Nobutaka Motohashi

GABAB receptors are up-regulated by chronic treatment with lithium or carbamazepine. GABA hypothesis of affective disorders?

The effects of lithium and carbamazepine on GABAA and GABAB receptors were examined. The binding of [3H]muscimol and [3H](-)-baclofen to synaptic membranes from rat brain was used to label GABAA and GABAB receptors, respectively. Neither the [3H]muscimol nor the [3H](-)-baclofen binding site was displaced by lithium or carbamazepine even at a concentration of 100 microM. A single treatment with either of these drugs did not induce any change in [3H]muscimol and [3H](-)-baclofen binding sites in the frontal cortex and hippocampus. [3H](-)-Baclofen binding sites were up-regulated in the hippocampus but not in the frontal cortex following chronic treatment with lithium or carbamazepine. These results suggest that one common mechanism of action of lithium and carbamazepine is mediated by GABAB receptors and that GABA is involved in the pathophysiology of affective disorders.

SEROTONIN-INDUCED PLATELET CALCIUM MOBILIZATION IS ENHANCED IN MANIA

The time-course of 5-HT-induced intracellular Ca2+ mobilization in platelets displays biphasic curves; a rapid peak occurs within 10 sec, followed by a prolonged plateau phase. In platelets of patients with affective disorders, many reports have suggested that there is an increase in the rapid peak in intracellular Ca2+ mobilization, but there is no report concerning the plateau phase in intracellular Ca2+ mobilization. We, then, assessed the time course of 5-HT-induced Ca2+ mobilization to compare untreated manic patients with euthymic bipolar disorders and normal subjects. Not only peak amplitude but also plateau phase were more significantly enhanced in the platelets of untreated manic patients than in those of normal controls. These results suggest that the serotonergic neural transmission by means of intracellular Ca2+ was enhanced by the prolonged plateau phase as well as by increased peak amplitude in platelets of mania. The enhanced rapid peak and plateau phase in untreated bipolar mania were restored to their control levels in treated euthymic bipolar disorders. These findings suggest that the reduction of the enhancement in Ca2+ mobilization might be related to either the effects of chronic treatment with lithium or the affective states of the patients.

Plasma L-tryptophan concentration in major depressive disorder: new data and meta-analysis.

OBJECTIVE Tryptophan, an essential amino acid, is the precursor to serotonin and is metabolized mainly by the kynurenine pathway. Both serotonin and kynurenine have been implicated in the pathophysiology of major depressive disorder (MDD). However, plasma tryptophan concentration in patients with MDD has not unequivocally been reported to be decreased, which prompted us to perform a meta-analysis on previous studies and our own data. DATA SOURCES We searched the PubMed database for case-control studies published until August 31, 2013, using the search terms plasma AND tryptophan AND synonyms for MDD. An additional search was performed for the term amino acid instead of tryptophan. We obtained our own data in 66 patients with MDD (DSM-IV) and 82 controls who were recruited from March 2011 to July 2012. The majority of the patients were medicated (N = 53). Total plasma tryptophan concentrations were measured by the liquid chromatography/mass spectrometry method. STUDY SELECTION We scrutinized 160 studies for eligibility. Original articles that were written in English and documented plasma tryptophan values in patients and controls were selected. DATA EXTRACTION We included 24 studies from the literature and our own data in the meta-analysis, which involved a total of 744 patients and 793 controls. Data on unmedicated patients (N = 156) and their comparison subjects (N = 203) were also extracted. To see the possible correlation between tryptophan concentrations and depression severity, meta-regression analysis was performed for 10 studies with the Hamilton Depression Rating Scale 17-item version score. RESULTS In our case-control study, mean (SD) plasma tryptophan level was significantly decreased in the MDD patients versus the controls (53.9 [10.9] vs 57.2 [11.3] μmol/L; P = .03). The meta-analysis after adjusting for publication bias showed a significant decrease in patients with MDD with a modest effect size (Hedges g, -0.45). However, analysis on unmedicated subjects yielded a large effect (Hedges g, -0.84; P = .00015). We found a weak association with depression severity in the meta-regression analysis (P = .049). CONCLUSIONS This meta-analysis provides convincing evidence for reduced plasma tryptophan levels in patients with MDD, particularly in unmedicated patients.

γ-Aminobutyric acid increases intracellular Ca2+ concentration in cultured cortical neurons: role of Cl− transport

The effect of gamma-aminobutyric acid (GABA) on intracellular Ca2+ concentration ([Ca2+]i) in cultured prenatal rat cortical neurons was investigated using fluorescence imaging. GABA or muscimol, but not baclofen, increased [Ca2+]i in a dose-dependent manner. The GABAA receptor antagonists, bicuculline and picrotoxin, inhibited the GABA response. Furosemide, an inhibitor of the Na+/K+/2Cl- cotransporter, inhibited the GABA response in a noncompetitive manner. Ethacrynic acid, an inhibitor of an ATP-dependent Cl- pump, also inhibited the GABA-induced increased in [Ca2+]i. These results suggest a role for Cl- transport processes in the GABA response. The coapplication of GABA and high K+ led to a non-additive increase in the GABA response. The GABA response was also inhibited by nifedipine, a voltage-gated Ca2+ channel blocker, and abolished by the absence of extracellular Ca2+. Results indicate that the GABA response shares a common pathway of Ca2+ movement with the high K(+)-induced response. These observations suggest that the stimulation with GABA results in Ca2+ influx through voltage-gated Ca2+ channels, and that these effects are dependent on Cl- transport systems.

Acute swim stress increases benzodiazepine receptors, but not GABAA or GABAB receptors, in the rat cerebral cortex

We have examined the effects of swim stress on gamma-aminobutyric acidA (GABAA), GABAB and benzodiazepine (BZD) receptors in synaptic membranes from rat brain. Acute, but not repeated, stress increased the number of BZD receptors in the cerebral cortex. The stress manipulation did not change BZD receptors either in the hippocampus or cerebellum. Furthermore, both GABAA and GABAB receptors did not change in the cerebral cortex, hippocampus or cerebellum after acute and repeated stress. GABA-stimulated BZD binding was not changed following acute or repeated stress. These results suggest that cortical BZD receptors are closely related to responses to acute stress.

Increase in Serotonin 1A Receptors in the Dentate Gyrus as Revealed by Autoradiographic Analysis Following Repeated Electroconvulsive Shock But Not Imipramine Treatment

The effects of repeated treatment with electroconvulsive shock (ECS) and imipramine on [3H]8-OH-DPAT binding to serotonin1A (5-HT1A) receptors in the rat brain were studied by quantitative autoradiographic analysis. A large number of binding sites for [3H]8-OH-DPAT were observed in the hippocampus, especially the dentate gyrus, CA1+CA2 field, dorsal raphe nucleus and septum. Repeated treatment with ECS, but not repeated imipramine treatment, significantly increased [3H]8-OH-DPAT binding sites in the dentate gyrus. These results suggest that the increase in [3H]8-OH-DPAT binding sites in the dentate gyrus may be important in ECS therapy for depressive illness.

TJS-010, a new prescription of oriental medicine, antagonizes tetrabenazine-induced supression of spontaneous locomotor activity in rats

1. The authors have determined the effect of TJS-010, a new prescription of oriental medicine, on the locomotor activity in rats. 2. Tetrabenazine(TBZ) decreased the spontaneous locomotion in rats, and attenuated the contents of amines and increased their metabolism in various regions in rat brain. 3. TJS-010 inhibited the locomotor suppression induced by TBZ: however, neither amine contents nor their metabolism was not altered, which suggested that TJS-010 postsynaptically modulated the transmission or transduction. 4. Imipramine also inhibited the decrease in locomotion induced by TBZ. 5. These results suggest a possibility that TJS-010 has an antidepressive effect.

A questionnaire survey of ECT practice in university hospitals and national hospitals in Japan

Abstract: Although electroconvulsive therapy (ECT) is being performed in many hospitals in Japan, there is little information on its present practice. We surveyed ECT practice to improve the practice of ECT in Japan. A mail questionnaire survey of ECT practice was conducted between 1997 and 1999 in Japan. Of 84 university hospitals and 37 national hospitals, 86 respondents (71%) were obtained. ECT was performed in 56 hospitals (65%). Details of ECT practice were further surveyed in 46 hospitals. The number of patients per year receiving ECT varied according to hospitals from 0.5 to 120. Unmodified ECT was still used in two thirds of the hospitals. Modified ECT was mainly performed in an operating room. Unilateral ECT was seldom used. Japan is an under-developed country for ECT and the practice of ECT must be improved.

Inhibitory effects of lithium ion on intracellular Ca2+ mobilization in the rat hippocampal slices

Lithium is well established as a treatment of manic-depressive illness. As for the mechanism of action of lithium, it is proposed that lithium has effects on intracellular calcium ion (Ca2+) movement. But there are few reports in which the effects of lithium on intracellular Ca2+ movement are observed in the mammalian brain. We therefore examined the effects of lithium on intracellular Ca2+ changes in the rat hippocampal slices with a Ca2+ sensitive dye fura-2, and analyzed by means of a fluorescence microscope, a video-camera and photometrical devices. From the results of treatment with various noradrenergic agonists or antagonists, noradrenaline (NA)-induced intracellular Ca2+ change appears to be mainly mediated by alpha 1-adrenoceptors (AR) rather than alpha 2- or beta-AR. Furthermore, they are considered to be mediated by both alpha 1A-AR and alpha 1B-AR, and to be partly dependent on extracellular Ca2+. Lithium decreased NA-induced intracellular Ca2+ mobilization by attenuation of T1/2 rather than a change in the peak value, and antagonized ouabain-induced intracellular Ca2+ increase. Lithium may therefore suppress intracellular Ca2+ movement by enhancing the extrusion of intracellular Ca2+.

Reduced cerebrospinal fluid ethanolamine concentration in major depressive disorder

Amino acids play key roles in the function of the central nervous system, and their alterations are implicated in psychiatric disorders. In the search for a biomarker for major depressive disorder (MDD), we used high-performance liquid chromatography to measure amino acids and related molecules in the cerebrospinal fluid (CSF) of 52 patients with MDD (42 depressed and 10 remitted; DSM-IV) and 54 matched controls. Significant differences were found in four amino acid concentrations between the depressed patients and controls. After Bonferroni correction, only ethanolamine (EA) levels remained significantly reduced in depressed patients (nominal P = 0.0000011). A substantial proportion of the depressed patients (40.5%) showed abnormally low CSF EA levels (<12.1 μM) (P = 0.000033; OR = 11.6, 95% CI: 3.1–43.2). When patients with low EA and those with high EA levels were compared, the former had higher scores for overall depression severity (P = 0.0033) and ‘Somatic Anxiety’ symptoms (P = 0.00026). In unmedicated subjects, CSF EA levels showed a significant positive correlation with levels of homovanillic acid (P = 0.0030) and 5-hydroxyindoleacetic acid (P = 0.019). To our knowledge, this is the first study showing that patients with MDD have significantly lower CSF EA concentrations compared with control subjects. CSF EA could be a state-dependent biomarker for a subtype of MDD.