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Kamishoyosan (KSS), a Japanese traditional herbal formula, is used to treat symptoms related to the autonomic nervous system in men and women; it is especially known for improving the symptoms of irritability (e.g., bad temper and persistent anger). Although clinical and ethological studies of KSS have been conducted, its efficacy in reducing irritability remains to be validated. In the present study, male and female ddY-strain mice were isolation-reared for 8 weeks (from the third postnatal week) to induce pathologically aggressive biting behavior (ABB), which was used as an indicator of irritability. The ABB of mice toward metal rods was measured using the Aggressive Response Meter. An intraperitoneal administration of KSS (100 mg/kg) effectively reduced ABB in male and female mice at 2 h after the administration; however, this effect was canceled by prior administration of WAY-100635 [a 5-hydroxytryptoamine (5-HT)-1A receptor antagonist; 0.5 mg/kg] and bicuculline (a type-A gamma-aminobutyric acid receptor antagonist; 1.0 mg/kg). Additionally, tamoxifen, ICI-182780, and G-15 (all estrogen receptor antagonists) inhibited the action of KSS in a dose-dependent manner. Furthermore, gene expression of tryptophan hydroxylase (Tph) 1 and Tph2 were increased and 5-HT immunofluorescence was slightly increased in the dorsal raphe nucleus (DRN) of isolation-reared mice administered with KSS. Collectively, these results indicate that KSS effectively reduces ABB in isolation-reared male and female mice through stimulation of 5-HT production in the DRN. Our findings also suggest that gene expression of estrogen receptor (Esr) 2 increased in the DRN might be associated with the reduction of ABB., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Members of expeditions to Antarctica may show changes in biological and physiological parameters involved in lipid, glucose, and thyroid hormone metabolism as they adapt to the environment; however, alterations in amino acid (AA) levels and sleep among expedition members in Antarctica have yet to be fully elucidated. We hypothesized that there would be alterations of blood AA levels, and ornithine (Orn) ingestion would affect biological parameters and sleep in Japanese expedition members during the summer in Antarctica. Japanese Antarctica Research Expedition members (22 people) who stayed in Antarctica for 3 months from December 2010 were examined, and a randomized double-blind study of Orn ingestion (400 mg/d) for 4 weeks was performed. Sleep conditions were evaluated subjectively by the Oguri-Shirakawa-Azumi (brief version) questionnaire. The blood of Japanese Antarctica Research Expedition members in Antarctica showed higher creatine kinase, lactate dehydrogenase, and ammonia levels than that in Japan. On blood AA analysis, aspartate, Orn, and serine were significantly higher, and alanine and tryptophan (Trp) were significantly lower in Antarctica than in Japan. The Trp ratio, the value of Trp divided by the sum of phenylalanine, tyrosine, and branched-chain AAs, was significantly lower in Antarctica than in Japan. Although sleep deteriorated during the stay in Antarctica, Orn ingestion, to some extent, improved sleep compared with the placebo group in Antarctica, suggesting that Orn is effective for people with heavy physical workloads in places such as Antarctica., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: Yokukansan, a traditional Japanese medicine, has been approved by the Ministry of Health, Labour, and Welfare of Japan as a remedy for neurosis, insomnia or night crying and irritability in children. It has recently been reported to improve behavioural and psychological symptoms of dementia, such as hallucinations, agitation, and aggressiveness in patients with some forms of senile dementia. Little is known about the mechanism underlying the effectiveness of yokukansan. Our aim was to clarify the involvement of yokukansan in serotonergic function in para-chloroamphetamine (PCA)-induced aggressive behaviour in rats., Methods: The effect of yokukansan on social interactions, including social and aggressive behaviour, was examined in PCA-injected rats. Concentration and release level of serotonin (5-HT) in the hypothalamus were measured., Key Findings: PCA reduced not only the 5-HT concentration but also the high K(+)-induced 5-HT release in the rat hypothalamus. Social interaction tests showed a significant decrease in social behaviour and a significant increase in aggressive behaviour in the PCA-treated rats. The decrease in social behaviour was ameliorated by the 5-HT1A agonist buspirone and further decreased by a 5-HT1A antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-hexanecarboxamide trihydrochloride (WAY-100635), whereas it was further decreased by the 5-HT2A agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), and ameliorated by the 5-HT2A antagonist ketanserin. On the other hand, the increase in aggressive behaviour was ameliorated by buspirone but not affected by WAY-100635, whereas it was enhanced by DOI and ameliorated by ketanserin. A single injection of yokukansan ameliorated the PCA-induced decrease in social behaviour but not aggressive behaviour. Chronic treatment for 14 days with yokukansan ameliorated PCA-induced abnormal behaviour, decreased social behaviour and increased aggressive behaviour, but it did not ameliorate PCA-induced decreases in the cerebral 5-HT concentration and 5-HT release. The ameliorative effects of chronic yokukansan on behaviour were counteracted by co-administration of WAY-100635., Conclusions: These results suggest that yokukansan might have two different effects: an acute effect on social behaviour and a chronic effect on aggressive behaviour. One of the mechanisms of these effects of yokukansan may be related to the agonistic effect on 5-HT1A receptors.

In social insects, biogenic amines are thought to play regulatory roles in the transition between reproductive states in females. To determine the effect of dopamine on the reproductive development of workers in primitively eusocial societies, isolated workers of the paper wasp Polistes chinensis were supplied with oral dopamine. Ovarian development was accelerated in dopamine-fed workers as compared to control workers of the same age fed only sucrose solution. Oral dopamine increased brain levels of dopamine and its metabolite (N-acetyldopamine). Brain levels of tyramine or octopamine were also increased by dopamine application in one of two colonies; levels of the tyramine metabolite N-acetyltyramine were unchanged. These results indicate that dopamine plays a gonadotropic role in isolated workers in the primitively eusocial wasp, similar to the gonadotropic role previously reported for juvenile hormone. This is the first study to report effects of dopamine on ovarian development in workers of the paper wasp.

The bedtime of preschoolers/pupils/students in Japan has become progressively later with the result sleep duration has become progressively shorter. With these changes, more than half of the preschoolers/pupils/students in Japan recently have complained of daytime sleepiness, while approximately one quarter of junior and senior high school students in Japan reportedly suffer from insomnia. These preschoolers/pupils/students may be suffering from behaviorally induced insufficient sleep syndrome due to inadequate sleep hygiene. If this diagnosis is correct, they should be free from these complaints after obtaining sufficient sleep by avoiding inadequate sleep hygiene. However, such a therapeutic approach often fails. Although social factors are often involved in these sleep disturbances, a novel clinical notion--asynchronization--can further a deeper understanding of the pathophysiology of these disturbances. The essence of asynchronization is a disturbance in various aspects (e.g., cycle, amplitude, phase and interrelationship) of the biological rhythms that normally exhibit circadian oscillation, presumably involving decreased activity of the serotonergic system. The major trigger of asynchronization is hypothesized to be a combination of light exposure during the night and a lack of light exposure in the morning. In addition to basic principles of morning light and an avoidance of nocturnal light exposure, presumable potential therapeutic approaches for asynchronization involve both conventional ones (light therapy, medications (hypnotics, antidepressants, melatonin, vitamin B12), physical activation, chronotherapy) and alternative ones (kampo, pulse therapy, direct contact, control of the autonomic nervous system, respiration (qigong, tanden breathing), chewing, crawling). A morning-type behavioral preference is described in several of the traditional textbooks for good health. The author recommends a morning-type behavioral lifestyle as a way to reduce behavioral/emotional problems, and to lessen the likelihood of falling into asynchronization.

Objectives: High glycemic index (GI) carbohydrates may increase brain serotonin, which in turn acts to alleviate premenstrual symptoms, because, although the main determinant of brain serotonin concentration is a high plasma ratio of tryptophan to other large neutral amino acids, a high-GI diet has been shown to increase this ratio. In this observational cross-sectional study, we investigated associations between dietary GI and other dietary carbohydrates and premenstrual symptoms., Methods: Subjects were 640 female Japanese dietetic students 18-22 y of age. Dietary carbohydrates were assessed using a validated, self-administered, comprehensive diet history questionnaire. Menstrual cycle symptoms were assessed using the retrospective version of the Moos Menstrual Distress Questionnaire (MDQ). Independent associations of dietary GI and glycemic load and intake of available carbohydrate and dietary fiber with the MDQ total score and subscale scores (pain, concentration, behavioral change, autonomic reactions, water retention, and negative affect) in the premenstrual phase (expressed as percentages relative to those in the intermenstrual phase) were examined., Results: Dietary GI was independently inversely associated with total MDQ score in the premenstrual phase (P for trend = 0.02). Dietary GI also showed independent and inverse associations with several MDQ subscale scores in the premenstrual phase, including concentration, autonomic reactions, and water retention (P for trend < 0.05). Conversely, dietary glycemic load and intake of available carbohydrate and dietary fiber were not associated with any of the MDQ scores in the premenstrual phase., Conclusion: Dietary GI was independently associated with decreased premenstrual symptoms in a group of young Japanese women.

Background and Purpose: It is widely accepted that antiplatelet therapy is effective for secondary prevention of atherosclerotic vascular diseases. We performed a double-blind, controlled clinical-pharmacological study to investigate the antiplatelet efficacy of sarpogrelate, a selective 5-hydroxytryptamine (5-HT(2A)) receptor antagonist, in patients with ischemic stroke, using a new assessment system employing combinations of 5-HT and epinephrine as agonists., Methods: Forty-seven patients with ischemic stroke were randomly assigned to three groups: 15 patients received 25 mg sarpogrelate (group L), 16 patients received 50 mg (group M), and 15 patients received 100 mg (group H) orally, three times daily for 7 days. The effect was expressed as maximum intensity of platelet aggregation on the last day of medication. Two combinations of agonists, 0.5 micromol/l 5-HT plus 3 micromol/l epinephrine, and 1 micromol/l 5-HT plus 3 micromol/l epinephrine, were used to induce platelet aggregation., Results: With both combinations of agonists, sarpogrelate treatment inhibited platelet aggregation dose-dependently (p < 0.025, Jonckheere test). In multiple-group comparison, the effect in group H was greater than that in group L or M (p < 0.025, Wilcoxon rank-sum test)., Conclusion: Sarpogrelate treatment inhibited platelet aggregation dose-dependently in patients with ischemic stroke, as judged by a new assessment system employing combinations of 5-HT and epinephrine as agonists.

Serotonin transporter gene (SLC6A4) is one of the most promising candidate genes for psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BP). Two functional polymorphisms, 5HTTLPR and 5HTTVNTR, have been a focus for genetic association analyses; however, no conclusive results have been obtained. We conducted, 1) a mutation search of SLC6A4, 2) LD mapping to select 'tagging' markers (10 SNPs and 5HTTVNTR, while 5HTTLPR was treated as an independent marker because of its allelic form), and 3) association analysis of these 'tagging' markers and independent markers (5HTTLPR and Asn605Lys) with SCZ and BP in Japanese patients. In this mutation search, a nonsynonymous SNP, Asn605Lys, was detected. No associations of 'tagging' markers and independent markers with such conditions were found. These results indicate that SLC6A4 might not play a major role in SCZ and BP in Japanese patients, a finding that agrees with both the common disease-common variant hypothesis and common disease-rare variant hypothesis.

Autism is now widely accepted as a biological disorder which, by and large, starts before birth. It has been shown that serotonin (5-HT) is associated with several psychological processes and hyperserotoninemia is observed in some autistic patients. The results of previous reports about family-based association studies between the serotonin transporter (5-HTT) gene promoter polymorphism and autism are controversial. In this study, an analysis using the transmission/disequilibrium test (TDT) between the 5-HTT gene promoter polymorphism and autism in 104 trios, all ethnically Japanese, showed no significant linkage disequilibrium (P=0.17). Recently, it has been reported that some haplotypes at the serotonin transporter locus may be associated with the pathogenesis of autism. Therefore, further investigations by haplotype analyses are necessary to confirm the implications of genetic variants of the serotonin transporter in the etiology of autism.

Serotonin transporter gene may play a critical role in a regulation of mood and other aspects of mental status. A large number of association studies have investigated a correlation between the polymorphism in the serotonin transporter-linked promoter region (5-HTTLPR) and anxiety-related personality traits. The results, however, have been inconsistent. Heterogeneity of subjects regarding gender, occupation, social-class and other environmental factors, in addition to effects of other genes, might have confounded the results. Here, we studied an association between the 5-HTTLPR polymorphism and personality traits in primarily female (78%) healthy subjects (n=244), who had homogeneous backgrounds regarding ethnicity (Japanese) and occupation. Personality traits of the subjects were assessed with the revised NEO Personality Inventory. No significant association was observed between the polymorphism and neuroticism or other personality traits, in all subjects, all females (n=190) or female nurses (n=159). Thus, our findings provided no evidence for an association between the 5-HTTLPR polymorphism and anxiety-related or other personality traits.

The serotonin (5-HT) system in the brain is a global modulator thought to tune up a unique subset of brain keynotes such as emotion, motivation, and sleep/conscious states in the deepest seats of cognition and behavior. In pursuit for coherent accounts of such higher-order issues, we have been trying to deduce the system dynamics of 5-HT in full span from the perturbation-response couples elicited by our most quick, specific, extensive, and reversible depletion of the brain 5-HT so far available via plasma precursor annihilation by injection of a tryptophan degrading enzyme (TSO) (ISTRY meetings-1986 in Cardiff, -92 in Nagoya and -98 in Hamburg). Herein discussed are the dynamics of the 5-HT depletion both in the whole brain and regional dimensions, and then the perturbation-induced manifestation of a continuous behavioral quiescence underlain by chaotic patterns of sleep/waking states. This response in sharp contrast to those by earlier serotonin depletors, prompts us to consider a serious revision of the current 5-HT scenario. In the light of our research, future directions will be discussed together with the RTD (rapid tryptophan depletion) claiming the impaired brain 5-HT turnover by a partial decline of plasma tryptophan.

Recently two independent research groups consistently reported a significant association between the serotonin transporter (5-HTT) gene and late-onset sporadic Alzheimer's disease (AD). They found that the "short" allele of the 5-HTT gene-linked polymorphic region (5-HTTLPR), which is associated with reduced transcriptional activity of the gene, increases the risk of developing late-onset AD. The present study tried to replicate this finding in a Japanese sample. We genotyped 41 patients with early-onset AD (<65 years), 82 with late-onset AD, and 336 controls. There was no significant difference in genotype or allele distribution between either patient group and controls in our sample, suggesting that the 5-HTTLPR does not play a major role in the pathogenesis of AD in Japanese.

We determined polymorphism in the serotonin (5-HT) transporter gene-linked polymorphic region (5-HTTLPR) in 501 healthy Japanese, individuals, using the polymerase chain reaction of Lesch et al., with minor modifications. The distribution of allele frequencies was determined and found to differ from that in Caucasians. We also investigated the relationship of polymorphism in 5-HTTLPR to anxiety traits, by having 189 of the 501 subjects complete a self-rating questionnaire for anxiety and depression. Subjects with the short/short (s/s) genotype had significantly higher anxiety scores than those with the long/long (l/l) or l/s genotype. It is suggested that populations with the s/s genotype of 5-HTTLPR have stronger anxiety-related personality traits than those with the 1 allele.

A polymorphism in the 5' region of the serotonin transporter gene modulates its transcription efficiency. Its short allele has been reported to be associated with neurotic traits. The serotonin transporter is the action site of selective serotonin re-uptake inhibitors, widely used in the treatment of panic disorder. We examined an association between the polymorphism and panic disorder in a case-control study consisting of 66 Japanese patients and 150 controls. The short allele was significantly more frequent in the Japanese than in Caucasians. The patients and the controls had similar allele frequencies, indicating no association between the polymorphism and panic disorder in most Japanese patients.

There is some evidence suggesting that a polymorphism of variable number of tandem repeats (VNTR) in the second intron of the serotonin transporter (5-HTT) gene and another variation which lies 1.2 kb upstream of the promoter of the gene (5-HTTLPR) are associated with affective disorders. However, conflicting results have also been reported. We examined an allelic association of these two polymorphisms in a Japanese sample of 191 patients with affective disorders (142 bipolar and 49 unipolar) and 212 controls. Substantial differences in the number and frequency of alleles between Caucasians and Japanese were observed for both polymorphisms. A significant association between the VNTR polymorphism and bipolar disorder (genotypic association: odds ratio 2.2, 95% CI 1.2-4.0; allelic association: odds ratio 1.7, 95% CI 1.0-3.0) was found, but not between the 5-HTTLPR polymorphism and bipolar disorder. No significant association with unipolar depression was detected using either genetic marker, although this may be attributable to the relatively small number of subjects with unipolar depression. Our results suggest that the VNTR itself or another unknown functional polymorphism which would be in linkage disequilibrium to the VNTR has an effect on susceptibility to bipolar disorder.

To characterize the structure of Fugu G-protein coupled receptor family and its evolutionary divergence, we have cloned and sequenced the Fugu 5-HT type 1 receptor genes by Polymerase Chain Reaction (PCR) with degenerate primers followed by phage library screening. The analysis of the deduced amino acid sequences showed that F1A alpha and F1A beta have the highest homology to the human 5-HT1A receptor (71.5% and 63.7%, respectively). Another clone, F1D, showed highest (70.5%) homology to the human type 1D receptor. The amino acid residues that are important for ligand binding have been conserved in these Fugu genes. The phylogenetic tree analysis suggests that the duplication event of the Fugu type 1A receptor may have occurred after the divergence of Fugu and the tetrapod lineage.