OBJECTIVE: The aim of this study was to investigate five polymorphisms in the SLC6A4 gene in patients with recurrent aphthous stomatitis (RAS) and healthy controls. DESIGN: Totally, 239 subjects were enrolled in this case-control study: 86 patients with RAS and 153 healthy individuals were genotyped for serotonin transporter length polymorphic region (5-HTTLPR) polymorphism, variable number tandem repeat (STin2) and single nucleotide polymorphisms (rs25531, rs3813034, rs1042173) in the SLC6A4 gene by polymerase chain reaction with/without restriction analysis. RESULTS: No significant differences in the allele or genotype frequencies in all studied polymorphisms between RAS patients and healthy controls (P > 0.05) were detected. However, the haplotype analysis detected a higher frequency of LA12 (HTTLPR, rs25531, STin2) haplotype in RAS patients in comparison with healthy controls (P < 0.05, OR = 1.63, 95 % CI = 1.07-2.49). CONCLUSIONS: Our study indicates a possible relationship between SLC6A4 and susceptibility to RAS in the Czech population.

• Klíčová slova
• Polymorphism, Recurrent aphthous stomatitis, SLC6A4, Serotonin transporter gene,
• MeSH
• aftózní stomatitida * genetika   MeSH
• frekvence genu MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• membránové transportní proteiny pro serotonin * genetika   MeSH
• recidiva MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• membránové transportní proteiny pro serotonin * MeSH
• SLC6A4 protein, human MeSH Prohlížeč

Both serotonin and the serotonin transporter, which transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons, play an important role in the pathophysiology of several psychiatric disorders. Mutations associated with the serotonin transporter gene may result in changes in serotonin transporter function. The serotonin transporter gene promoter variant, consisting of a long (L) and a short (S) variant, is one of the major factors which contribute to the etiology of many psychiatric disorders. In this regard, many studies have been published on association of this variant with various psychiatric disorders. This repeat length variant in the promoter region of this gene has been shown to affect the rate of serotonin uptake and may play a role in post-traumatic stress disorder and depression-susceptibility in people experiencing emotional trauma. Associations between a functional variant in the serotonin transporter anxiety-related personality traits were found, as well as the risk of developing depression, alcoholism or suicidal behavior. Understanding of possible associations of these variants and psychiatric disorders would bring progress in principles and treatment of many disorders.

• MeSH
• alkoholismus genetika   MeSH
• chování sebezraňující genetika   MeSH
• dítě MeSH
• duševní poruchy genetika   MeSH
• genetická predispozice k nemoci MeSH
• lidé MeSH
• membránové transportní proteiny pro serotonin genetika   MeSH
• mutantní proteiny fyziologie   MeSH
• polymorfismus genetický fyziologie   MeSH
• poruchy nálady genetika   MeSH
• poruchy příjmu potravy genetika   MeSH
• vývojové poruchy u dětí genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• membránové transportní proteiny pro serotonin MeSH
• mutantní proteiny MeSH

Anorexia nervosa is a serious psychiatric disorder characterized by the inability to maintain normal body weight. The frequently studied polymorphisms in the serotonin 5-HT2A receptor gene (-1438A/G) and in serotonin transporter 5-HTT gene (LPR, VNTR) have led to controversial results in different populations. The aim of the study was to address association of the above-mentioned polymorphisms with anorexia nervosa in the Czech population. We genotyped a well-defined group of 75 patients with anorexia nervosa (average age of 25.39 years, SD 6.18; average BMI 14.65 (SD 1.38)). The control group consisted of 65 Caucasian healthy females (average age 25.76 years, SD 5.12; average BMI 20.69, SD 1.85). The 5-HT2A receptor -1438A/G polymorphism analysis showed a trend for the association with odds ratios for risk allele A being in the same direction. In combination with a previously published Polish cohort, the allelic test reached a suggestive borderline (P = 0.0362, chi2 statistics, 1 df). In meta-analysis which included all published results for allelic tests, the resulting P value was highly significant (0.0003, chi2 statistics, 1 df). Using quantitative association of 5-HTR2A polymorphism with BMI in the Czech sample, a borderline association (P = 0.055) was observed. In 5-HTT, LPR polymorphism analysis, unlike in 5-HT2A, neither allelic nor quantitative association with BMI for the bi-allelic 5-HTT marker was observed. Results of this study support previous reports of a significant role of the A allele (-1438A/G, 5-HT2A receptor) as a risk factor in anorexia nervosa.

• MeSH
• alely MeSH
• dospělí MeSH
• frekvence genu MeSH
• genotyp MeSH
• lidé MeSH
• membránové transportní proteiny pro serotonin genetika   MeSH
• mentální anorexie genetika   MeSH
• mladý dospělý MeSH
• optimální tělesná hmotnost MeSH
• polymorfismus genetický * MeSH
• receptor serotoninový 5-HT2A genetika   MeSH
• serotonin genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• membránové transportní proteiny pro serotonin MeSH
• receptor serotoninový 5-HT2A MeSH
• serotonin MeSH

BACKGROUND: Serotonin (5-HT) is a biogenic monoamine with diverse functions in multiple human organs and tissues. During pregnancy, tightly regulated levels of 5-HT in the fetoplacental unit are critical for proper placental functions, fetal development, and programming. Despite being a non-neuronal organ, the placenta expresses a suite of homeostatic proteins, membrane transporters and metabolizing enzymes, to regulate monoamine levels. We hypothesized that placental 5-HT clearance is important for maintaining 5-HT levels in the fetoplacental unit. We therefore investigated placental 5-HT uptake from the umbilical circulation at physiological and supraphysiological levels as well as placental metabolism of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA) and 5-HIAA efflux from trophoblast cells. METHODS: We employed a systematic approach using advanced organ-, tissue-, and cellular-level models of the human placenta to investigate the transport and metabolism of 5-HT in the fetoplacental unit. Human placentas from uncomplicated term pregnancies were used for perfusion studies, culturing explants, and isolating primary trophoblast cells. RESULTS: Using the dually perfused placenta, we observed a high and concentration-dependent placental extraction of 5-HT from the fetal circulation. Subsequently, within the placenta, 5-HT was metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which was then unidirectionally excreted to the maternal circulation. In the explant cultures and primary trophoblast cells, we show concentration- and inhibitor-dependent 5-HT uptake and metabolism and subsequent 5-HIAA release into the media. Droplet digital PCR revealed that the dominant gene in all models was MAO-A, supporting the crucial role of 5-HT metabolism in placental 5-HT clearance. CONCLUSIONS: Taken together, we present transcriptional and functional evidence that the human placenta has an efficient 5-HT clearance system involving (1) removal of 5-HT from the fetal circulation by OCT3, (2) metabolism to 5-HIAA by MAO-A, and (3) selective 5-HIAA excretion to the maternal circulation via the MRP2 transporter. This synchronized mechanism is critical for regulating 5-HT in the fetoplacental unit; however, it can be compromised by external insults such as antidepressant drugs.

• Klíčová slova
• Clearance, Fetal development, Homeostasis, Placenta, Serotonin,
• MeSH
• aminy MeSH
• kinetika MeSH
• kyselina hydroxyindoloctová MeSH
• lidé MeSH
• placenta * MeSH
• serotonin * MeSH
• těhotenství MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aminy MeSH
• kyselina hydroxyindoloctová MeSH
• serotonin * MeSH

INTRODUCTION: Variance in hypothalamic-pituitary-adrenal (HPA) axis reactivity is considered to be one of the sources of differences in infant temperament. The cortisol enters into interactions with dopamine and serotonin, so it is expected that polymorphisms in genes coding monoamine metabolism influence both HPA axis reactivity and temperament. METHODS: We therefore explore the relationship among 5-HTTLPR S/L, MAOA H/L, and COMT Val158Met polymorphisms, the stress reaction of newborn infants after a heel stick blood draw (measured by determining salivary cortisol at three time points), and temperament assessed at the age of 3 months using Rothbart's Infant Behavior Questionnaire-Revised (IBQ-R) with a sample of 84 infants. RESULTS: The decrease in the salivary cortisol correlated with nine primary scales and all three secondary scales of IBQ-R. Children with a greater cortisol decrease were assessed as less susceptible to negative emotions, more extraverted, and more regulated. The polymorphisms that were observed were related both to the course of the stress reaction and to temperament. The 5-HTTLPR S allele was connected to higher scores for Negative Emotionality and lower scores for Orienting/Regulatory Capacity. The presence of the MAOA L allele predisposed its carriers to higher scores for Negative Emotionality, lower scores for Orienting/Regulatory Capacity, and a lower decrease in cortisol. The Met allele of COMT Val158Met polymorphism was connected to a higher Positive Affectivity/Surgency and Orienting/Regulatory Capacity and a greater cortisol decrease. CONCLUSIONS: Contrary to previous studies referring mainly basal cortisol and its increase, the results of our study emphasize the importance of cortisol elimination in infant temperament. Another interesting finding was a higher cortisol increase, higher Distress to Limitations, Negative Emotionality, and Approach in MAOA LL homozygotes which are traditionally understood as more vulnerable toward early stress in developing later externalizing behavior.

• Klíčová slova
• 5-HTTLPR, COMT, HPA axis reactivity, MAOA, gene polymorphisms, infant temperament,
• MeSH
• chování kojenců fyziologie   MeSH
• hydrokortison metabolismus   MeSH
• katechol-O-methyltransferasa genetika   MeSH
• kojenec * MeSH
• lidé MeSH
• membránové transportní proteiny pro serotonin genetika   MeSH
• monoaminoxidasa genetika   MeSH
• novorozenec MeSH
• polymorfismus genetický MeSH
• systém hypotalamus-hypofýza metabolismus   MeSH
• temperament fyziologie   MeSH
• Check Tag
• kojenec * MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• COMT protein, human MeSH Prohlížeč
• hydrokortison MeSH
• katechol-O-methyltransferasa MeSH
• membránové transportní proteiny pro serotonin MeSH
• monoamine oxidase A, human MeSH Prohlížeč
• monoaminoxidasa MeSH
• SLC6A4 protein, human MeSH Prohlížeč

The neurotransmitter serotonin has been critically implicated in the pathogenesis of several mental disorders. The serotonin transporter (5-HTT) is a key regulator of serotonergic neurotransmission and its genetic variability is associated with increased risk of psychopathology. One well known polymorphic locus in the 5-HTT gene affecting its expression is a tandem repeat in the promoter region (5-HTTLPR). It has been reported that 5-HTT is functionally coupled with the neuronal nitric oxide synthase (NOS1 or nNOS), an enzyme catalyzing the production of nitric oxide (NO). We have previously demonstrated that a tandem repeat polymorphism in the promoter of NOS1 exon 1f (Ex1f-VNTR) is associated with sensorimotor gating, a marker of inhibitory processing and a well established endophenotype of several neuropsychiatric disorders. Here we investigated the combined genetic effects of NOS1 Ex1f-VNTR and 5-HTTLPR on sensorimotor gating, measured by prepulse inhibition (PPI) of the acoustic startle reflex, in 164 healthy adults. We found no evidence for the interaction between NOS1 Ex1f-VNTR and 5-HTTLPR on PPI. PPI was associated with NOS1 Ex1f-VNTR, but not 5-HTTLPR. Our data suggest that while NOS1 plays a role in sensorimotor gating, the nitrergic pathway of gating regulation does not involve the action of 5-HTT.

• MeSH
• dospělí MeSH
• exony MeSH
• fenotyp MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• membránové transportní proteiny pro serotonin genetika   MeSH
• minisatelitní repetice MeSH
• mladý dospělý MeSH
• prepulsní inhibice genetika   MeSH
• promotorové oblasti (genetika) MeSH
• senzorimotorický kortex fyziologie   MeSH
• synthasa oxidu dusnatého, typ I genetika   MeSH
• úleková reakce genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• membránové transportní proteiny pro serotonin MeSH
• NOS1 protein, human MeSH Prohlížeč
• SLC6A4 protein, human MeSH Prohlížeč
• synthasa oxidu dusnatého, typ I MeSH

BACKGROUND: Pharmacological approach is the most effective way of treatment of ADHD and its early application prevents from the progress of secondary disorders. The study on present neurotransmitter systems in pathology of ADHD can be helpful in selecting appropriate drug, since there are used various substances with different mechanisms of functioning in treatment of the hyperkinetic syndrome. METHOD: Within our study there were selected the genes of dopaminergic (DRD2, DRD3, DAT1), noradrenergic (DBH) and serotoninergic (5-HTT) systems. With the use of molecular-genetic methods based on association strategy "case-control" there were analysed genes including 11 polymorphisms. The presence of risk alleles was examined in comparison of the sample of 100 ADHD children to a control group of another 100 subjects, who were checked by child psychiatrists and examined with the Conners test in order to exclude eventual cases with ADHD symptoms. RESULTS: Our research suggests the association of some genes with ADHD. It could be concluded: 1) the risk of ADHD is significantly increased in the presence of one risk allele in genes DRD2 (O.R.=7,5), 5-HTT (O.R.=2,7) and DAT1 (O.R.=1,6). 2) The risk of ADHD is significantly increased at homozygotes for risk alleles in genes DRD2 (O.R.=54,8), 5-HTT (O.R.=6,7) and DAT1 (O.R.=6,6). For polymorphisms G444A and C1603T in DBH, which were detected by univariant analysis, haplotype analysis was performed and resulted in conclusion that: 3) the risk of ADHD is significantly increased in the presence of allele DBH +444A as well as in the presence of allele DBH +1603T (O.R.=15).

• MeSH
• dítě MeSH
• dopamin-beta-hydroxylasa genetika   MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• hyperkinetická porucha genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• membránové transportní proteiny pro serotonin genetika   MeSH
• mutační analýza DNA MeSH
• proteiny přenášející dopamin přes plazmatickou membránu genetika   MeSH
• receptory dopaminu D2 genetika   MeSH
• receptory dopaminu D3 genetika   MeSH
• rizikové faktory MeSH
• studie případů a kontrol MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dopamin-beta-hydroxylasa MeSH
• DRD3 protein, human MeSH Prohlížeč
• membránové transportní proteiny pro serotonin MeSH
• proteiny přenášející dopamin přes plazmatickou membránu MeSH
• receptory dopaminu D2 MeSH
• receptory dopaminu D3 MeSH
• SLC6A3 protein, human MeSH Prohlížeč
• SLC6A4 protein, human MeSH Prohlížeč

Huntington's disease (HD) is a demential, neurodegenerative inheritable disease affecting middle-aged patients. HD is characterized by uncontrolled choreiform movements, psychiatric symptoms and cognitive decline. Histopathological changes in HD brains reveal a considerable damage to basal ganglia, particularly affecting middle-sized spiny neurons from the caudate-putamen region. Neurochemical changes are specifically oriented to deplete GABAergic and cholinergic systems, while molecular alterations include an increased expression of CAG trinucleotide at exon 1 from the huntingtin (htt) gene, as well as aggregation of mutant htt. Although several hypotheses regarding the mechanisms by which neurotoxicity is triggered in HD brains have been suggested on the basis of experimental evidence, so far it remains not clear which of them are predominant or whether they are complementary. Recent experimental evidence through transgenic mice models reveal an interesting interaction between expanded CAG triplets, mutant htt, and the increase in toxic metabolites from the kynurenine pathway. Further evidence supports the assumption that different toxic mechanisms (i.e. excitotoxicity, energy metabolism impairment, inflammatory events, oxidative stress, etc.) are confluent and depend on each other. In this review we will briefly summarize some of those findings and propose a final integrative hypothesis for HD.

• MeSH
• buněčná smrt MeSH
• dusíkaté sloučeniny MeSH
• energetický metabolismus MeSH
• excitační aminokyseliny metabolismus   MeSH
• Huntingtonova nemoc chemicky indukované   genetika   metabolismus   patologie   MeSH
• kyselina chinolinová MeSH
• kyselina kynurenová metabolismus   MeSH
• lidé MeSH
• membránové transportní proteiny pro serotonin genetika   MeSH
• modely nemocí na zvířatech MeSH
• mutace MeSH
• myši transgenní MeSH
• myši MeSH
• neurony metabolismus   patologie   MeSH
• oxidační stres MeSH
• propionáty MeSH
• trinukleotidové repetice MeSH
• tryptofan metabolismus   MeSH
• vápník metabolismus   MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• 3-nitropropionic acid MeSH Prohlížeč
• dusíkaté sloučeniny MeSH
• excitační aminokyseliny MeSH
• kyselina chinolinová MeSH
• kyselina kynurenová MeSH
• membránové transportní proteiny pro serotonin MeSH
• propionáty MeSH
• Slc6a4 protein, mouse MeSH Prohlížeč
• tryptofan MeSH
• vápník MeSH

The increasing use of cannabis during pregnancy raises concerns about its impact on fetal development. While cannabidiol (CBD) shows therapeutic promise, its effects during pregnancy remain uncertain. We investigated CBD's influence on tryptophan (TRP) metabolism in the human placenta. TRP is an essential amino acid that is metabolized via the serotonin and kynurenine (KYN) pathways, which are critical for fetal neurodevelopment. We used human term villous placental explants, an advanced ex vivo model, to study CBD's impact on key TRP metabolic enzymes. In addition, vesicles isolated from the microvillous membrane (MVM) of the human placenta were used to assess CBD's effect on placental serotonin uptake. Explants were exposed to CBD at therapeutic (0.1, 1, 2.5 μg/ml) and non-therapeutic (20 and 40 μg/ml) concentrations to determine its effects on the gene and protein expression of key enzymes in TRP metabolism and metabolite release. CBD upregulated TRP hydroxylase (TPH) and downregulated monoamine oxidase (MAO-A), resulting in reduced levels of 5-hydroxyindoleacetic acid (HIAA). It also downregulated serotonin transporter expression and inhibited serotonin transport across the MVM by up to 60% while simultaneously enhancing TRP metabolism via the kynurenine pathway by upregulating indoleamine-pyrrole 2,3-dioxygenase (IDO-1). Among kynurenine pathway enzymes, kynurenine 3 monooxygenase (KMO) was upregulated while kynurenine aminotransferase 1 (KAT-1) was downregulated; the former is associated with neurotoxic metabolite production, while the latter is linked to reduced neuroprotective metabolite levels. Overall, these results indicate that CBD modulates TRP catabolism in the human placenta, potentially disrupting the tightly regulated homeostasis of the serotonin and KYN pathways.

• Klíčová slova
• Cannabidiol, Kynurenine, Pregnancy, Serotonin, Tryptophan,
• MeSH
• kanabidiol * farmakologie   MeSH
• kynurenin metabolismus   MeSH
• lidé MeSH
• placenta * metabolismus   účinky léků   MeSH
• serotonin * metabolismus   MeSH
• těhotenství MeSH
• tryptofan * metabolismus   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kanabidiol * MeSH
• kynurenin MeSH
• serotonin * MeSH
• tryptofan * MeSH

BACKGROUND: Three primary monoamines-serotonin, norepinephrine, and dopamine-play major roles in the placenta-fetal brain axis. Analogously to the brain, the placenta has transport mechanisms that actively take up these monoamines into trophoblast cells. These transporters are known to play important roles in the differentiated syncytiotrophoblast layer, but their status and activities in the undifferentiated, progenitor cytotrophoblast cells are not well understood. Thus, we have explored the cellular handling and regulation of monoamine transporters during the phenotypic transitioning of cytotrophoblasts along the villous pathway. METHODS: Experiments were conducted with two cellular models of syncytium development: primary trophoblast cells isolated from the human term placenta (PHT), and the choriocarcinoma-derived BeWo cell line. The gene and protein expression of membrane transporters for serotonin (SERT), norepinephrine (NET), dopamine (DAT), and organic cation transporter 3 (OCT3) was determined by quantitative PCR and Western blot analysis, respectively. Subsequently, the effect of trophoblast differentiation on transporter activity was analyzed by monoamine uptake into cells. RESULTS: We present multiple lines of evidence of changes in the transcriptional and functional regulation of monoamine transporters associated with trophoblast differentiation. These include enhancement of SERT and DAT gene and protein expression in BeWo cells. On the other hand, in PHT cells we report negative modulation of SERT, NET, and OCT3 protein expression. We show that OCT3 is the dominant monoamine transporter in PHT cells, and its main functional impact is on serotonin uptake, while passive transport strongly contributes to norepinephrine and dopamine uptake. Further, we show that a wide range of selective serotonin reuptake inhibitors affect serotonin cellular accumulation, at pharmacologically relevant drug concentrations, via their action on both OCT3 and SERT. Finally, we demonstrate that BeWo cells do not well reflect the molecular mechanisms and properties of healthy human trophoblast cells. CONCLUSIONS: Collectively, our findings provide insights into the regulation of monoamine transport during trophoblast differentiation and present important considerations regarding appropriate in vitro models for studying monoamine regulation in the placenta.

• Klíčová slova
• Cell differentiation, Membrane transport, Monoamines, Neuroplacentology, Placenta, Trophoblast,
• MeSH
• dopamin metabolismus   MeSH
• lidé MeSH
• noradrenalin farmakologie   MeSH
• placenta metabolismus   MeSH
• serotonin * metabolismus   farmakologie   MeSH
• těhotenství MeSH
• trofoblasty * metabolismus   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dopamin MeSH
• noradrenalin MeSH
• serotonin * MeSH