Norio Yokota

Attenuated Left Prefrontal Activation during a Verbal Fluency Task in Patients with Depression

Functional neuroimaging studies on patients with depression have found abnormal activity in the left prefrontal and anterior cingulate cortex compared with healthy controls. Other studies have shown that these regions become active in healthy subjects during verbal fluency tasks, while patients with depression show impaired performance on such tasks. We used functional magnetic resonance imaging to investigate changes in cerebral blood oxygenation associated with a verbal fluency task in depressed patients and healthy volunteers. In contrast to 10 age- and sex-matched healthy control subjects who activated the left prefrontal cortex and the anterior cingulate cortex during word generation, 10 depressed subjects showed attenuated activation in the left prefrontal cortex and did not show significant activation in the anterior cingulate cortex. These findings suggest that impaired performance during verbal fluency task in depressed patients is associated with abnormal neural responses within these regions.

Negative correlation between right prefrontal activity during response inhibition and impulsiveness: A fMRI study

Abstract.Behavioral disinhibition in Go/No–Go task is thought to be associated with impulsiveness in humans. Recent imaging studies showed that neural circuits involving diverse areas of the frontal cortex and other association cortex sites such as the parietal cortex are implicated in the inhibition of response during No–Go trials. The aim of the present study was to investigate the association between regional cerebral activation during No–Go trials and impulsiveness. Seventeen righthanded healthy volunteers participated in the study. We used functional magnetic resonance imaging to measure the brain activation during a Go/No–Go task. The Barratt Impulsiveness Scale, 11th version (BIS–11) was used to measure impulsiveness. Activated regions included the right middle frontal gyrus and the inferior parietal lobe, which is consistent with previous neuroimaging studies. A negative correlation was observed between the motor impulsiveness of BIS–11 and No–Gorelated activation in the right dorsolateral prefrontal cortex (RDLPFC). Our results suggest that the RDLPFC is the area most sensitive to differences in individual motor impulsiveness and its activity may be an indicator of the individual capacity for response inhibition.

Plasma dehydroepiandrosterone sulfate in unipolar major depression

Summary. We investigated plasma dehydroepiandrosterone sulfate (DHEAS) and cortisol levels in 12 patients with unipolar depression and 11 matched normal controls. The depressed patients showed significantly higher values of plasma DHEAS and cortisol than the controls. After 4 weeks of treatment with antidepressants (mainly clomiplamine), the high plasma DHEAS levels recovered.This finding showed the possible relationship between plasma DHEAS levels and depression, as well as cortisol levels.

Response of patients with major depression and silent cerebral infarction to antidepressant drug therapy, with emphasis on central nervous system adverse reactions.

BACKGROUND AND PURPOSE We previously found that silent cerebral infraction (SCI) is present in most patients older than 50 years with major depression. The present study was designed to clarify the response to antidepressant pharmacotherapy in patients with major depression associated with SCI. METHODS Using clinical charts, we retrospectively studied patients older than 50 years who were admitted for antidepressant drug therapy. Patients with bipolar affective disorder and those with focal neurological symptoms were excluded. All patients underwent magnetic resonance imaging and were classified as SCI-negative or SCI-positive. The SCI-positive group was subclassified into those with moderate SCI (either perforating area or cortical area) (n = 15) and those with severe SCI (both perforating and cortical areas) (n = 7). Duration of treatment in hospital and the incidence of central nervous system adverse reactions to the antidepressant drugs were compared between the two groups. RESULTS The duration of hospital treatment in patients with severe SCI was significantly longer than in those with moderate SCI (P < .01). The percentage of patients with adverse central nervous system reactions to antidepressant drugs was significantly higher in the SCI-positive group than in the SCI-negative group (P < .05). Patients with severe SCI had significantly more adverse reactions than those with moderate SCI (P < .05). CONCLUSIONS Depressed patients with severe SCI required longer hospital treatment and had more drug-related adverse reactions of the central nervous system. These findings suggest that the depression associated with severe SCI may be resistant to treatment.

Effect of chronic tryptophan depletion on the circadian rhythm of wheel-running activity in rats.

The effect of chronic treatment with a tryptophan (TRP)-free diet on the free-running circadian wheel-running rhythm and the central serotonergic system was investigated in blinded male rats. The long-term TRP-free diet did not change periods of activity, but disordered their patterns. This seemed to be due to masking, entrainment, enhancement of the morning activity, and obscuring of the activity onset as well as appearance of some periodic activities within the subjective night. A long-term TRP-fre diet decreased the concentration of TRP, 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in all brain regions tested: frontal cortex, hippocampus, thalamus, hypothalamus, midbrain, and pons. Density of 5-HT1A receptor binding was significantly decreased in the frontal cortex and hypothalamus, whereas no significant change was observed in the density of 5-HT2 receptor binding in all regions. These results suggest that the period of primary circadian pacemaker is not affected, but its oscillation, as well as the coupling strength between the primary and secondary pacemakers, is weakened by the dysfunction of the serotonergic system caused by chronic TRP depletion.

Chronic treatment with antidepressants, verapamil, or lithium inhibits the serotonin-induced intracellular calcium response in individual C6 rat glioma cells.

The effects of chronic treatment with antidepressants, verapamil, or lithium on serotonin (5-HT)-induced Ca2+ increase were investigated in single C6BU-1 glioma cells with digital imaging microscopy. Clomipramine and citalopram, at a concentration of 100 nM, decreased the peak values of 5-HT-induced [Ca2+]i changes. Verapamil (100 nM), a calcium antagonist, and lithium (1 mM) also inhibited the peak amplitudes in the same way. The present findings suggest that chronic treatment with antidepressants, verapamil, or lithium, at therapeutic concentrations, have the common action of inhibiting 5-HT-mediated [Ca2+]i increase.

Effect of dantrolene on KCl- or NMDA-induced intracellular Ca2+ changes and spontaneous Ca2+ oscillation in cultured rat frontal cortical neurons

SummaryDantrolene has been known to affect intracellular Ca2+ concentration ([Ca2+]i) by inhibiting Ca2+ release from intracellular stores in cultured neurons. We were interested in examining this property of dantrolene in influencing the [Ca2+]i affected by the NMDA receptor ligands, KCl, L-type Ca2+ channel blocker nifedipine, and two other intracellular Ca2+-mobilizing agents caffeine and bradykinin. Effect of dantrolene on the spontaneous oscillation of [Ca2+]i was also examined. Dantrolene in μM concentrations dose-dependently inhibited the increase in [Ca2+]i elicited by NMDA and KCl. AP-5, MK-801 (NMDA antagonists), and nifedipine respectively reduced the NMDA and KCl-induced increase in [Ca2+]i. Dantrolene, added to the buffer solution together with the antagonists or nifedipine, caused a further reduction in [Ca2+]i to a degree similar to that seen with dantrolene alone inhibiting the increase in [Ca2+]i caused by NMDA or KCl. At 30 μM, dantrolene partially inhibited caffeine-induced increase in [Ca2+]i whereas it has no effect on the bradykinin-induced change in [Ca2+]i. The spontaneous oscillation of [Ca2+]i in frontal cortical neurons was reduced both in amplitude and in base line concentration in the presence of 10 μM dantrolene. Our results indicate that dantrolenes mobilizing effects on intracellular Ca2+ stores operate independently from the influxed Ca2+ and that a component of the apparent increase in [Ca2+]i elicited by NMDA or KCl represents a dantrolene-sensitive Ca2+ release from intracellular stores. Results also suggest that dantrolene does not affect the IP3-gated release of intracellular Ca2+ and that the spontaneous Ca2+ oscillation is, at least partially, under the control of Ca2+ mobilization from internal stores.

Effect of interferon-α on DOI-induced wet-dog shakes in rats

SummaryAcute (1h) intraperitoneal (ip) treatment with interferon (IFN)-α-2a (300IU/g) significantly inhibited wet-dog shakes (WDS) induced by (±)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI; 0.5, 1.0mg/kg), which is mediated by serotonin (5-hydroxytryptamine; 5-HT)2 receptor in rats. IFN-α did not affect spontaneous locomotion. The inhibition of DOI (0.5mg/kg)-induced WDS by IFN-α was dose (90–300 IU/g)- and time (1–6 h)-dependent, and was prevented by 30 min pretreatment with naltrexone (NLTX; 1.0mg/kg, ip), an opioid receptor antagonist. Acute (1h) intracerebroventricular (icv) treatment with IFN-α (1,500IU/rat) also inhibited DOI (0.5mg/kg)-induced WDS, and the effect was blocked by NLTX (50μg/rat, icv). These results suggest that IFN-α may modulate 5-HT2 receptor-mediated behavior through opioid receptors in the central nervous system.

Differential regulation by pregnenolone sulfate of intracellular Ca2 increase by amino acids in primary cultured rat cortical neurons

We investigated the effects of pregnenolone sulfate (PS) on the [Ca2+]i increase induced by gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) using fluorescence imaging. PS inhibited the 50 microM GABA-induced increase in [Ca2+]i in a dose-dependent manner with an IC50 of 30 microM. The inhibitory effect of PS was apparent within 5 min and was in a non-competitive manner, suggesting that PS may act directly to the membrane level but indirectly to the GABA binding sites. Our previous study has already shown that the GABA-induced Ca2+ increase involves GABAA receptors and the similar pathway to a high K(+)-induced Ca2+ response (Takebayashi et al., 1996). Because 50 microM of PS could not inhibit a 25 mM K(+)-induced Ca2+ increase, it seems likely that the site of the inhibitory action of PS on the GABA-induced Ca2+ increase may be independent of the pathway of the high K(+)-induced Ca2+ response, but rather at GABAA receptor complex. In contrast, PS potentiated the 50 microM NMDA-induced increase in [Ca2+]i in a dose-dependent manner. The magnitude of the NMDA response was approximately doubled in the presence of 100 microM of PS. However, PS did not affect the acetylcholine(Ach)-induced increase in [Ca2+]i. Furthermore, corticosterone had little effect on the GABA- and NMDA-induced Ca2+ increases, indicating that the alteration of the Ca2+ response is specific for PS. In conclusion, it is suggested that PS modulates differentially [Ca2+]i increase induced by GABA and NMDA.

Differential Regulation of Intracellular Signaling Systems by Sodium Fluoride in Rat Glioma Cells

Abstract: We investigated the rapid and slow effects of NaF on intracellular signaling systems such as Ca2+ homeostasis and cyclic GMP (cGMP) generation in rat glioma C6 cells, using the Ca2+‐sensitive dye fura‐2 and cGMP enzyme immunoassay. We found that the following: (a) NaF enhanced cGMP generation in a concentration‐dependent manner. This enhancement was abolished by pretreatment with 100 µM BAPTA tetraacetoxymethyl ester or in the presence of W‐7 in a concentration‐dependent manner. NG‐Monomethyl‐l‐arginine (NMMA), a competitive inhibitor of nitric oxide synthase (NOS), also inhibited the NaF‐induced generation of cGMP. These results suggest that NaF‐induced cGMP generation occurs via a calcium/calmodulin‐ and NOS‐dependent pathway. (b) The basal intracellular Ca2+ concentration ([Ca2+]i) was transiently greater at 1 and 3 h after pretreatment with NaF. W‐7 and W‐13 antagonized the increase in [Ca2+]i, whereas NMMA had little effect. This suggests that the NaF‐induced change in basal [Ca2+]i was mediated by a calmodulin‐dependent pathway but was independent of a NOS‐sensitive pathway. (c) The serotonin (5‐HT)‐induced intracellular mobilization of Ca2+ was reduced by pretreating the cells with NaF. The reduction in Ca2+ mobilization was antagonized by genistein, a tyrosine kinase inhibitor. W‐7, W‐5, and H‐8 had no effect. Results suggest that NaF differentially regulates the cGMP generation, basal [Ca2+]i, and 5‐HT2A receptor function in C6 glioma cells.