The wide variability of perospirone metabolism and the effect of perospirone on prolactin in psychiatric patients
○Yutaro Suzuki1. Kazushi Sawamura1,2. Shin Ono1,3. Naoki Fukui1. Takuro Sugai1. Junzo Watanabe1. Nobuto Tsuneyama1,4. Yoshimasa Inoue5. Toshiki Someya,1.
Adjunctive treatment with low-dosage aripiprazole for blonanserin-induced hyperprolactinemia in a female patient with schizophrenia
○Makoto Ishitobi. Hirotaka Kosaka. Ken-ichi Shukunami. Tetsuhito Murata. Yuji Wada.
Hyperprolactinemia is a frequent and severe side effect of antipsychotic treatment. Hyperprolactinemia can cause sexual dysfunction, amenorrhea, infertility, galactorrhea, and osteoporosis. Recently, aripiprazole has been widely reported as effective in the treatment of antipsychotic-induced hyperprolactinemia because of its partial agonistic actions to dopamine D2 receptor with high-affinity. However, to our knowledge, there has been no report showing earlier changes of serum prolactin levels that occur within a week by adjunctive aripiprazole treatment to antipsychotic-induced hyperprolactinemia. Moreover, the minimum dosage of aripiprazole sufficient to improve antipsychotic-induced hyperprolactinemia has not been reported in the literature. We report a case of a 32-year-old female patient with schizophrenia who showed blonanserin-induced hyperprolactinemia (serum prolactin level: 128 μg/ml). A low-dosage aripiprazole (6mg/day) was added to her drug regimen (blonanserin: 24mg/day) to improve blonanserin-induced hyperprolactinemia. Serum prolactin level was declined rapidly 12 hours later and normalized within five days by adjunctive low-dosage aripiprazole treatment. Her breast pain and galactorrhea was improved 10 days after the initiation of aripiprazole without worsening psychotic symptoms.Based on this case report, it is suggested that adjunctive low-dosage aripiprazole is sufficient for early improvement of antipsychotic-induced hyperprolactinemia.
Change in the expressions of myelination/oligodendrocyte- related genes during puberty in the rat brain
○Tadasu Matsuoka. Tomiki Sumiyoshi. Masahiko Tsunoda. Michio Suzuki. Masayoshi Kurachi.
Promoted expression of glia-derived neurotrophic factor in cultured rat cortical astrocytesexposed to nicotine
○Hirofumi Kawagoe. Takeshi Takarada. Yukio Yoneda
This study was aimed to elucidate the mechanisms underlying in vivo neuroprotection by nicotine. RT-PCR revealed constitutive expression of mRNA for ten different nAChR subunits in cultured rat cortical astrocytes. Nicotine selectively induced mRNA expression of GDNF amongst different neurotrophic factors, in addition to promoting the release, in astrocytes. Nicotine significantly increased the luciferase activity in cortical astrocytes transfected with the luciferase reporter plasmid linked to GDNF promoter. MTT reduction was significantly decreased in cultured rat cortical neurons exposed to H2O2, while the decreased vitality was rescued after the culture with conditioned medium from astrocytes previously exposed to nicotine. These results suggest that nAChRs may be functionally expressed by rat cortical astrocytes to promote the synthesis and release of GDNF through transactivation toward neuroprotection.
New functional variant in SLC6A4 gene as candidate of the individualized treatment of depression -The result of RCT-
○ Masaki Kato1. Masataka Wakeno1. Yoshiteru Takekita1. Gaku Okugawa1. Shinpei Nounen2. Shinji Tetsuo3. Shiho Sakai1. Junichi Azuma2. Toshihiko Kinoshita1.
The variability in antidepressant response is due to therapeutic agents and genetic factors. Among genetic factors, 5-HTTLPR was the most widely studied for its effect to SSRI. Among therapeutic agents, each antidepressants have own profile and could be influenced differently by 5-HTTLPR. Actually, in our previous RCT, we found fluvoxamine (FLV) was significantly less effective than paroxetine (PAX) in the S/S carrier (p=0.013), but not in the L carriers. Recently, another SNP rs25531A/ G within L allele was reported to robustly affect 5-HTTLPR expression. Therefore we aimed to compare the effects of PAX and FLV taking the individual background in rs25531 polymorphism as well as 5-HTTLPR into account. A total of 100 Japanese depressed patients were enrolled in a randomized 6-week study and genotyped to discriminate between L and S alleles, followed by the A to G substitution. The clinical response was evaluated using the Hamilton Rating Scale for Depression was assessed at each visit. The low-expression S and LG alleles were grouped together as S' compared with the high-expression LA allele as L'. This triallelic polymorphism was associated with HAM-D score change in total sample (p=0.04). Subsequent comparison of PAX and FLV in each genotype group, FLV was significantly less improved compared to PAX in S'carrier on the HAM-D change over time (P=0.0002), while not in L'carrier. The stratification following rs25531A/G within the 5-HTTLPR L variant could lead the precise comparative analysis and the individualized medication in treatment of depression.
Effects of liquiritigenin and iso-liquiritigenin, which are isolated from Glycyrrhiza, on a menopausal depressive-like state in ovariectomized mice
○Lyttle Kerise1. Noriko Yamada2. Hiroyuki Yoshimura1
Hormone replacement therapy is known to manifest serious adverse effects on menopausal women, and therefore the development of alternative therapy has received great interest. It was reported recently that the Glycyrrhiza radix, which is used for the treatment of menopausal syndrome in traditional Chinese medicine, has an estrogenic component, liquiritigenin which is a β-estrogen receptor agonist. As we found that bilateral ovariectomy produced the menopausal depressive-like state in female mice, we investigated whether or not liquiritigenin alleviates the menopausal depressive-like state in female mice, comparing with isoliquiritigenin. Female ICR mice (9 weeks of age) were ovariectomized and chronic liquiritigenin and isoliquiritigenin at four dose levels, (0, 2.5, 5.0, 7.5 mg/kg/day) administered orally for 14 days. We determined both the immobility time in the forced swimming test and the general motor activity in a neutral cage. Liquiritigenin shortened the ovariectomyinduced prolongation of immobility time in a dose-dependent manner without causing motor dysfunction. Contrast to this, liquiritigenin did not affect the duration of immobility time in intact female mice. On the other hand, isoliquiritigenin, isomer of liquiritigenin, did not show any significant effects on the immobility time. These results suggest that liquiritigenin has an antidepressant effect on the menopausal depressivelike state in female mice.
Psychopharmacological identifi cation of a new antidepressant-like component, (E)-9,10-dihydroxy-2-decenoic acid, from Honeybee royal jelly
○Hiroyuki Yoshimura 1,4. Noriko Yamada 2,4. Naoko Bekku3,4
The treatment of menopausal depression with estrogen alone or in combination with progesterone has adverse effects on cardiovascular diseases and uterine and breast cancers. These side effects warrant the development of new therapies. Most antidepressants have been preclinically evaluated in male animals without regard to gender differences. We recently developed a procedure for predicting drug effects on the menopausal depression-like state of female mice. Using this animal model, we evaluated the effect of honeybee royal jelly (RJ), which is known to promote good health in older women, on the depression-like state of female mice following ovariectomy. As an index of depression, the period of immobility during forced swimming tests was used. Crude RJ and an isolated ingredient, (E)-9,10-dihydroxy-2-decenoic acid (DDA:C10H18O4), improved the performance in swimming tests but did not affect general motor activity, suggesting that the improvement was not due to augmented motor behaviour. Neither RJ nor DDA altered the uterine weight of ovariectomized mice, and it was different from the effect of chronic estrogen treatment regimens. Another component isolated from RJ, trans-10-hydroxy-2-decenoic acid, failed to show a significant effect in our model. At present, the yield of DDA from crude lyophilized RJ powder is 0.004%, and chemical synthesis of DDA from malic acid is the subject of ongoing studies. These findings may lead to new therapies for preventing or treating mood disorders in perimenopausal women.
Involvement of the sigma receptor in in anti-immobility effects of fluvoxamine in mice
○Yumi Sugimoto1. Kumiko Saitoh2. Yoshiro Hotta2. Noriko Tagawa3. Yoshiharu Kobayashi3. Jun Yamada1
We previously found mice strain differences in immobility time and sensitivity to the selective serotonin reuptake inhibitor (SSRI) fluvoxamine in the forced swimming test, which is the evaluation method for antidepressants. Although it was reported that SSRIs are less effective in the forced swimming test, we found that in DBA/2 mice, fluvoxamine induced clear anti-immobility effects. Recently it has been reported that fluvoxamine has an affinity with sigma receptors and that sigma recpeotrs may be involved in pharmacological effects of fluvoxamine. In this study, therefore, we studied involvement of sigma receptors in anti-immobility effects elicited by fluvoxamine. Male DBA/2 mice were used in all experiments. Forced swimming test was performed following the method of Porsolt et al. Immobility was recorded during a 6-min swimming test. Fluvoxamine was administered i.p. Fluvoxamine induced apparent antiimmobility effects in DBA/2 mice without affecting locomotor activity. Anti-immobility effects of fluvoxamine were significantly antagonized by the sigma1 receptor antagonist BD 1047. We previously found that antiimmobility effects of fluvoxamine are mediated by the 5-HT1A receptors, since the selective 5-HT1A receptor antagonist WAY 100635 inhibited anti-immobility effects of fluvoxamine. Our present results suggest that antidepressant-like effects of fluvoxamine may be also involved in the sigma1 receptor in addition to the 5-HT1A receptor.
Studies on drug dependence (Rept. 443): Research for the molecular mechanisms underlying sleep disturbance induced by chronic treatment wit SSRI and SNRI
○ Rahmadi Mahardian. Minoru Narita. Satoshi Imai. Naoko Kuzumaki. Tsutomu Suzuki
Recent reports has shown that SSRI and SNRI in acute or chronic treatment cause unpleasant side effects to the patients, In the present study, using electroencephalography (EEG) and electromyography (EMG), we found that chronic treatment with paroxetine and milnacipran significantly induced sleep disturbance, which was characterized by the increased in total wake time and decreased total NREM sleep. Furthermore, RTPCR analysis demonstrated that chronic treatment with paroxetine or milnacipran significantly increased the mRNA expressions of 5HTT, NET and DAT, orexin receptor 1 and 2 in the mouse hypothalamus. Moreover, chronic treatment with paroxetine or milnacipran upregulates the H1R and HDC mRNA expressions in the frontal cortex of mice. In contrast, chronic treatment with paroxetine or milnacipran failed to affect the mRNA expressions of serotonin receptor (5-HTR) 1a, 2a, 2c, 3a, 4 and 7 in both hypothalamus and frontral cortex of mice. In conclusion, the present findings suggest that chronic treatment with either paroxetine or milnacipran causes sleep disturbance associated with the increased orexinergic transmission in the hypothalamus and histaminergic transmission in the frontal cortex. Although further studies are still needed, these imbalances of orexinergic, histaminergic and monoaminergic neurotransmission may, at least in part, be responsible for the side effects such as sleep disturbance induced by chronic treatment with SSRI or SNRI in rodents.
Improving Data Quality Throughout the Course of Global Alzheimer's Trials
○David Miller1. Cynthia McNamara1,2. Sarah Podolin1,2. Morihiro Sugishita3
Background: Challenges exist to both adequately train potential investigators and to ensure their proper administration and scoring of the efficacy instruments over the course of global Alzheimer's disease clinical trials. Methods: Relatively inexperienced potential raters received enriched training on the primary efficacy instruments (ADAS-Cog and ADCS-ADL) and were required to successfully rate videotaped patient interviews on both scales in advance of the general Investigators' Meeting (IM). At that IM, they along with all potential raters received additional training and were required to certify on additional videos. Once certified to rate, all raters participated in a proprietary ratings surveillance program designed to identify and remediate any nonadherence to ADAS-Cog and MMSE administration and scoring conventions during the trial. Results of remediations are reviewed by region, degree and whether the rater received enriched training. Results: Previous research noted comparable initial certification rates for enriched vs. general raters. Of 1271 raters, 36% held a doctorate, and 20% required enriched training. Remediation rates did not differ significantly by education. In all 6 geographical regions, remediation rates between those who received enriched training vs. those who did not were comparable. In all regions, the ADAS-Cog required remediation more often than the MMSE. Conclusion: Enriched training results in raters who perform equally well to more experienced raters in terms of initial certification and needing remediation in trial. Further analysis is warranted.
Responsiveness of Ifrd1 as a differentiation regulator in neural progenitors to brain ischemia
○Shiho Konishi. Takeshi Takarada. Yukio Yoneda.
We have identified interferon-related developmental regulator-1 (Ifrd1) as the gene responsible for predominant astroglial differentiation in neural progenitor cells isolated from adult mouse hippocampus. In the mouse embryonic carcinoma P19 cells endowed to differentiate into neuronal and astroglial cells, marked but transient expression was at first seen in MAP2 mRNA within 8 days in culture, followed by Ifrd1 mRNA expression in line with GFAP mRNA later. In P19 cells with transient overexpression of Ifrd1 expression vector, a significant decrease was found in MAP2 mRNA expression. MCAO for 2 h induced a rapid but transient increase in Ifrd1 mRNA expression in ipsilateral mouse cerebral hemisphere immediately after reperfusion, along with delayed increases in mRNA levels of HO-1, xCT and nestin within 24 h. These results suggest that Ifrd1 may promote astroglial differentiation of neural progenitors with a role in mechanisms associated with the pathogenesis of ischemic brain damage at an early pathological stage in adult mice.
Regulation by ryanodine receptors of proliferative activity in neural stem/ progenitor cells derived from subventricular zone of adult mice
○Tatsuo Shiba. Masanori Yoneyama. Kiyokazu Ogita
Subventricular zone (SVZ) of adult brain has neural stem/progenitor cells (NPCs) that generate new neurons throughout life. In the NPCs, intracellular Ca2+ is known to play a critical role in regulating different stages of early brain development and neurogenesis. To elucidate participation of Ca2+ signaling pathway in proliferation of the NPCs, we evaluated the effect of the ryanodine receptor (RyR) blocker dantrolene on proliferative activity in the NPCs derived from the SVZ of adult mice. Cells were prepared from the SVZ of 5-week-old male mice and then primarily cultured in DMEM/F12 medium with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) for 8 days in vitro (DIV). After replating, the cells were secondarily cultured for 5 DIV under the same conditions in the absence or presence of dantrolene. To determine the expression of RyR subunits in the NPCs, we performed RT-PCR analysis using total RNA prepared from the NPCs. Although there exist 3 subunits of RyR in the NPCs, RyR3 level was the highest. ELISA for 5'-bromo-2'- deoxyuridine revealed that a marked decrease in the proliferative activity was seen by treatment with dantrolene in a dose-dependent manner. However, dantrolene was ineffective in releasing lactate dehydrogenase into the culture medium. Moreover, treatment with dantrolene resulted in a marked reduction in STAT3 and Pax6 mRNA in the NPCs. These results suggest that Ca2+ release from the endoplasmic reticulum via the RyR would positively regulate proliferative activity in the NPCs of adult mouse SVZ.
The effectiveness and safety of blonanserin in drugnaive patients with schizophrenia: An open label trial
○Takashi Oshimo. Hitoshi Takahashi. Jun Ishigooka
Objective: The purpose of this study is to investigate the effectiveness and safety of blonanserin in drug-naive patients with schizophrenia. Methods: A total of 12 patients were enrolled in an open-label 12-week study. Dosing was determined by clinical judgment. The main efficacy were measured in the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Change (CGI-C). Patients with＞50% reduction in PANSS total score plus a final CGI-S score of ≦3(mildly ill) were considered as responders. Results: Of 12 subjects, 2 subjects dropped out before assessment, 10subjects were assessed as an intent-to-treat sample. The mean dosage of blonanserin was 4.2mg/day (SD, 2.0) at last observation. The responder rate was 90% (9/10). Akathisia was the most frequent side effect (20%[2/10]), being tolerated by reducing the dosage of blonanserin. Body weight and metabolic parameters such as cholesterol triglycerides and fasting glucose did not change, however only plasma prolactine level mildly elevated during this study. Conclusions: Based on this experience with blonanserin, which did not have a overly sedating effect and had clearly antipsychotic effects, there is a possibility that it could become the preeminent drug for treating drug-naive schizophrenia. More evidence, however, is required in the form of studies of larger numbers of cases following long-term use.
Lurasidone in the Treatment of Acute Schizophrenia: Results of the Double-Blind, Placebo-Controlled PEARL 2 Trial
○Masaki Kato1. Herbert Meltzer2. Josephine Cucchiaro3. Masaaki Ogasa3. Amir Kalali4. Antony Loebel3
Objective: To evaluate short-term efficacy and safety of lurasidone in patients with acute schizophrenia.
Effi cacy and Safety of Lurasidone in Schizophrenia: Results of a Phase 2, Placebo-Controlled, Study
○Yoshiteru Takekita1. Masaaki Ogasa2. Mitsutaka Nakamura3. Josephine Cucchiaro2. Antony Loebel2
Objective: To evaluate the safety and efficacy of lurasidone in patients with an acute exacerbation of schizophrenia. Methods: Patients were randomized to 6 weeks of double-blind treatment with a fixed dose of lurasidone 80 mg or placebo. Patients remained in the hospital until Day 28, after which they could be discharged at the discretion of the investigator. The primary efficacy measure was the BPRSd from the PANSS. The protocol was approved by institutional review boards at each site. Study conduct was consistent with the Declaration of Helsinki.
Silent extrapyramidal syndrome induced by aripiprazole
○Michiaki Morita. Satoshi Kawamura. Hisatsugu Miyata. Youhei Hiruma. Kazuhiko Nakayama
Aripiprazole is the first developed antipsychotic to act as a dopamine D2 receptor partial agonist with a low risk of extrapyramidal syndrome (EPS). We report a case in which aripiprazole induced a unique profile of EPS characterized by a depression-like state without any typical motor dysfunctions. Among various types of depression-like states that can appear in the course of schizophrenia, "akinetic depression" is known to be associated with akinesia, which may resemble major depression phenomenologically and is difficult to distinguish from PPD. The depression-like state observed in the present patient was also difficult to distinguish from PPD, and showed rapid amelioration upon administration of promethazine. The antihistamininergic action of promethazine produces a sedative effect that could have contributed to amelioration of the depression-like state seen in this case. However, this possibility seems unlikely because of the extremely rapid improvement that was observed. The most plausible explanation for this recovery was the anticholinergic effect of promethazine, suggesting that the depressionlike state in the present case, as well as "akinetic depression", belongs to the category of EPS. This is the first report to indicate that aripiprazole may induce a so-called "silent EPS" characterized by a depression-like state in patients with intrinsic vulnerability. The subject was assured that all her personal information would be confidential and written informed consent was obtained.
Reductions of polypharamacies of antipsychotic drugs with high dose in Japan; results from the REAP-3 study
○Wakako Nakano1. Reiji Yoshimura1. Shu-yu Yang2. Naotaka Shinfuku3. Senta Fujii4. Tsutomu Hoshuyama5. Kang Sim6. Mian-Yoon Chong7. Chay Hoon Tan8. Jun Nakamura1
Objectives: The Research on Asian Psychotropic Prescription (REAP) project, a pharmacoepidemiological cross-sectional survey has been previously conducted in 2001 and 2004 in six regions in Asia. The survey performed in 2001 demonstrated that the polypharmacy of first-generation antipsychotic drugs (FGA) with high dose were still popular in Japan. Subsequently, the survey in 2004 elucidated that the prescription of second-generation antipsychotic drugs (SGA) was gradually increased. In the present study, we performed the third survey in 2008, as a part of REAP-3 project, to elucidate the changes in prescription patterns of antipsychotic drugs in Japan.Methods: Japanese inpatients who met a diagnosis of schizophrenia according to the ICD-10 or DSM-IV were assessed regarding social and clinical characteristics, doses of all psychotropic medications prescribed and adverse effects of medications. Results: A total of 1724 patients (2001:627; 2004:583; 2008:514) were evaluated. There was a significant increase in the uses of the SGA (2001: 50.4%; 2008: 85.0%) in Japan. Also, there was a significantly decrease in the amount of daily doses of chlorpromazine equivalence from 2001to 2008 (2001: 909.2±846.9 mg; 2008: 637.4±511.5mg). Polypharmacies of antipsychotic drugs were significantly decreased from 2001 to 2008 (2001: 78.6%; 2008: 60.9%). Conclusions: Polypharamacies of antipsychotic drugs with high doses have been gradually changed in Japan.
Action of aripiprazole, its metabolite and experimental dopamine partial agonists at human dopamine D2 and D3 receptors
○Yoshihiro Tadori. Tetsuro Kikuchi
Aripiprazole is the first dopamine D2 receptor partial agonist approved in the world for the treatment of schizophrenia. Aripiprazole's partial agonist activity has been claimed to predict its clinical efficacy and favorable side-effect profile. Its success may promote development of novel partial agonists for the treatment of psychiatric disorders. We conducted an in vitro comparative analysis between aripiprazole, its human metabolite OPC-14857, RGH-188, its metabolite didesmethyl- RGH-188 (DDM-RGH-188), bifeprunox, and SDZ 208-912. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal CHO cell lines expressing D2S, D2L, D3 Ser-9 and D3 Gly-9 of human dopamine receptors. All test compounds behaved as dopamine D2/D3 receptors partial agonists. Aripiprazole's intrinsic activities at dopamine D2S and D2L receptors were similar to that of OPC-14857 and RGH-188, lower than that of dopamine and bifeprunox, and higher than that of DDM-RGH-188 and SDZ 208-912. Aripiprazole's intrinsic activities at dopamine D3 Ser-9 and D3 Gly-9 receptors were similar to that of OPC- 14857, lower than that of dopamine, bifeprunox, RGH-188 and DDMRGH- 188, and higher than that of SDZ 208-912. These findings may help to guide the efforts of drug discovery with regard to defining the most appropriate magnitude of intrinsic activities at dopamine D2 and D3 receptors for successful development of psychotropic agents.
Behavioral pharmacology of plant-derived substances (23): Effects of essential oils on ambulation in mice. Comparison with their effects on Shuttle type conditioned avoidance response
Our previous study that used Shuttle type conditioned avoidance response in mice revealed that some essential oils (EOs) possess psychostimulants like properties and others do depressants like properties. The current study was conducted to further examine these notions using ambulatory activity, a kind of spontaneous motor activity, since psychostimulants increase ambulatory activity of mice and depressants decrease the activity. Ambulatory activities of male ICR mice were measured using a tilt-type ambulometer. Mice were individually placed in bucket-like activity cages. 30 minutes later, various doses of various kinds of Eos were intraperitoneally administered to the mice, followed by 60 minutes continuous measurements of ambulatory activities. Frankincense, Cypress, Niaouli, Basil, Rosemary, Majoram, Geranium, Rosewood and Myrtle did not produce significant effects on mouse ambulation. Peppermint and Thyme increased ambulation. These results were compared with results of Shuttle type conditioned avoidance response to clarify pharmacological properties of EOs.
Behavioral changes and neural regeneration after hippocampal dentate injury in mice
○Yukari Nakayama1. Asako Yokoi1. Maki Tokuda1. Sarina Okamoto1. Makoto Shuto2. Masanori Yoneyama1. Kiyokazu Ogita1
Our previous study showed that trimethyltin chloride (TMT) causes neuronal loss in the hippocampal dentate gyrus selectively 2 days later, with recovery of the dentate gyrus 7 days afterward. To confirm neural regeneration after hippocampal dentate injury, in this study, we examined behavioral changes and NMDA receptor signals in the dentate granule cells newly generated after neuronal damage induced by TMT. TMT (2.8 mg/kg) was i.p. injected into ddY male mice and then NMDA (100 mg/kg) was injected on days 7 and 28 after TMT injection. TMT treatment led to a significant decrease in the levels of NMDA receptor subunits (NR1, NR2A, and NR2B) in the dentate gyrus on day 2 to 7, with recovery of the levels at least on day 28 after treatment. NMDA-induced tail biting behavior was significantly attenuated on day 7 after TMT treatment, compared to that in naive animals. On day 28 after TMT treatment, however, NMDAinduced behavioral changes were similar to those in naive animals. In addition, NMDA-induced expression of c-Fos in the dentate granule cells was decreased on day 7, and it was completely abolished on day 28 after TMT treatment. No significant change in locomotor activity was seen at least until day 56 after TMT treatment. However, forced swimming test revealed that depressive behavior was observed on day 14 after TMT treatment. Taken together, the dentate gyrus would be capable of regenerating functionally after the neuronal loss in mice. However, a transient depressive symptom could take place during neural regeneration after hippocampal dentate injury.
Lithium decreases VEGF mRNA expression in leukocytes of healthy subjects and bipolar patients
○Junichi Iga. Kumiko Kikuchi. Masahito Nakataki. Shinya Watanabe. Syusuke Numata. Tetsuro Ohmori Department of Psychiatry, University of Tokushima School of Medicine, Tokushima, Japan
Vascular endothelial growth factor (VEGF) is thought to be involved in the pathophysiology of mood disorders and the target of antidepressants, however the relationship between the molecular effects of lithium and VEGF is less known. The aim of this study is to elucidate molecular effects of lithium on VEGF expression using leukocytes of healthy subjects and patients with bipolar disorder.8 healthy male subjects participated in the first study. Lithium was prescribed for 2 weeks enough to reach therapeutic serum concentration (0.6-1.0mM). Leukocyte counts and serum lithium concentrations were determined at baseline (before medication), 1-week, 2-week medication and post-2-week (2-week after stopping medication). VEGF mRNA levels in leukocytes were determined at each time point by real-time PCR. VEGF mRNA levels were also examined in 9 lithium-treated bipolar patients and age- and sex- matched healthy controls in the second study. All subjects signed an informed consent form. In the first study, leukocyte counts were significantly increased at 2-week compared with baseline and normalized at post-2-week. VEGF mRNA levels were significantly decreased at 2-week and at post-2-week compared with baseline. There were no correlations between VEGF expression and either leukocyte counts or serum lithium concentration. Consistent with the first study, VEGF mRNA levels were significantly decreased in the lithium-treated bipolar patients compared with healthy controls.Our investigation suggests that molecular action of lithium may be mediated in part by its effects on VEGF.
No association between polymorphisms of Brain-derived neurotrophic factor (BDNF) Val66Met and psychiatric symptoms in systemic lupus erythematosus
○Atsuko Ikenouchi-Sugita1. Reiji Yoshimura1. Taro Kishi2. Wakako Umene-Nakano1. Asuka Katsuki1. Kazuyoshi Saito3. Nakao Iwata2. Yoshiya Tanaka3. Jun Nakamura1.
Background: Brain-derived neurotrophic factor (BDNF) plays an important role in the regulation of synaptic plasticity and neurotransmitter release across multiple neurotransmitter systems. Recent studies have suggested that BDNF plays a role in the pathogenesis of psychiatric symptoms in patients with systemic lupus erythematosus (SLE). Objectives: We hypothesized that the polymorphism of BDNF Val66Met is associated with the emergence of psychiatric symptoms (PS) and serum BDNF levels in SLE patients. To examine the hypothesis, we compared the BDNF Val66Met polymorphism and serum BDNF levels in patients with SLE with or without PS. Methods: Psychiatric symptoms were assessed in 54 patients with SLE. PS were evaluated using the Brief Psychiatric Rating Scale (BPRS). Genotyping was carried out using a 54-nuclease assay. Serum BDNF levels were measured by ELISA. Results: The presence of the Met allele was not significantly associated with the presence of psychiatric symptoms, or with serum BDNF levels in patients with SLE. Conclusion: Our data do not support the common variant Val66Met of the BDNF gene as an etiologic factor in the various forms of PS and serum BDNF levels in SLE.
Risperidone in the treatment of corticosteroid-induced mood disorders in systemic lupus erythematosus: a case series
○Katsuji Nishimura. Masako Omori. Jun Ishigooka
Little has been reported on the treatment of corticosteroid-induced mood disorders (CIMDs) in systemic lupus erythematosus (SLE). The authors describe the use of risperidone in the treatment of CIMDs in 5 female inpatients with SLE, accompanied by manic features in 3 patients, and mixed features in 2. The CIMDs developed in a mean of 13.2 days (range, 2-28 days) of corticosteroid administration. The mean dosage of corticosteroids administered was 52.0 mg/day (range, 40-60 mg/day) as prednisolone. The mean score of the Young Mania Rating Scale (YMRS) at baseline was 28.6 points (range, 20-43 points). Risperidone was started at a mean of 2.2 mg/day (range, 1-4 mg/day). Two weeks later, the YMRS score was decreased to a mean of 6.4 points (range, 2-8 points). During this period the corticosteroid dosage was the same as that at baseline. All CIMDs in these 5 patients were resolved completely during the following reduction in corticosteroid dosage and risperidone was discontinued. The mean dosage of corticosteroids at this time was 28.6 mg/day (range, 15- 45 mg/day) as prednisolone. These 5 patients tolerated risperidone well. There were no evidences of central nervous system manifestation of SLE or secondary causes (e.g., infection or metabolic derangement) in these patients. Although the dosage reduction of corticosteroids may contribute to the ultimate resolution of CIMDs, results of this study show risperidone to be beneficial in the treatment of CIMDs in patients with SLE.
Role of phosphodiesterase 4 in dopamine D1 receptor/cAMP/PKA signaling in the frontal cortex
○Mahomi Kuroiwa. Takahide Syutou. Akinori Nishi
Dopamine plays an important role in the regulation of psychic and cognitive functions in the frontal cortex. The effect of dopamine is largely mediated through the cAMP/PKA signaling cascade, and therefore phosphodiesterase (PDE) is likely involved in the action of dopamine. Multiple PDEs with different substrate specificity and subcellular localization are expressed in neurons. PDE4B has been reported to associate with schizophrenia as it interacts with the disrupted in schizophrenia 1 (DISC1) protein. In this study, we investigated the effects of a PDE4 inhibitor, rolipram, on the phosphorylation of PKA substrates including DARPP-32 in the frontal cortex. The inhibition of PDE4 by rolipram upregulates D1 receptor/cAMP/PKA signaling in cortical pyramidal neurons, leading to the phosphorylation of DARPP-32 at Thr34, GluR1 at Ser845, and other postsynaptic and presynaptic PKA-substrates in slices and in vivo. The inhibition of PDE4 improves cognitive functions as measured with PPI. In neural circuitry involved in PPI, relatively selective upregulation of D1 receptor/cAMP/PKA/DARPP-32 signaling in the frontal cortex by rolipram seems to be required for the enhancement of PPI. Thus, the PDE4 inhibitor regulates biochemical and behavioral functions related to dopamine D1 receptor signaling in the frontal cortex, which can be a part of antipsychotic actions of the inhibitor.
Translocation of glutamine transporter expressed in C6 glioma cells
○Aya Sako. Masato Ogura. Noritaka Nakamichi. Takeshi Takarada. Yukio Yoneda
In glutamatergic neurons, the neurotransmitter glutamate is recycled through the glutamine (Gln)/glutamate cycle that involves Gln transporter (GlnT) responsible for the incorporation of extracellular Gln. We have shown the functional expression of GlnT in astrocytes isolated from rat cerebral cortex and hippocampus, in addition to neurons. In cultured cortical astrocytes, transient overexpression of GlnT led to significant exacerbation of the cytotoxicity of H2O2 on MTT assays. In rat astrocytic C6 glioma cells with stable overexpression of GlnT, similarly, a drastic decrease was seen in cellular viability after the exposure to H2O2 when determined by MTT assays and PI staining. In these stable transfectants, GlnT was rather ubiquitously distributed throughout all cellular components, while exposure to H2O2 led to translocation of immunoreactive GlnT into membrane components close to adjacent cells. These results suggest that GlnT may be a determinant of the vulnerability to active oxygen stress through altered translocation in astroglia.
Association between GIRK3 gene polymorphisms and postoperative analgesic requirements after major abdominal surgery
○Daisuke Nishizawa1. Makoto Nagashima2. Ryoji Katoh2. Yasuo Satoh3. Megumi Tagami3. Shinya Kasai1. Yasukazu Ogai1. Junko Hasegawa1. Masakazu Hayashida4. Kazutaka Ikeda1
Opioids are commonly used as effective analgesics for the treatment of acute and chronic pain. However, considerable individual differences have been widely observed in sensitivity to opioids. We focused on a G-proteinactivated inwardly rectifying potassium (GIRK) channel subunit, GIRK3, that is an important molecule in opioid signal transmission, and examined genetic polymorphisms. In our initial polymorphism search, a total of ten singlenucleotide polymorphisms (SNPs) were identified in the whole exon, 5'-flanking, and exon-intron boundary regions of the GIRK3 gene. A total of 112 patients who underwent major open abdominal surgery in hospitals were recruited as the subjects in the association study with written informed consent. The study protocol was approved by the Institutional Review Board at each related Institute. In an association study, carrying T alleles in the C1781T SNP and in the C1817T SNP were significantly associated with decreased postoperative 24-h analgesic requirements. The total dose (mean±SEM) of rescue analgesics converted to equivalent fentanyl doses was 1.10±0.23 and 0.61±0.11 μg/kg for the C/C and combined C/T and T/T genotypes in the C1781T SNP, respectively (p=0.035), and 1.00±0.16 and 0.40±0.10 μg/kg for the C/C and combined C/ T and T/T genotypes in the C1817T SNP, respectively (p=0.002). The results indicate that these SNPs could serve as markers that predict decreased analgesic requirements. Our findings will provide valuable information for achieving satisfactory pain control and open new avenues for personalized pain treatment.