Shigeru Morinobu

Correlation of regional cerebral blood flow with performance on neuropsychological tests in schizophrenic patients

Regional cerebral blood flow (rCBF) was determined by the 133Xe inhalation technique (Headtome II: ring detection SPECT) in 53 DSM-III schizophrenic patients. The rCBF values were corrected by using end-tidal carbon dioxide concentration values (PECO2). After rCBF measurement, neuropsychological tests--Word Fluency Test, Maze Test and Wisconsin Card Sorting Test--were performed. There were significant correlations between frontal rCBF and scores on each neuropsychological test. In particular, a moderate correlations between the frontal rCBF and the performance on the Wisconsin Card Sorting Test was noted. It seems likely that decrease of rCBF in prefrontal regions at rest reflects a disturbance of frontal lobe function in schizophrenic patients.

Effects of genetic defects in the CYP2C19 gene on the N-demethylation of imipramine, and clinical outcome of imipramine therapy

Abstract  The relationship between the genetic polymorphism of S‐mephenytoin 4′‐hydroxylation catalyzed by CYP2C19 and the N‐demethylation of imipramine was examined in 10 Japanese depressed patients. Five patients, who were poor metabolizers of S‐mephenytoin, were determined to be either homozygous for a mutation in exon 5 or heterozygous for mutations in exon 4 and exon 5 of the CYP2C19 gene. In contrast, five patients, who were extensive metabolizers, had no mutations. The demethylation index (the desipramine/imipramine ratio) was significantly lower in patients with genetic defects. Plasma levels of imipramine and 2‐hydroxyimipramine normalized by the daily dose (mg) per weight (kg) were significantly higher in patients with genetic defects. This suggests that the N‐demethylation of imipramine is impaired in patients with genetic defects in the CYP2C19 gene, and that genotype determination may be useful in preventing side effects induced by unexpectedly elevated levels of imipramine.

Influence of aging on the contractile response to endothelin of rat thoracic aorta.

Age-related changes in the contractile response to endothelin-1 and ACh were assessed in thoracic aortas isolated from 2-, 6- and 24-month-old male Fischer 344 rats. In aortic strips with an intact endothelium, the maximal contractile response to endothelin-1 decreased with development to maturity. Removal of the endothelium did not affect the contractile response to endothelin-1. Endothelin-1 did not elicit a relaxant response in phenylephrine-precontracted strips. The ACh-induced relaxation decreased in senescent rats. These results indicate that the contractile response of aortic smooth muscle to endothelin-1 decreases with age, and that the endothelial vasorelaxant factors do not contribute to this age-induced modulation.

Acetylcholinesterase activities and monoamine metabolite levels in the cerebrospinal fluid of patients with alzheimer's disease

We measured cholinesterase (ChE) activity and monoamine metabolite levels in the cerebrospinal fluid (CSF) of 22 patients with early-onset Alzheimer type dementia (Alzheimers disease; AD) and of 32 controls. Acetylcholinesterase (AChE) activity, 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) levels were significantly lower in AD patients than in controls. However, there was an overlap in values of each CSF parameter. The measurement of various CSF parameters rather than one alone was more useful as a diagnostic aid. CSF ChE activities correlated with scores on the GBS rating scale, Hasegawa dementia scale, and Wechsler Adult Intelligence Scale, but the monoamine metabolite levels did not. Although cholinergic and monoaminergic deficits may coexist in AD patients, cholinergic deficits tend to be more often associated with cognitive decline than the monoaminergic deficits.

Modulation by aging of the coronary vascular response to endothelin-1 in the rat isolated perfused heart

SummaryChanges with age in the coronary vascular response to endothelin-1 were investigated in perfused hearts isolated from 2-, 6- and 24-month-old (mo) male Fisher-344 rats. Endothelin-1 injected as a single bolus (0.3, 3 and 30 nmol) into the coronary artery supply caused dose-dependent vasoconstriction in all three age groups. While there was no age-related change in the vasoconstriction induced by the lower doses (0.3 and 3 nmol), the higher dose (30 nmol) elicited a more pronounced vasoconstriction in 6- and 24-mo rats than that in 2-mo rats. NG-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide formation, markedly enhanced the vasoconstriction induced by 30 nmol endothelin-1 in 2-and 6-mo rats but only slightly and non-significantly enhanced that vasoconstriction in 24-mo rats. Haemoglobin, which inhibits activation of guanylate cyclase by nitric oxide, enhanced the endothelin-1-induced vasoconstriction in 2-mo rats, but not in 6- and 24-mo rats. The acetylcholine-induced coronary vasodilation was more pronounced in 2- and 6-mo rats than in 24-mo rats and was attenuated by L-NNA in 2- and 6-mo rats. The coronary vasodilation induced by nitroprusside (0.1 mmol), a pharmacological precursor of nitric oxide, did not change with age. Endothelin-1 (30 nmol) markedly increased the release of 6-keto-prostaglandin F1α, (6-keto-PGF1α) in all three age groups. The prostaglandin synthesis inhibitor indomethacin enhanced the endothelin-1-induced vasoconstriction in 2- and 6-mo rats to a similar extent. These results indicate that endothelium-derived vasodilators such as endothelium-derived relaxing factor (EDRF) and prostacyclin may be released by endothelin-1 to modulate the endothelin-1-induced coronary vasoconstriction. The endothelial cell function to release EDRF in response to endothelin-1 decreases with aging. This decrease in EDRF release may be the main factor in the increase with age of the endothelin-1-induced coronary vasoconstriction.

Influence of stress and antidepressant treatment on 5-HT-stimulated phosphoinositide hydrolysis in rat brain

The aim was to elucidate the role of 5-hydroxytryptamine (5-HT)-stimulated phosphoinositide (PI) metabolism in stress situations and in the behavioral improvement produced by chronic antidepressant treatment. Rat cerebral cortex slices were used for the purpose. Forced swimming for 15 min and longer induced changes in behavioral activities of rats associated with a significant reduction of 5-HT-stimulated PI metabolism, without any changes in density and affinity of 5-HT2 receptors. This suggests that modulation of the receptor coupling process but not of the 5-HT2 receptor binding characteristics may be responsible for the significant reduction of 5-HT-stimulated PI metabolism in stress situations. Chronic antidepressant treatment tended to reduce 5-HT-stimulated PI metabolism. This treatment improved significantly the behavioural activities during forces swimming, and prevented the forced swimming-induced reduction of 5-HT-stimulated PI metabolism. It is postulated that chronic antidepressant treatment may improve behavioral activities in relation to PI metabolism in stress situations.

Chronic dexamethasone administration decreases noradrenaline-stimulated, but not serotonin-stimulated, phosphoinositide metabolism in the rat brain

The present study was undertaken to investigate the effects of chronic administration of dexamethasone on the noradrenaline- and serotonin-stimulated (5-HT-stimulated) phosphoinositide metabolism in hippocampus and frontal cortex of the rat brain. For determination of phosphoinositide metabolism, slices from selected regions of the rat brain (hippocampus or frontal cortex) were loaded with myo- [3H] inositol and stimulated with the agonists (noradrenaline or 5-HT) in the presence of LiCl (7.5 mM). Administration of dexamethasone (1 mg/kg/day) every 2nd day for 14 days markedly reduced the noradrenaline-stimulated phosphoinositide metabolism in the rat hippocampus (IP1: 60% of the control value). In the rat frontal cortex, the noradrenaline-stimulated phosphoinositide metabolism was less depressed by the chronic administration of dexamethasone (IP1: 84% of the control value). However, the chronic administration of dexamethasone did not affect the 5-HT-stimulated phosphoinositide metabolism in the rat brain. The binding characteristics of α1-adrenoceptors and 5-HT2A receptors were unaffected by the chronic treatment with dexamethasone. These results indicate that chronic administration of dexamethasone induces regional and neurotransmitter-specific changes of phosphoinositide metabolism in rat brain. The results suggest that the reduction of noradrenaline-stimulated phosphoinositide metabolism is due do modification of the intracellular signal transduction system.

Enhancement of 5-hydroxytryptamine-stimulated phosphoinositide hydrolysis in the rat cerebral cortex by repeated immobilization stress.

The present study was undertaken to investigate the influence of repeated immobilization stress on phosphoinositide hydrolysis induced by 5-hydroxytryptamine (5-HT) and noradrenaline in the rat cerebral cortex. Three groups of rats subjected to stress intervention were immobilized for 2 h per day for 3, 7, and 14 days. The stress intervention of any duration did not alter noradrenaline-stimulated phosphoinositide hydrolysis. The 3- and 7-day repeated immobilization enhanced 5-HT-stimulated phosphoinositide hydrolysis, whereas the characteristics of 5-HT2 receptor binding did not change. Chronic treatment with imipramine partially, but significantly, suppressed the increase in 5-HT-stimulated phosphoinositide hydrolysis, induced by the 3-day repeated immobilization. These findings imply that modulation of 5-HT-stimulated phosphoinositide hydrolysis occurs in stressful situations and that the therapeutic effects of tricyclic antidepressant drugs might be related to the modulation of phosphoinositide hydrolysis mediated by 5-HT receptors.

Noradrenergic function and the dexamethasone suppression test in depression

Abstract: We measured the plasma free 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) levels and the serum Cortisol levels before and after the oral administration of dexamethasone.

Stress and BDNF Signal Transduction: Implications for Stress-Related Psychiatric Disorders

It is well known that stress is a major risk factor for psychiatric disorders, such as major depression and posttraumatic stress disorder (PTSD). These illnesses can have some common symptoms, such as psychogenic amnesia, diminished interest, and impaired concentration, suggesting that the underlying pathophysiology of depression and PTSD may have common features (Friedman and Yehuda 1995). Clinical studies have provided support for this possibility. Brain imaging studies have demonstrated that the volume of the hippocampus is decreased in patients with major depression (Sheline et al. 1996) or patients with PTSD (Bremner et al. 1995). These findings suggest that atrophy or death of neurons in the hippocampus may contribute to the pathogenesis of depression and PTSD. In support of this hypothesis, basic research studies have demonstrated that chronic stress causes atrophy or, in extreme cases, death of hippocampal neurons in rats and nonhuman primates.