and resistance should be recommended to improve QOL among inpatients with schizophrenia.

Association of Typical versus Atypical Antipsychotics with Symptoms and Quality of Life in Schizophrenia

Background Several reports on patients with chronic schizophrenia suggest that atypical versus typical antipsychotics are expected to lead to better quality of life (QOL) and cognitive function. Our aim was to examine the association of chronic treatment with typical or atypical antipsychotics with cognitive function, psychiatric symptoms, QOL, and drug-induced extrapyramidal symptoms in long-hospitalized patients with schizophrenia. Methodology and Principal Findings The Hasegawa Dementia Scale-Revised (HDS-R), Brief Psychiatric Rating Scale (BPRS), the Schizophrenia Quality of Life Scale, translated into Japanese (JSQLS), and the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) were used to evaluate cognitive function, psychiatric symptoms, QOL, and drug-induced extrapyramidal symptoms. We examined the correlation between the dose of antipsychotics and each measure derived from these psychometric tests. The student t-test was used to compare scores obtained from psychometric tests between patients receiving typical and atypical antipsychotics. Results showed significant correlations between chlorpromazine (CPZ)-equivalent doses of typical antipsychotics and atypical antipsychotics, and the total BPRS score and BPRS subscale scores for positive symptoms. CPZ-equivalent doses of typical antipsychotics were correlated with the JSQLS subscale score for dysfunction of psycho-social activity and DIEPSS score. Furthermore, the total BPRS scores, BPRS subscale score for positive symptoms, the JSQLS subscale score for dysfunction of psycho-social activity, and the DIEPSS score were significantly higher in patients receiving typical antipsychotics than atypical antipsychotics. Conclusion and Significance These findings suggest that long-term administration of typical antipsychotics has an unfavorable association with feelings of difficulties mixing in social situations in patients with chronic schizophrenia.

Negative Correlation between Affective Symptoms and Prefrontal Activation during a Verbal Fluency Task: A Near-Infrared Spectroscopy Study

Only a few studies have examined the relationships between affective symptoms, cognitive function (e.g. verbal fluency), quality of life (QOL), and brain activation in a nonclinical population. The aim of the present study was to assess these relationships and examine the underlying cortical mechanisms in a nonclinical population. Fifty-two healthy male volunteers were assessed for depressive symptoms using the Zung Self-Rating Depression Scale (SDS), for apathy using the Apathy Scale, and QOL using the Medical Outcomes Study short-form 36-item questionnaire (SF36). The volunteers also performed a verbal fluency test (VFT) while hemoglobin concentration changes were assessed on the surface of the frontal cortex using 24-channel near-infrared spectroscopy (NIRS). The SDS and Apathy Scale scores showed significant negative correlations with the scores of most of the SF36 subscales. Frontal activation had a significant negative correlation with the SDS scores and the Apathy Scale. These results suggest that the degree of affective symptoms is associated with a lower QOL in a nonclinical population, and that cortical hypoactivation during a VFT measured by NIRS may objectively identify individuals with a high degree of affective symptoms.

Influence of immobilization stress on the expression and phosphatase activity of protein phosphatase 2A in the rat brain

BACKGROUND Protein phosphatase 2A (PP2A) is a major kinase phosphatase that plays an important role in regulating the activities of protein kinase cascades. It has been revealed that stress changes neuronal gene expression by activating these cascades. We examined the expression of the catalytic subunit C and serine and threonine phosphatase activity of PP2A in the rat frontal cortex and hippocampus following various immobilization stress paradigms. METHODS Immunoblot and immunohistochemical analyses were performed to examine the expression of PP2A. The level of phosphatase activity of PP2A was determined as the amount of free phosphate generated from a synthetic phosphopeptide. RESULTS Immunoblot analysis revealed no significant change in the level of PP2A immunoreactivity in response to either a single or repeated stress. Immunohistochemical analysis revealed that neither a single nor repeated stress changed PP2A immunoreactivity in the hippocampus; however, the levels of serine and threonine phosphatase activity in the frontal cortex and hippocampus were significantly upregulated in response to a single or repeated stress. CONCLUSIONS These results demonstrated that both a single and repeated immobilization stress upregulated the activity of PP2A in the rat brain, suggesting that PP2A may be involved, at least in part, in the downregulation of protein kinase activation induced by stress.

Depressive symptoms and apathy are associated with psychomotor slowness and frontal activation

Affective symptoms, such as depression and apathy, and cognitive dysfunction, such as psychomotor slowness, are known to have negative impacts on the quality of life (QOL) of patients with mental and physical diseases. However, the relationships among depressive symptoms, apathy, psychomotor slowness, and QOL in a non-clinical population are unclear. The aim of the present study was to assess these relationships and examine the underlying cortical mechanisms in a non-clinical population. Fifty-two healthy male volunteers were assessed for depressive symptoms using the Zung Self-rating Depression Scale (SDS), for apathy measured using the Apathy Scale, and QOL using the Short-Form 36 item questionnaire (SF36). The volunteers also performed the Trail Making Test Part A (TMT-A) while undergoing assessment of hemoglobin concentration changes in the frontal cortical surface using 24-channel near-infrared spectroscopy (NIRS). The scores of the SDS and Apathy Scale showed significant negative correlations with the scores of most of subscales of the SF36. In addition, the SDS score had a significant positive correlation with the time to complete the TMT-A. Further, activation of several frontal cortical areas had a significant positive correlation with the scores of the SDS and Apathy Scale. These results suggest that the degree of depressive symptoms and apathy are associated with a lower QOL in a non-clinical population and that cortical hyperactivation during a psychomotor task measured by NIRS may identify objectively individuals with a high degree of depressive symptoms and apathy.

Imipramine, but not lithium, induces the serine/threonine phosphatase activity of calcineurin without affecting its mRNA expression in the rat brain

Abstract. The influence of imipramine and lithium on the expression of calcineurin (CaN) and its serine/threonine phosphatase activity in the rat frontal cortex and hippocampus was examined. Northern blot analysis demonstrated that single or repeated (14 day) administration of imipramine did not affect the levels of CaN A (catalytic subunit) mRNA in rat brain. Similarly, the administration of lithium for 1 or 14 days had no effect on the expression of CaN A mRNA. In contrast, the acute administration of imipramine significantly increased CaN activity in the cortex and hippocampus. In addition, the chronic (14 day) administration also significantly increased CaN activity. However, administration of lithium for either 1 or 14 days did not influence CaN activity. These findings indicate that imipramine, but not lithium, increases the phosphatase activity of CaN, suggesting that the changes in neuronal functions induced by CaN may be involved in the molecular activity of imipramine.

Stress Vulnerability Induced by Neonatal Isolation and the Disturbance Between the Phosphorylation and Dephosphorylation of CREB

Lifetime prevalence of posttraumatic stress disorder (PTSD) has been found to range from 1.0% to 12.3% based on general-population and service-sector samples (Fairbank et al. 1995), which demonstrates that not all victims suffer from PTSD. It is conceivable that individual differences in stress reactivity may play a role in the development of PTSD. In addition, traumatization in early development, e.g., physical abuse or separation from parents, has been shown to be associated with the development of PTSD (Fairbank et al. 1995; Bremner et al. 1999; Pine and Cohen 2002). Various animal studies indicate that early adverse experiences change stress reactivity in adult rats (Kaufman et al. 2000). Neonatal isolation as well as maternal separation affects the response of the hypothalamo-pituitary-adrenal (HPA) axis to acute stress in adult rats (Francis et al. 1999; Ladd et al. 1996; Plotsky and Meaney 1993). Furthermore, neonatal isolation induces an increase in the central noradrenaline drive and reduction in the activity of the inhibitory central GABA/BZ system in adulthood (Caldji et al. 2000; Liu et al. 2000). Recent molecular pharmacological studies have revealed that while glucocorti-