Antinociception Induced by Moringa Stenopetela (Baker f.) Cufod. Leaves Extract and Possible Mechanisms of Action

Moringa stenopetala (Baker f.) Cufod., is an endemic species growing in the south of Ethiopia. M. stenopetala is often consumed as food and used in traditional medicine and it has also been traditionally used for relieving of pain in Ethiopia. This study aimed to investigate the antinociceptive effect and mechanisms of action of M. stenopetala leaves methanol extract in mice. The per-oral doses of 50, 100, and 200 mg/kg of M. stenopetala extract were tested for antinociceptive action by using hot-plate, tail-immersion, and writhing tests. The possible mechanisms of in the antinociceptive action were investigated by pre-treatment with 5 mg/kg naloxone (non-selective opioid antagonist), 1 mg/kg ketanserin (5-HT2A/2C receptor antagonist), and 1 mg/kg yohimbine (α2 adrenoceptor antagonist). The methanol extract of M. stenopetala showed antinociceptive effect in all tests. The significant involvement of 5-HT2A/2C receptors and α2 adrenoceptors in antinociception induced by M. stenopetala extract in the hot-plate and tail-immersion tests, as well as significant contribution of opioid receptors and α2 adrenoceptors in writhing test, were identified. In conclusion, these findings demonstrate that the methanol extract of M. stenopetala has potential in pain management. Thisstudywillcontributetonewtherapeuticapproachesandprovideguidancefornewdrug development studies.

Lower limb muscle strength and serotonin receptor gene polymorphism as factors associated in women with fibromyalgia

Abstract Background: Fibromyalgia (FM) is a chronic pain syndrome characterized by generalized skeletal muscle chronic pain. Its etiology is not well defined, because there are several factors that may trigger it such as physical and/or emotional stresses, or a genetic susceptibility, involving serotonergic, dopaminergic and catecholaminergic paths. The objective of this study was to investigate the association between the strength of the lower limb, genetic polymorphism of the serotonin receptor gene HTR2a in women with fibromyalgia. Methods: In this observational study of case-control type 48 women were evaluated who belonged to the group with FM (52 ± 12 years) and 100 women in the control group (58±11 years). Socio demographic and anthropometric data were collected and peripheral blood samples for DNA extraction; genotypic analyzes were performed by means of PCR in real time by TaqMan® system. The lower limb muscle strength was assessed through the test of sitting down and standing up for 30 s. The chi-square test or Fischer Exact was used for possible associations among the variables; the t-test for independent samples was used to compare the averages among the groups; the value of significance adopted was 5%. Results: There was an association between the polymorphism of the HTR2A gene with FM, demonstrating that carriers of the genotype GG have 24.39 times more likely to develop the syndrome (IC95% 5.15-115.47; p = 0.01). It was observed an association between FM and the test to sit and stand up demonstrating that women with fibromyalgia have lower limb muscle strength ( p = 0.01). The study showed that the white race has 3.84 times more likely to develop FM (p = 0.01). Conclusion: The results of this study suggest that women of Caucasian ethnicity with GG genotype or G allele presented greater risk of developing fibromyalgia and that these patients have lower limb muscle strength compared to the control group.

The Role of Serotonin in Ventricular Repolarization in Pregnant Mice

PURPOSE: The mechanisms underlying repolarization abnormalities during pregnancy are not fully understood. Although maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant for normal fetal development in mice, its role in mothers remains unclear. We evaluated the role of serotonin in ventricular repolarization in mice hearts via 5Htr3 receptor (Htr3a) and investigated the mechanism of QT-prolongation during pregnancy. MATERIALS AND METHODS: We measured current amplitudes and the expression levels of voltage-gated K⁺ (Kv) channels in freshly-isolated left ventricular myocytes from wild-type non-pregnant (WT-NP), late-pregnant (WT-LP), and non-pregnant Htr3a homozygous knockout mice (Htr3a(−/−)-NP). RESULTS: During pregnancy, serotonin and tryptophan hydroxylase 1, a rate-limiting enzyme for the synthesis of serotonin, were markedly increased in hearts and serum. Serotonin increased Kv current densities concomitant with the shortening of the QT interval in WT-NP mice, but not in WT-LP and Htr3a(−/−)-NP mice. Ondansetron, an Htr3 antagonist, decreased Kv currents in WT-LP mice, but not in WT-NP mice. Kv4.3 directly interacted with Htr3a, and this binding was facilitated by serotonin. Serotonin increased the trafficking of Kv4.3 channels to the cellular membrane in WT-NP. CONCLUSION: Serotonin increases repolarizing currents by augmenting Kv currents. Elevated serotonin levels during pregnancy counterbalance pregnancy-related QT prolongation by facilitating Htr3-mediated Kv currents.

Association of Serotonin Receptors with Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-analysis / 华中科技大学学报（医学）（英德文版）

Attention deficit hyperactivity disorder (ADHD) is one of the most common mental disorders in childhood,with a high heritability about 60％ to 90％.Serotonin is a monoamine neurotransmitter.Numerous studies have reported the association between the serotonin receptor family (5-HTR) gene polymorphisms and ADHD,but the results are still controversial.In this study,we conducted a meta-analysis of the association between 5-HTR1B,5-HTR2A,and 5-HTR2C genetic variants and ADHD.The results showed that the 861G allele of 5-HTR1B SNP rs6296 could significantly increase the risk of ADHD (OR=1.09,95％ CI:1.01-1.18);the 5-HTR2C gene rs518147 (OR=1.69,95％ CI:1.38-2.07) and rs3813929 (OR =1.57,95％ CI:1.25-1.97) were all associated with the risk of ADHD.In addition,we also carried on a casecontrol study to explore the relevance between potential candidate genes 5-HTR 1 A,5-HTR1E,5-HTR3A and ADHD.The results indicated that 5-HTR1A rs6295 genotype (CC+CG vs.GG OR=2.00,95％ CI:1.23-3.27) and allele (OR=1.77,95％ CI:1.16-2.72) models were statistically significantly different between case group and control group.This study is the first comprehensive exploration and summary of the association between serotonin receptor family genetic variations and ADHD,and it also provides more evidence for the etiology of ADHD.

Association of Serotonin Receptors with Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-analysis / 华中科技大学学报（医学）（英德文版）

Attention deficit hyperactivity disorder (ADHD) is one of the most common mental disorders in childhood,with a high heritability about 60％ to 90％.Serotonin is a monoamine neurotransmitter.Numerous studies have reported the association between the serotonin receptor family (5-HTR) gene polymorphisms and ADHD,but the results are still controversial.In this study,we conducted a meta-analysis of the association between 5-HTR1B,5-HTR2A,and 5-HTR2C genetic variants and ADHD.The results showed that the 861G allele of 5-HTR1B SNP rs6296 could significantly increase the risk of ADHD (OR=1.09,95％ CI:1.01-1.18);the 5-HTR2C gene rs518147 (OR=1.69,95％ CI:1.38-2.07) and rs3813929 (OR =1.57,95％ CI:1.25-1.97) were all associated with the risk of ADHD.In addition,we also carried on a casecontrol study to explore the relevance between potential candidate genes 5-HTR 1 A,5-HTR1E,5-HTR3A and ADHD.The results indicated that 5-HTR1A rs6295 genotype (CC+CG vs.GG OR=2.00,95％ CI:1.23-3.27) and allele (OR=1.77,95％ CI:1.16-2.72) models were statistically significantly different between case group and control group.This study is the first comprehensive exploration and summary of the association between serotonin receptor family genetic variations and ADHD,and it also provides more evidence for the etiology of ADHD.

Glucosylsphingosine Activates Serotonin Receptor 2a and 2b: Implication of a Novel Itch Signaling Pathway

Recent reports claimed that glucosylsphingosine (GS) is highly accumulated and specifically evoking itch-scratch responses in the skins of atopic dermatitis (AD) patients. However, it was unclear how GS can trigger itch-scratch responses, since there were no known molecular singling pathways revealed yet. In the present study, it was verified for the first time that GS can activate mouse serotonin receptor 2a (mHtr2a) and 2b (mHtr2b), but not 2c (mHtr2c) that are expressed in HEK293T cells. Specifically, effects of GS on all mouse serotonin receptor 2 subfamily were evaluated by calcium imaging techniques. The GS-induced intracellular calcium increase was dose-dependent, and antagonists such as ketanserin (Htr2a antagonist) and RS-127445 (Htr2b antagonist) significantly blocked the GS-induced responses. Moreover, the proposed GS-induced responses appear to be mediated by phospholipase C (PLC), since pretreatment of a PLC inhibitor U-73122 abolished the GS-induced responses. Additionally, the GS-induced calcium influx is probably mediated by endogenous TRPC ion channels in HEK293T cells, since pretreatment of SKF-96365, an inhibitor for TRPC, significantly suppressed GS-induced response. In conclusion, the present study revealed for the first time that GS can stimulate mHtr2a and mHtr2b to induce calcium influx, by utilizing PLC-dependent pathway afterwards. Considering that GS is regarded as a pruritogen in AD, the present study implicates a novel GS-induced itch signaling pathway.

Ondansetron Inhibits Voltage-Gated K⁺ Current of Ventricular Myocytes from Pregnant Mouse

BACKGROUND: The Htr3a antagonist, ondansetron, has been reported to prolong the QT interval and induce Torsades de pointes in the treatment of postoperative nausea and vomiting. To explore the mechanisms underlying these findings, we examined the effects of ondansetron on the mouse cardiac voltage-gated K⁺ (Kv) channel. METHODS AND RESULTS: Ondansetron increased QT intervals in late pregnant (LP) mice. We measured the Kv channels in freshly isolated left ventricular (LV) myocytes from non-pregnant (NP) and late pregnant (LP) mice, using patch-clamp electrophysiology. Ondansetron blocked Kv current at a dose of 50 µM, and reduced the amplitude of peak current densities in a dose-dependent manner (0, 1, 5, 50 µM), in LP but not in NP mice. In contrast, serotonin and the Htr3 agonist, m-CPBG, increased Kv current densities in NP, but not in LP mice. Interestingly, during pregnancy, serum serotonin levels were markedly increased, suggesting the saturation of the effect of serotonin. Immunostaning data showed that Kv4.3 protein and Htr3a co-localize at the membrane and t-tubule of cardiomyocytes. Moreover, Kv4.3 membrane trafficking was enhanced in response to Htr3a-mediated serotonin stimulation in NP, but not in LP mice. Membrane analysis showed that serotonin enhances Kv4.3 membrane trafficking in NP, but not LP mice. CONCLUSION: Ondansetron reduced Kv current densities, and reduced the Kv4.3 membrane trafficking in LP mouse ventricular cardiomyocytes. This data suggests that QT prolongation by ondansetron is mediated by the reduction of Kv current densities and Kv4.3 membrane trafficking.

A family-based association study of the HTR1B gene in eating disorders

Objective: To explore the association of three polymorphisms of the serotonin receptor 1Dβ gene (HTR1B) in the etiology of eating disorders and their relationship with clinical characteristics. Methods: We analyzed the G861C, A-161T, and A1180G polymorphisms of the HTR1B gene through a family-based association test (FBAT) in 245 nuclear families. The sample was stratified into anorexia nervosa (AN) spectrum and bulimia nervosa (BN) spectrum. In addition, we performed a quantitative FBAT analysis of anxiety severity, depression severity, and Yale-Brown-Cornell Eating Disorders Scale (YBC-EDS) in the AN and BN-spectrum groups. Results: FBAT analysis of the A-161T polymorphism found preferential transmission of allele A-161 in the overall sample. This association was stronger when the sample was stratified by spectrums, showing transmission disequilibrium between the A-161 allele and BN spectrum (z = 2.871, p = 0.004). Quantitative trait analysis showed an association between severity of anxiety symptoms and the C861 allele in AN-spectrum participants (z = 2.871, p = 0.004). We found no associations on analysis of depression severity or preoccupation and ritual scores in AN or BN-spectrum participants. Conclusions: Our preliminary findings suggest a role of the HTR1B gene in susceptibility to development of BN subtypes. Furthermore, this gene might have an impact on the severity of anxiety in AN-spectrum patients.

Associations between Serotonergic Genes and Escitalopram Treatment Responses in Patients with Depressive Disorder and Acute Coronary Syndrome: The EsDEPACS Study

Genes related to serotonin are associated with responses to treatment for depression. We examined associations between the serotonin transporter (5-HTT) and serotonin 2a receptor (5-HTR2a) genes and responses to treatment for depressive disorders in acute coronary syndrome (ACS). A total of 255 patients who met the DSM-IV major or minor depressive disorder and recently developed ACS were randomly assigned to the escitalopram (n=127) or placebo (n=128) group in this 24-week double-blind trial (ClinicalTrial.gov identifier: NCT00419471). Remission was defined as a Hamilton Rating Scale for Depression (HAMD) score < or =7. Assays were performed for the 5-HTTLPR, STin2 VNTR, 5-HTR2a 102T/C, and 5-HTR2a 1438A/G genotypes. Escitalopram was superior to placebo for treating depressive disorder with ACS but there were no significant associations between serotonergic genes and treatment responses even when considering ACS severity. The effect of escitalopram was independent of 5-HTT and 5-HTR2a polymorphisms.

Advances in antidepressants based on the regulation of serotonin receptors / 中国药科大学学报

@#The etiology and pathogenesis of depression is complex, the regulation of serotonin signaling pathway is one of the most important mechanisms for commercially available antidepressants. In addition to serotonin transporter, recent studies have shown many other serotonin receptor subtypes also play an important role in the treatment of depression, which has become one of the hot topics of antidepressants. Therefore, the progress of serotonin receptors and new structure with the activity of regulating serotonin receptors as well as part of the structure-activity relationships are reviewed in this paper in order to provide reference for the further research and development of antidepressants.

Association of serotonin transporter (SLC6A4) & receptor (5HTR1A, 5HTR2A) polymorphisms with response to treatment with escitalopram in patients with major depressive disorder : A preliminary study.

Background & objectives: Genetic factors have potential of predicting response to antidepressants in patients with major depressive disorder (MDD). In this study, an attempt was made to find an association between response to escitalopram in patients with MDD, and serotonin transporter (SLC6A4) and receptor (5HTR1A, 5HTR2A) polymorphisms. Methods: Fifty five patients diagnosed as suffering from MDD, were selected for the study. The patients were treated with escitalopram over a period of 6-8 wk. Severity of depression, response to treatment and side effects were assessed using standardised instruments. Genetic variations from HTR1A (rs6295), HTR2A (rs6311 and rs6313) and SLC6A4 (44 base-pair insertion/deletion at 5-HTTLPR) were genotyped. The genetic data of the responders and non-responders were compared to assess the role of genetic variants in therapeutic outcome. Results: Thirty six (65.5%) patients responded to treatment, and 19 (34.5%) had complete remission. No association was observed for genotype and allelic frequencies of single nucleotide polymorphisms (SNPs) among remitter/non-remitter and responder/non-responder groups, and six most common side-effects, except memory loss which was significantly associated with rs6311 (p=0.03). Interpretation & conclusions: No significant association was found between the SNPs analysed and response to escitalopram in patients with MDD though a significant association was seen between the side effect of memory loss and rs6311. Studies with larger sample are required to find out genetic basis of antidepressant response in Indian patients.

Effects of sleep deprivation on the gene expression of 5-serotonin 1A receptor and dopamine 2 receptor in different brain regions of rats / 中华行为医学与脑科学杂志

Objective To analyze the influence of sleep deprivation on expression of serotonin receptor 1A(5-HT1A) and dopanine-2 receptor (D2R) gene and to explore the differences between different neurotransmitter pathways involved in sleep regulation through measuring the gene expression of 5-HT1A and D2R in regions of hippocampus,hypothalamus and striatum with different sleep deprivation models.Methods Sleep deprivation was performed to male SD rats of 10-week-old for 24 hours,48 hours and 72 hours respectively as the experimental group and a control group was taken for comparison.The expressions of 5-HT1A and D2R gene in regions of hippocampus,hypothalamus and striatum were detected through RT-PCR technique to analyze the influence of sleep deprivation on gene expression in different regions.Results Sleep deprivation had a significant effect on the gene expression of 5-HT1A in regions of hippocampus and striatum(F=56.203,P＜0.01 ; F=77.288,P＜0.01).The three experimental groups were all superior to the control group and the difference was of statistic significance(P＜0.05).In the hippocampus region,the expression quantity of the 72 hours group(0.618±0.054) was superior to that of the 24 hours group and of the 48 hours group(24 hours:0.404±0.023,P＜0.01 ;48 hours:0.455±0.042.P＜0.05).In the striatum region,the differences between the 24 hours group(0.413±0.033),the 48 hours group(0.464±0.034)and the 72 hours group(0.610±0.040) were all of statistic significance(all P＜0.05).Sleep deprivation had a significant effect on the expression of D2R gene in regions of hippocampus and striatum(F=74.708,P＜0.01 ; F=80.687,P＜0.01).The expression quantity of the three experimental groups in regions of hippocampus (24 hours:0.386±0.027,48 hours:0.318±0.014,72 hours:0.250±0.010) and striatum(24 hours:0.396±0.013,48 hours:0.349±0.017,72 hours:0.260±0.013) were all inferior to the control group.The differences were of statistic significance (all P＜0.05).There was a negative correlation between the gene expressions of 5-HT1A and D2R of rats of the three experience groups(all P＜0.05).Conclusion For the sleep deprivation rats,the gene expression of 5-HT1A rises while that of D2R falls in regions of hippocampus,hypothalamus,and there is a negative correlation between the expressions of the two genes.

Antiallodynic effects of intrathecal tianeptine in a neuropathic pain rat

BACKGROUND: Tianeptine is an antidepressant drug which is used for treating depression. Interestingly, the tianeptine has shown antinociceptive effects within a variety of nociceptions. The aim of this study is to investigate the antiallodynic effects of tianeptine in neuropathic pain rats and also determine the involvements of serotonergic, alpha-2 adrenergic and adenosine receptors at the spinal level. METHODS: Neuropathic pain was induced by ligation of left lumbar at 5th and 6th spinal nerves in male Sprague-Dawley rats. PE-10 catheters were placed into the thoracolumbar subarachnoid space for drug injections. Mechanical allodynia was evaluated by measuring the withdrawal threshold to von Frey filament when applying on the plantar surface of rats. The effects of intrathecal tianeptine were observed at 15, 30, 60, 90, 120, 150, 180 minutes after delivery. Antagonists for serotonergic (dihydroergocristine), alpha-2 adrenergic (yohimbine) and adenosine (CGS 15943) receptors were intrathecally administered 10 minutes prior to tianeptine in order to evaluate the involvement of both receptors. RESULTS: Intrathecal tianeptine increased dose-dependently at the withdrawal threshold in the ligated paw. Pretreatment with intrathecal dihydroergocristine, yohimbine and CGS 15943 antagonized the antiallodynic effects of tianeptine. CONCLUSIONS: These results suggested that intrathecal tianeptine attenuates the spinal nerve ligation induced tactile allodynia. Serotonergic, alpha-2 adrenergic and adenosine receptors are all involved in the antiallodynic effects of tianeptine at the spinal level.

No association between the HTR1A gene and suicidal behavior: a meta-analysis / A não associação entre o gene HTR1A e comportamento suicida: uma metanálise

OBJECTIVE: Dysfunction of serotonin 1A receptors (HTR1A) may play a role in the genesis of suicidal behavior. We studied the association between a functional polymorphism in the HTR1A gene and suicidal behavior. METHOD: We performed a meta-analysis of published genetic association studies by searching through Medline, PubMed, and Web of Science databases to analyze a possible correlation between the rs6295 polymorphism and suicidal behavior in different populations. RESULTS: Four studies comprising a total of nine hundred and fifty seven patients with suicidal behavior and nine hundred and fifty seven controls were the eligible. The G allele of the rs6295 polymorphism may not be associated with suicidal behavior (Random-effects model: OR = 1.08; 95 percent CI: 0.80-1.45; p(Z) = 0.80) in presence of heterogeneity (Q = 17.84, df = 4, p = 0.0013). In a second analysis that presented no heterogeneity, a negative association was also observed (OR = 0.94; 95 percentCI: 0.79-1.13; p(Z) = 0.99). CONCLUSION: To our knowledge, the present study is the first meta-analysis searching for a correlation between rs6295 of HTR1A and suicidal behavior. Our results showed no association between HTR1A and suicidal behavior. However, more studies assessing different populations, as well as larger samples, are needed.

OBJETIVO: É possível que uma disfunção nos receptores 1A de serotonina (HTR1A) desempenhe um papel na origem do comportamento suicida. Estudamos a associação entre um polimorfismo funcional no gene HTR1A e comportamento suicida. MÉTODO: Realizamos uma metanálise de estudos de associação genética já publicados através de uma busca nos banco de dados do Medline, PubMed e Web of Science para identificar uma possível correlação entre o polimorfismo rs6295 e comportamento suicida em diferentes populações. RESULTADOS: Foram selecionados quatro estudos com um total de 957 pacientes com comportamento suicida e 957 controles. O alelo G do polimorfismo rs6295 não pôde ser associado a comportamento suicida (modelo de efeitos aleatórios: OR = 1,08; 95 por centoCI: 0,80-1,45; p(Z) = 0,80) na presença de heterogeneidade (Q = 17,84, df = 4, p = 0,0013). Em uma segunda análise, sem heterogeneidade, também foi observada uma associação negativa (OR = 0,94; 95 por centoCI: 0,79-1,13; p(Z) = 0,99). CONCLUSÃO: Pelo que nos consta, trata-se da primeira metanálise cujo objetivo é identificar uma correlação entre o polimorfismo rs6295 do HTR1A e comportamento suicida. Os nossos resultados não demonstraram existir uma correlação entre o HTR1A e comportamento suicida. No entanto, são necessários estudos adicionais que incluam outras populações, assim como amostras maiores.

Endophenotypes and serotonergic polymorphisms associated with treatment response in obsessive-compulsive disorder

OBJECTIVES: Approximately 40-60% of obsessive-compulsive disorder patients are nonresponsive to serotonin reuptake inhibitors. Genetic markers associated with treatment response remain largely unknown. We aimed (1) to investigate a possible association of serotonergic polymorphisms in obsessive-compulsive disorder patients and therapeutic response to selective serotonin reuptake inhibitors and (2) to examine the relationship between these polymorphisms and endocrine response to intravenous citalopram challenge in responders and non-responders to serotonin reuptake inhibitors and in healthy volunteers. METHODS: Patients with obsessive-compulsive disorder were classified as either responders or non-responders after long-term treatment with serotonin reuptake inhibitors, and both groups were compared with a control group of healthy volunteers. The investigated genetic markers were the G861C polymorphism of the serotonin receptor 1Dβ gene and the T102C and C516T polymorphisms of the serotonin receptor subtype 2A gene. RESULTS: The T allele of the serotonin receptor subtype 2A T102C polymorphism was more frequent among obsessive-compulsive disorder patients (responders and non-responders) than in the controls (p<0.01). The CC genotype of the serotonin receptor subtype 2A C516T polymorphism was more frequent among the non-responders than in the responders (p<0.01). The CC genotype of the serotonin receptor subtype 1Dβ G681C polymorphism was associated with higher cortisol and prolactin responses to citalopram (p<0.01 and p<0.001, respectively) and with a higher platelet-rich plasma serotonin concentration among the controls (p<0.05). However, this pattern was not observed in the non-responders with the same CC genotype after chronic treatment with serotonin reuptake inhibitors. This CC homozygosity was not observed in the responders.

Improving the voding dysfunction by a 5-HT1A receptor agonist in rats with chronic spinal cord injury / 中华泌尿外科杂志

Objective To investigate the effect of 5-hydroxytryptamine serotonin receptor-1A (5-HT1 A) agonists on micturition dysfunction in rats with chronic spinal cord injury (SCI).Methods Female SD rats weighing 175 -200 g were used.Seven of the rats were modified for a spinal cord injury model (transsection at T10).Eight weeks later,control rats and SCI rats were tested.Rats were anesthetized with urethane ( 1.3 g/kg ).A polyethylene (PE) -50 catheter was placed in the left jugular vein for intravenous drug administration.A PE-90 catheter was inserted through the bladder dome,and the other end of the bladder catheter was connected to a syringe pump for continuous infusion of saline and to a pressure transducer for intravesical pressure monitor.Dose-response curves for 8-OH-DPAT were followed by the WAY-100635 test.The capacity,residual volume,micturition volume,and EUS-EMG were measured.Results With an increasing dose of 8-OH-DPAT,the capacity of the bladder decreased from 33.2 ± 8.3 ml to 22.8 ± 2.4 ml.The micturition volume was increased from 0.14 ± 0.08 ml to 0.38 ± 0.09 ml.The residual volume decreased from 3.68 ± 1.36 ml to 1.84 ± 0.21 ml,and peak intravesical pressure changed from 27.1 ± 3.6 mm Hg to 22.8 ± 2.4 mm Hg.Control rats showed little significant change in the cystometric variable.Effects of 8-OH-DPAT were reversed by WAY-100635.That 8-OH-DPAT induced phasic relaxation occured in spinal cord-injured rats but the control group showed no significant change.ConclusionsThe 5-HTIA/7 receptor agonist 8-OH-DPAT may induce periodic EUS relaxation during voiding in urethane-anesthetized chronic spinal cordinjured rats.And this could result in an increase in micturition volume,a decrease in bladder capacity,and thus an increase in voiding efficiency.

Association study between genetic monoaminergic polymorphisms and OCD response to clomipramine treatment / Estudo de associação entre polimorfismos genéticos monoaminérgicos e resposta à clomipramina no tratamento do TOC

In the present paper, we investigated the 5HTTLPR and STin2 polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4), the G861C polymorphism (rs6296) of the serotonin receptor 1D beta (HTR1B), the T102C (rs6113) and C516T (rs6305) polymorphisms of the serotonin receptor gene subtype 2A (HTR2A), the DAT UTR, DAT intron 8 and DAT intron 14 of the dopamine transporter gene (SLC6A3), the Val-158-Met (rs4680) polymorphism of the COMT and the silent mutation G1287A (rs5569) in the norepinephrine transporter gene (SLC6A2). We genotyped 41 obsessive-compulsive disorder (OCD) outpatients, classified as good-responders (n=27) and poor-responders (n=14) to treatment with clomipramine according to the Yale Brown Obsessive-Compulsive Scale (YBOCS). Patients who achieved a reduction in symptoms of 40 percent or more in YBOCS after 14 weeks of treatment were considered good-responders. Genotypes and alleles distribution of the investigated polymorphisms were compared between both groups. We did not find association between the studied polymorphisms and clomipramine response in our sample.

No presente estudo, investigaram-se os polimorfismos 5HTTLPR e STin2 da região promotora do gene transportador de serotonina (SLC6A4), o G861C (rs6296) do receptor de serotonina 1D beta (HTR1B), os polimorfismos T102C (rs6113) e C516T (rs6305) do gene do receptor da serotonina subtipo 2A (HTR2A), os polimorfismos UTR, intron 8 e intron 14 do gene transportador de dopamina (SLC6A3), o Val-158-Met (rs4680) da COMT e a mutação G1287A (rs5569) do gene do transportador de norepinefrina (SLC6A2). Foram genotipados 41 pacientes com transtorno obsessivo-compulsivo (TOC), classificados como bons-respondedores (n=27) e maus-respondedores (n=14) ao tratamento com clomipramina, por meio do uso da Escala de Sintomas Obsessivos-Compulsivos Yale Brown (YBOCS). Foram considerados bons-respondedores os pacientes que tiveram redução nos sintomas em 40 por cento ou mais na YBOCS, após 14 semanas de tratamento. A distribuição dos genótipos e alelos estudados foi comparada entre os dois grupos. Não foi encontrada associação entre estes polimorfismos investigados e a resposta à clomipramina na amostra estudada.

Polimorfismos dos genes do receptor de serotonina (5-HT2A) e da catecol-O-metiltransferase (COMT): fatores desencadeantes da fibromialgia? / Serotonin receptor (5-HT 2A) and catechol-O-methyltransferase (COMT) gene polymorphisms: Triggers of fibromyalgia?

INTRODUÇÃO: A fibromialgia é uma síndrome reumática caracterizada por dor difusa e crônica associada a fadiga, insônia, ansiedade, depressão, perda de memória e tontura. Embora os mecanismos fisiológicos que controlam a fibromialgia não tenham sido estabelecidos, fatores neuroendócrinos, genéticos ou moleculares podem estar envolvidos. OBJETIVO: O objetivo do presente estudo foi caracterizar os polimorfismos dos genes do receptor de serotonina (5-HT2A) e da catecolO-metiltransferase (COMT) em pacientes brasileiros com fibromialgia, a fim de avaliar sua participação na etiologia da doença. MATERIAL E MÉTODOS: O DNA genômico extraído de 102 amostras de sangue (51 pacientes, 51 controles) foi usado para a caracterização molecular dos polimorfismos dos genes 5-HT2A e COMT, por meio de PCR-RFLP. RESULTADOS: A análise molecular dos polimorfismos do gene 5-HT2A demonstrou frequências de 25,49 por cento C/C, 49,02 por cento T/C e 25,49 por cento T/T, nos pacientes com fibromialgia, e 17,65 por cento C/C, 62,74 por cento T/C e 19,61 por cento T/T, no grupo controle, não apresentando diferença significativa entre o grupo de pacientes e o grupo controle. Os polimorfismos do gene da COMT em pacientes com fibromialgia apresentaram uma frequência de 17,65 por cento e 45,10 por cento para os genótipos H/H e L/H, respectivamente. No grupo controle, as frequências foram de 29,42 por cento, para H/H, e 60,78 por cento, para L/H, sem diferença significativa entre ambos os grupos. Entretanto, houve diferença significativa na frequência do genótipo L/L em pacientes (37,25 por cento) e controles (9,8 por cento), o que permitiu a diferenciação entre os dois grupos. CONCLUSÃO: A frequência do genótipo L/L foi maior nos pacientes com fibromialgia. Apesar de a fibromialgia envolver uma situação poligênica e fatores ambientais, o estudo molecular do SNP rs4680 do gene da COMT pode auxiliar a identificação de indivíduos suscetíveis.

INTRODUCTION: Fibromyalgia is a rheumatic syndrome characterized by diffuse and chronic pain associated with fatigue, sleep disorders, anxiety, depression, memory loss, and dizziness. Although the physiological mechanisms that control fibromyalgia have not been precisely established, neuroendocrine, genetic or molecular factors may be involved in fibromyalgia. OBJECTIVE: The aim of the present study was to characterize serotonin receptor (5-HT2A) and catecholO-methyltransferase (COMT) gene polymorphisms in Brazilian patients with fibromyalgia and to evaluate the participation of these polymorphisms in the etiology of the disease. MATERIAL AND METHODS: Genomic DNA extracted from 102 blood samples (51 patients, 51 controls) was used for molecular characterization of the 5-HT2A and COMT gene polymorphisms by PCR-RFLP. RESULTS: Analysis of the 5-HT2A polymorphism revealed a frequency of 25.49 percent C/C, 49.02 percent T/C and 25.49 percent T/T in patients, and of 17.65 percent C/C, 62.74 percent T/C and 19.61 percent T/T in the control group, with no differences between the two groups.Analysis of the COMT polymorphism in patients showed a frequency of 17.65 percent and 45.10 percent for genotypes H/H and L/H, respectively. In the control group the frequency was 29.42 percent for H/H and 60.78 percent for L/H, also with no differences between the two groups. However, there was a significant difference in the frequency of the L/L genotype between patients (37.25 percent) and controls (9.8 percent), which permitted differentiation between the two groups. CONCLUSION: The L/L genotype was more frequent among fibromyalgia patients. Though considering a polygenic situation and environmental factors, the molecular study of the rs4680 SNP of the COMT gene may be helpful to the identification of susceptible individuals.

Effects of Genetic and Environmental Factors on the Depression in Early Adulthood

OBJECTIVES: The authors purposed to present data for explaining gene-environmental interaction causing depressive disorder by examining the effects of genetic factors related to the serotonin system and environmental factors such as stressful life events in early adulthood. METHODS: The subjects were 150 young adults(mean age 25.0+/-0.54), a part of 534 freshmen who had completed the previous study of genotyping of TPH1 gene. We assessed characteristics of life events, depression and anxiety scale and checked if they had a depressive disorder with DSM-IV SCID interview. Along with TPH1 A218C genotype confirmed in previous study, TPH2 -1463G/A and 5HTR2A -1438A/G genes were genotyped using the SNaPshotTM method. RESULTS: In comparison with the group without C allele of TPH1 gene, the number of life events had a significant effect on the probability of depressive disorder in the group with C allele. Other alleles or genotypes did not have a significant effect on the causality of life events and depressive disorder. CONCLUSION: The results of this study suggest that TPH1 C allele is a significant predictor of onset of depressive disorder following environmental stress. It means that the TPH1 gene may affect the gene-environmental interaction of depressive disorder.

Is there an association between T102C polymorphism of the serotonin receptor 2A gene and urinary incontinence?

The regulation of bladder function is influenced by central serotonergic modulation. Several genetic polymorphisms related to serotonin control have been described in the literature. T102C polymorphism of the serotonin receptor 2A gene (5-HT2A) has been shown to be associated with certain diseases such as non-fatal acute myocardial infarction, essential hypertension, and alcoholism. In the present study, we examined the association between 5-HT2A gene polymorphism and urinary incontinence in the elderly. A case-control study was performed in 298 elderly community dwellers enrolled in the Gravataí-GENESIS Project, Brazil, which studies gene-environmental interactions in aging and age-related diseases. Clinical, physical, biochemical, and molecular analyses were performed on volunteers. 5-HT2A genotyping was determined by PCR-RFLP techniques using the HpaII restriction enzyme. The subjects had a mean age of 68.05 ± 6.35 years (60-100 years), with 16.9 percent males and 83.1 percent females. The C allele frequency was 0.494 and the T allele frequency was 0.506. The CC genotype frequency was 21.78 percent, the CT genotype frequency was 55.24 percent and the TT genotype frequency was 22.98 percent. We found an independent significant association between the TT genotype (35.7 percent) and urinary incontinence (OR = 2.06, 95 percentCI = 1.16-3.65). Additionally, urinary incontinence was associated with functional dependence and systolic hypertension. The results suggest a possible genetic influence on urinary incontinence involving the serotonergic pathway. Further investigations including urodynamic evaluation will be performed to better explain our findings.