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1.
Artigo em Russo | MEDLINE | ID: mdl-33244961

RESUMO

OBJECTIVE: To identify polymorphisms in the genes of dopaminergic and serotonergic systems associated with the risk of suicidal behavior in individuals with dependence on synthetic cathinones. MATERIAL AND METHODS: One hundred and eighty-two men with the diagnosis of Substance dependence (ICD-10 F15) tested positive for metabolites of synthetic cathinones (a-PVP, MDPV) in the urine were studied. Genotyping was performed for rs1800497 DRD2, rs4646984 DRD4, VNTR 40 b.p. SLC6A3, rs27072 SLC6A3, rs6313 HTR2A and rs6296 HTR1B using PCR and RFLP technique. RESULTS AND CONCLUSION: It was found that the genes of the serotonergic system HTR2A and HTR1B are predictors of the development of some endophenotypes of suicidal behavior in individuals with dependence on synthetic cathinones.


Assuntos
Alcaloides , Transtornos Relacionados ao Uso de Substâncias , Suicídio , Proteínas da Membrana Plasmática de Transporte de Dopamina , Endofenótipos , Humanos , Masculino , Polimorfismo Genético , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT2A de Serotonina/genética , Transtornos Relacionados ao Uso de Substâncias/genética
2.
PLoS Genet ; 16(8): e1009003, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866139

RESUMO

Sensory systems rely on neuromodulators, such as serotonin, to provide flexibility for information processing as stimuli vary, such as light intensity throughout the day. Serotonergic neurons broadly innervate the optic ganglia of Drosophila melanogaster, a widely used model for studying vision. It remains unclear whether serotonin modulates the physiology of interneurons in the optic ganglia. To address this question, we first mapped the expression patterns of serotonin receptors in the visual system, focusing on a subset of cells with processes in the first optic ganglion, the lamina. Serotonin receptor expression was found in several types of columnar cells in the lamina including 5-HT2B in lamina monopolar cell L2, required for spatiotemporal luminance contrast, and both 5-HT1A and 5-HT1B in T1 cells, whose function is unknown. Subcellular mapping with GFP-tagged 5-HT2B and 5-HT1A constructs indicated that these receptors localize to layer M2 of the medulla, proximal to serotonergic boutons, suggesting that the medulla neuropil is the primary site of serotonergic regulation for these neurons. Exogenous serotonin increased basal intracellular calcium in L2 terminals in layer M2 and modestly decreased the duration of visually induced calcium transients in L2 neurons following repeated dark flashes, but otherwise did not alter the calcium transients. Flies without functional 5-HT2B failed to show an increase in basal calcium in response to serotonin. 5-HT2B mutants also failed to show a change in amplitude in their response to repeated light flashes but other calcium transient parameters were relatively unaffected. While we did not detect serotonin receptor expression in L1 neurons, they, like L2, underwent serotonin-induced changes in basal calcium, presumably via interactions with other cells. These data demonstrate that serotonin modulates the physiology of interneurons involved in early visual processing in Drosophila.


Assuntos
Receptor 5-HT1B de Serotonina/genética , Receptores 5-HT1 de Serotonina/genética , Receptores 5-HT2 de Serotonina/genética , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Animais , Ritmo Circadiano/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Regulação da Expressão Gênica/genética , Interneurônios/metabolismo , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Neurotransmissores/genética , Receptores de Serotonina/genética , Serotonina/genética , Percepção Visual/genética
3.
Biochem Pharmacol ; 175: 113870, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32088264

RESUMO

The 5-HT1A and 5-HT1B serotonin receptors are abundantly expressed in the CNS and constitute validated as well as putative drug targets in a variety of psychiatric and cognitive disorders, alcoholism/addiction, pain and migraine. In the present study we have characterized the functional properties of human 5-HT1A and 5-HT1B stably co-expressed with the human G-protein-activated inwardly rectifying K+ channel 2 (GIRK2) in HEK293 cells in the fluorescence-based FLIPR® Membrane Potential Blue (FMP) assay. Serotonin and other agonists induced robust decreases in fluorescence levels in the 5-HT1A/GIRK2- and 5-HT1B/GIRK2-HEK293 cells in a concentration-dependent manner in the assay, and these responses could be inhibited by selective 5-HT1A/5-HT1B antagonists and by the Gαi/o-protein inhibitor pertussis toxin (PTX). Five additional stable HEK293 cell lines co-expressing 5-HT1A or 5-HT1B with GIRK2 and one of the PTX-insensitive Gαi/o-subunit mutants Gαi1C351I, Gαi2C352I and Gαo1C351I were constructed, and 5-HT1A/5-HT1B-mediated responses through these specific Gαi/o-subunits were measured in these cells pretreated with PTX in the FMP assay. The functional properties of 16 reference 5-HT1 agonists were characterized at the seven cell lines, which constitutes the most detailed pharmacological profiling and comparison of 5-HT1A and 5-HT1B receptor signaling in the same assay published to date. We propose that this approach to assay 5-HT1-mediated signaling through endogenous Gαi/o-proteins in HEK293 cells or through specific Gαi/o-subunits in a fairly high-throughput manner holds some advantages to other functional assays for Gαi/o-coupled receptors. The assay will facilitate detailed profiling of the Gαi/o- and Gßγ-mediated signaling of 5-HT1A and 5-HT1B at the molecular level, and it could also be used to identify novel modulators for the receptors.


Assuntos
Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Potenciais da Membrana , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1B de Serotonina/metabolismo , Bioensaio , Relação Dose-Resposta a Droga , Fluorescência , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Células HEK293 , Humanos , Ligantes , Potenciais da Membrana/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT1B de Serotonina/genética , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Transdução de Sinais , Transfecção
4.
Am J Clin Nutr ; 111(3): 613-621, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31858113

RESUMO

BACKGROUND: Preconception nutrition sets the stage for a healthy pregnancy. Maternal fatty acids (FAs) are related to beneficial neonatal outcomes with DNA methylation proposed as a mechanism; however, few studies have investigated this association and none with preconception FAs. OBJECTIVES: We examined the relations of maternal plasma FA concentrations at preconception (n = 346) and 8 weeks of gestation (n = 374) with newborn DNA methylation. METHODS: The Effects of Aspirin in Gestation and Reproduction Trial (2006-2012) randomly assigned women with previous pregnancy loss to low dose aspirin or placebo prior to conception. We measured maternal plasma phospholipid FA concentration at preconception (on average 4 mo before pregnancy) and 8 weeks of gestation. Cord blood DNA from singletons was measured using the MethylationEPIC BeadChip. We used robust linear regression to test the associations of FA concentration with methylation ß-values of each CpG site, adjusting for estimated cell count using a cord blood reference, sample plate, maternal sociodemographic characteristics, cholesterol, infant sex, and epigenetic-derived ancestry. False discovery rate correction was used for multiple testing. RESULTS: Mean ± SD concentrations of preconception marine (20:5n-3+22:6n-3+22:5n-3) and ω-6 PUFAs, SFAs, MUFAs, and trans FAs were 4.7 ± 1.2, 38.0 ± 2.0, 39.4 ± 1.8, 11.6 ± 1.1, and 1.0 ± 0.4 % of total FA, respectively; concentrations at 8 weeks of gestation were similar. Preconception marine PUFA concentration was associated with higher methylation at GRAMD2 (P = 1.1 × 10-8), LOXL1 (P = 5.5 × 10-8), SIK3 (P = 1.6 × 10-7), HTR1B (P = 1.9 × 10-7), and MCC (P = 2.1 × 10-7) genes. Preconception SFA concentration was associated with higher methylation at KIF25-AS1 and lower methylation at SLC39A14; other associations exhibited sensitivity to outliers. The trans FA concentration was related to lower methylation at 3 sites and higher methylation at 1 site. FAs at 8 weeks of gestation were largely unrelated to DNA methylation. CONCLUSIONS: Maternal preconception FAs are related to newborn DNA methylation of specific CpG sites, highlighting the importance of examining nutritional exposures preconceptionally. This trial was registered at clinicaltrials.gov as NCT00467363.


Assuntos
Metilação de DNA , Ácidos Graxos/sangue , Gravidez/genética , Adolescente , Adulto , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Gravidez/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT1B de Serotonina/metabolismo , Adulto Jovem
5.
J Biosci ; 44(4)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31502579

RESUMO

In previous studies, we found interferon-α (IFN-α) could reduce protein levels of p11, 5-hydroxytryptamine receptor 1b (5-HT1b) and 5-hydroxytryptamine receptor 4 (5-HT4), but does not influence their messenger RNA levels in SH-sy5y cells. Thus, we investigated the post-transcriptional modulation of these molecules by IFN-α. SH-sy5y cells were treated with IFN-α, NH4Cl or MG132 alone or in combination, and then the protein levels of p11, 5-HT1b and 5-HT4 were analyzed by western blots. The regulatory effects of p11 on 5-HT1b and 5-HT4 were also determined in p11 knock-down cells. NH4Cl but not MG132 could reverse the protein level of p11 in IFN-α-treated SH-sy5y cells. MG132 could recover the protein levels of 5-HT1b and 5-HT4 in p11 knock-down cells. The down-regulation effects of IFN-α on p11, 5-HT1b and 5-HT4 were associated with the lysosome and ubiquitin-proteasome-mediated pathways. p11 was identified as a potent regulator to modulate the ubiquitination of 5-HT1b and 5-HT4. Therefore, it could be potential target therapies in IFN-ainduced depression.


Assuntos
Depressão/tratamento farmacológico , Interferon-alfa/farmacologia , Receptor 5-HT1B de Serotonina/genética , Cloreto de Amônio/farmacologia , Linhagem Celular Tumoral , Peptídeos Penetradores de Células/genética , Depressão/genética , Depressão/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Leupeptinas/farmacologia , Lisossomos/efeitos dos fármacos , Lisossomos/genética , Proteólise , RNA Mensageiro/genética , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ubiquitina
6.
J Child Psychol Psychiatry ; 60(12): 1289-1299, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31321769

RESUMO

BACKGROUND: Serotonin system genes are commonly studied in obsessive-compulsive disorder (OCD), but genetic studies to date have produced inconsistent results, possibly because phenotypic heterogeneity has not been adequately accounted for. In this paper, we studied candidate serotonergic genes and homogenous phenotypic subgroups as presented through obsessive-compulsive (OC) trait dimensions in a general population of children and adolescents. We hypothesized that different serotonergic gene variants are associated with different OC trait dimensions and, furthermore, that they vary by sex. METHODS: Obsessive-compulsive trait dimensions (Cleaning/Contamination, Counting/Checking, Symmetry/Ordering, Superstition, Rumination, and Hoarding) were examined in a total of 5,213 pediatric participants in the community using the Toronto Obsessive-Compulsive Scale (TOCS). We genotyped candidate serotonin genes (directly genotyping the 5-HTTLPR polymorphism in SLC6A4 for 2018 individuals and using single nucleotide polymorphism (SNP) array data for genes SLC6A4, HTR2A, and HTR1B for 4711 individuals). We assessed the association between variants across these genes and each of the OC trait dimensions, within males and females separately. We analyzed OC traits as both (a) dichotomized based on a threshold value and (b) quantitative scores. RESULTS: The [LG + S] variant in 5-HTTLPR was significantly associated with hoarding in males (p-value of 0.003 and 0.004 for categorical and continuous analyses, respectively). There were no significant findings for 5-HTTLPR in females. Using SNP array data, there were significant findings for rumination in males for HTR2A SNPs (p-value of 1.04e-6 to 5.20e-6). CONCLUSIONS: This represents the first genetic association study of OC trait dimensions in a community-based pediatric sample. Our strongest results indicate that hoarding and rumination may be distinct in their association with serotonin gene variants and that serotonin gene variation may be specific to sex. Future genetic association studies in OCD should properly account for heterogeneity, using homogenous subgroups stratified by symptom dimension, sex, and age group.


Assuntos
Comportamento Compulsivo/genética , Estudos de Associação Genética , Colecionismo/genética , Comportamento Obsessivo/genética , Personalidade/genética , Ruminação Cognitiva/fisiologia , Serotonina/genética , Adolescente , Criança , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/genética , Polimorfismo de Nucleotídeo Único , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT2A de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Caracteres Sexuais
7.
J Sports Sci ; 37(14): 1655-1662, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30836829

RESUMO

Genetic factors are known to influence sport performance. The aim of the present study was to assess genetic variants in genes coding for proteins potentially modulating activity of brain emotion centres in a group of 621 elite athletes (212 endurance, 183 power and 226 combat athletes) and 672 sedentary controls. Ten statistically significant variants were identified in genes encoding elements of serotoninergic, catecholaminergic and hypothalamic-pituitary-adrenal systems in different sport groups. Of those the rs860573 variant in the FEV gene coding for transcription factor exclusively expressed in neurons of the central serotonin system is the only one whose frequency significantly differentiates all the groups of athletes studied, regardless of discipline, from the controls (p = 0.000026). Our results support the hypothesis that genetic variants potentially affecting mental processes and emotions, particularly in the serotonergic pathway, also influence the predispositions to athletic performance.


Assuntos
Desempenho Atlético/fisiologia , Emoções/fisiologia , Polimorfismo de Nucleotídeo Único , Receptores de Serotonina/genética , Adulto , Ansiedade/genética , Proteínas de Ligação a DNA/genética , Feminino , Genótipo , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Proteínas Nucleares/genética , Sistema Hipófise-Suprarrenal/fisiologia , Polônia , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT2C de Serotonina/genética , Receptores de Catecolaminas/genética , Estresse Psicológico/genética , Fatores de Transcrição , Adulto Jovem
8.
J Child Adolesc Psychopharmacol ; 29(2): 152-157, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30351181

RESUMO

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder whose etiology includes important genetic contributions. In a previous transmission disequilibrium study in which 75 complete trios were included, single-nucleotide polymorphisms (SNPs) in serotoninergic and GABAergic genes were associated with early-onset OCD. Our aim was to assess those findings in an extended collection of early-onset OCD trios. METHODS: A transmission disequilibrium test for SNPs in HTR1B (rs2000292), SLC18A1 (rs6586896), GAD1 (rs3791860), and GAD2 (rs8190748) was performed in a total of 101 early-onset OCD trios, from which 26 trios were newly recruited for the purpose of the present analysis. RESULTS: All the SNPs were overtransmitted from parents to OCD probands (p < 0.012, significant after Bonferroni correction). CONCLUSIONS: These results are consistent with the previous findings and constitute more evidence of the role of genetic factors related to serotoninergic and GABAergic pathways in the pathophysiology of early-onset OCD.


Assuntos
Predisposição Genética para Doença , Transtorno Obsessivo-Compulsivo/genética , Adolescente , Feminino , Glutamato Descarboxilase/genética , Humanos , Desequilíbrio de Ligação , Masculino , Transtorno Obsessivo-Compulsivo/fisiopatologia , Polimorfismo de Nucleotídeo Único , Receptor 5-HT1B de Serotonina/genética , Proteínas Vesiculares de Transporte de Monoamina/genética
9.
Behav Brain Res ; 356: 148-155, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29949735

RESUMO

Serotonin 5-HT1B receptors (5-HT1BRs) are distributed in hippocampal CA1 and play a pivotal role in cognitive function. Activation of 5-HT1BRs regulates synaptic plasticity at the excitatory synapses in the hippocampus. However, the role and its underlying mechanism of 5-HT1BR activation-mediated glutamatergic synaptic plasticity in spatial memory are not fully understood. In this study, spatial memory of Sprague-Dawley (SD) rats was assessed in a Morris water maze after bilateral dorsal hippocampal CA1 infusion of the 5-HT1BR antagonist GR55562 (25 µg/µL) or agonist CP93129 (25 µg/µL). GR55562 did not affect the spatial memory acquisition but significantly increased the target quadrant preference during the memory consolidation probe performed 14 d after the training session, while CP93129 impaired the memory consolidation process. Moreover, GR55562 significantly increased, while CP93129 significantly decreased, the density of dendritic spines on the distal apical dendrites of CA1 pyramidal neurons. Furthermore, western blot experiments indicated that GR55562 significantly increased, but CP93129 significantly reduced, the expression of Kalirin-7 (Kal-7), PSD95, and GluA2/3 subunits of AMPA receptors. Our results suggest that Kal-7 and Kal-7-mediatedalteration of AMPA receptor subtype expression may play crucial roles in the impact of hippocampal CA1 5-HT1BR activation on spatial memory consolidation.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/metabolismo , Consolidação da Memória/fisiologia , Memória Espacial/fisiologia , Animais , Região CA1 Hipocampal/fisiologia , Espinhas Dendríticas/metabolismo , Regulação da Expressão Gênica/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Plasticidade Neuronal , Células Piramidais/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT1B de Serotonina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Serotonina/metabolismo , Sinapses/metabolismo
10.
BMC Psychiatry ; 18(1): 303, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30231895

RESUMO

BACKGROUND: Schizophrenia is associated with multiple neurotransmitter disorders, including serotonin (5-hydroxytryptamine, 5-HT). The neuromodulatory action of serotonin on brain function largely depends on the action of specific subtypes of serotonin receptors. The serotonin receptor 1B (HTR1B) gene has been proposed to play putative roles in the development of multiple emotional and psychiatric disorders. METHODS: To study the relationship of HTR1B polymorphisms and schizophrenia, gene information was drawn from a cohort of 310 schizophrenic patients (152 men and 158 women) and 313 healthy controls (153 men and 160 women) of northern Han Chinese descent. The χ2 test was used to compare allele and genotype distributions between case and control groups. The haplotype and linkage equilibrium were also assessed in two group comparisons. RESULTS: We detected 14 SNPs. Male patients were observed to have higher frequencies of the A-allele and AA+AG genotype at rs1778258 than female patients (p = 0.012 and p = 0.015, respectively). Both the A-allele and AA+AG genotype were associated with schizophrenia risk (OR = 1.986 and OR = 2.061, respectively), although the statistical significance of the genotype was lost after Bonferroni correction. Linkage analysis showed that rs17273700, rs11568817, rs9361234 and rs58138557 polymorphisms exhibit strong linkage disequilibrium (LD). In addition, schizophrenic patients show stronger linkage between 11,568,817 and rs130058 than healthy controls. CONCLUSIONS: HTR1B polymorphisms are associated with schizophrenia in the northern Han Chinese population, which provides an etiological reference for schizophrenia.


Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Receptor 5-HT1B de Serotonina/genética , Esquizofrenia/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Feminino , Marcadores Genéticos , Genótipo , Haplótipos , Humanos , Masculino
11.
Cell Rep ; 23(13): 3852-3863, 2018 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-29949769

RESUMO

The ventral pallidum (VP) is part of the basal ganglia circuitry and a target of both direct and indirect pathway projections from the nucleus accumbens. VP is important in cocaine reinforcement, and the firing of VP neurons is modulated in vivo during cocaine self-administration. This modulation of firing is thought to be indirect via cocaine actions on dopamine in the accumbens. Here, we show that cocaine directly inhibits synaptic transmission evoked by selective stimulation of indirect pathway projections to VP neurons. The inhibition is independent of dopamine receptor activation, absent in 5-HT1B knockout mice, and mimicked by a serotonin transporter (SERT) blocker. SERT-expressing neurons in dorsal raphe project to the VP. Optogenetic stimulation of these projections evokes serotonin transients and effectively inhibits GABAergic transmission to VP neurons. This study shows that cocaine increases endogenous serotonin in the VP to suppress synaptic transmission selectively from indirect pathway projections to VP neurons.


Assuntos
Prosencéfalo Basal/metabolismo , Cocaína/farmacologia , Serotonina/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Animais , Núcleo Dorsal da Rafe/fisiologia , Potenciais Evocados/efeitos dos fármacos , Feminino , Luz , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neurônios/metabolismo , Receptor 5-HT1B de Serotonina/deficiência , Receptor 5-HT1B de Serotonina/genética , Receptores de Dopamina D2/metabolismo , Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia
12.
J Affect Disord ; 228: 222-228, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29275155

RESUMO

BACKGROUND: The serotonin receptor 1A and 1B (HTR1A/1B) gene have been suggested to be involved in the pathogenesis of major depressive disorder (MDD) and the antidepressant treatment response. Gene expression differences were partly mediated by genetic polymorphism and DNA methylation which might be affected by environmental factors. In the present study, we attempt to identify whether HTR1A/1B DNA methylation and genetic polymorphism could predict antidepressant treatment response. METHODS: 85 Chinese Han MDD patients were clinically assessed 8 weeks after of initiating escitalopram treatment for the first time. Antidepressant treatment response was assessed by changes in the Hamilton Depression Rating Scale-17 items (HAMD-17) score. The Life Events Scale (LES) and the Childhood Trauma Questionnaire (CTQ) were utilized as the assessment of previous life stress. The Illumina HiSeq platform was used to assess DNA methylation at 96 CpG sites located in HTR1A and HTR1B gene promoter regions. Six single nucleotide polymorphisms (SNPs) (HTR1A rs6294, rs116985176; HTR1B rs6296, rs6298, rs1228814, rs1778258) were genotype by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) or PCR sequencing. Regression analyses were used to explore the relationship between DNA methylation and SNP and antidepressant response. RESULTS: We identified two CpG sites predictor of antidepressant treatment response (CpG 668, amplicon HTR1A_1, NC_000005.10, P = 0.025; CpG 1401, amplicon HTR1B_4, NC_000006.12, P = 0.033). The interaction of four CpG sites hypomethylation of HTR1A/1B with high recent stress might result in impaired antidepressant treatment response. What's more, the present data indicated that age, environments and antidepressant treatment might affect DNA methylation status. It was found that DNA methylation status could be influenced by antidepressant treatment in turn. However, HTR1A and HTR1B genotypes did not influence antidepressant response and DNA methylation status. CONCLUSIONS: The results suggest that HTR1A/1B DNA hypomethylation and its interaction with recent life stress might drive impaired antidepressant treatment response. Meanwhile, DNA methylation, in turn, was modified by antidepressant treatment and environments. Our results offer new evidence for the role of epigenetic and genetic polymorphism in pharmacological response to antidepressants.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Citalopram/uso terapêutico , Metilação de DNA , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT1B de Serotonina/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Depressão/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica , Estresse Psicológico
13.
J Psychiatr Res ; 95: 269-275, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28923721

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is a very common psychiatric disorder across the life cycle and frequently presents comorbidities. Since ADHD is highly heritable, several studies have focused in the underlying genetic factors involved in its etiology. One of the major challenges in this search is the phenotypic heterogeneity, which could be partly attributable to the sexual dimorphism frequently seen in psychiatric disorders. Taking into account the well-known sexual dimorphic effect observed in serotonergic system characteristics, we differentially tested the influence of HTR1B SNPs (rs11568817, rs130058, rs6296 and rs13212041) on ADHD susceptibility and on its major comorbidities according to sex. The sample comprised 564 adults with ADHD diagnosed according to DSM-IV criteria and 635 controls. There was no association of any HTR1B SNPs tested in relation to ADHD susceptibility. As for the comorbidities evaluated, after correction for multiple tests, significant associations were observed for both rs11568817 and rs130058 with substance use disorders (Pcorr = 0.009 and Pcorr = 0.018, respectively) and for rs11568817 with nicotine dependence (Pcorr = 0.025) in men with ADHD. In women with ADHD, the same rs11568817 was associated with generalized anxiety disorder (Pcorr = 0.031). The observed effects of rs11568817 G allele presence conferring risk to either substance use disorders or generalized anxiety disorder according to sex, suggest an overall scenario where a higher transcriptional activity of HTR1B, resulting from the presence of this allele, is related to externalizing behaviors in men and internalizing behaviors in women. These results are consistent with and expand previous evidence of sexual dimorphism of the serotoninergic system.


Assuntos
Transtornos de Ansiedade/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Receptor 5-HT1B de Serotonina/genética , Caracteres Sexuais , Transtornos Relacionados ao Uso de Substâncias/genética , Adulto , Transtornos de Ansiedade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Tabagismo/epidemiologia , Tabagismo/genética , Adulto Jovem
14.
Am J Med Genet B Neuropsychiatr Genet ; 174(4): 458-466, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28512748

RESUMO

Although the heritability of ADHD is estimated to be high, identifying specific genetic markers remains challenging. Most studies to date have examined the genetic basis of ADHD by employing dichotomous diagnostic phenotypes, but, as ADHD symptoms tend to be phenotypically dimensional, an alternative and potentially informative approach is to examine continuous indices of inattention and hyperactivity-impulsivity symptoms. The current study aimed to identify genetic effects on dimensionally-focused adult ADHD-related phenotypes in 990 individuals of European ancestry with intentionally low levels of substance misuse to avoid confounding. The study used four complementary approaches: (1) analysis of a priori candidate loci identified in prior meta-analytic work; (2) gene-based analysis; (3) hypothesis-free genome-wide association testing; and (4) single nucleotide polymorphism (SNP) heritability via genomic-relatedness-matrix restricted maximum likelihood analysis (GREML). The GREML analysis included a bivariate model to test whether the ADHD symptom dimensions index the same genetic liability. The results revealed significant differential associations between two a priori loci and ADHD phenotypes, rs6296 in HTR1B with inattention and rs3746544 in SNAP-25 with hyperactivity-impulsivity. No significant gene-based or genome-wide associations were detected, but SNP heritability revealed that a large portion of genetic variance was accounted for by common SNPs (44%, 55%, and 59% for inattention, hyperactivity-impulsivity, and total ADHD, respectively) and substantial shared genetic variance across inattention and hyperactivity-impulsivity (86%). These findings reveal both unique and common patterns of genetic influences across dimensional ADHD-related phenotypes. More broadly, these findings reveal the value in using multiple methods to understand the genetic etiology of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Marcadores Genéticos , Predisposição Genética para Doença , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Receptor 5-HT1B de Serotonina/genética , Proteína 25 Associada a Sinaptossoma/genética , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Feminino , Humanos , Masculino , Fenótipo , Prognóstico , Adulto Jovem
15.
Asia Pac Psychiatry ; 9(2)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26123080

RESUMO

INTRODUCTION: Clinical, neuroimaging and other studies provided evidence that the dysfunction of the serotonin neurotransmitter system were found in Tourette syndrome (TS). This study is to explore the association between the polymorphism of C861G (rs6296) in HTR1B and TS in Han Chinese people. METHODS: Two hundred ninety-nine TS patients (260 TS trios and 39 TS patients) and 388 healthy controls were collected. The genotype of HTR1B C861G was detected using Taqman probes. The case-control study and family-based study was used separately to study association between HTR1B C861G and TS in Han Chinese people. RESULTS: In case-control study, no statistically significant difference was found in the distribution of HTR1B C861G polymorphism between TS patients and controls (for genotype: χ2 = 3.408, P = 0.182; for allele: χ2 = 0.395, P = 0.530, OR = 0.934, 95%CI: 0.754-1.156). In family-based study, we observed nonsignificant over-transmission of the G861 allele in HTR1B to TS offspring using the transmission disequilibrium test (TDT), haplotype relative risk (HRR) and haplotype-based HRR (HHRR) (TDT χ2 = 0.410, P = 0.560; HRR = 1.151, χ2 = 0.421, P = 0.517, 95% CI: 0.753-1.759; HHRR = 0.919, χ2 = 0.467, P = 0.495, 95%CI: 0.720-1.172). DISCUSSION: Our study suggested that the polymorphism of HTR1B C861G is not a risk factor for TS in Han Chinese population. However, the result should be replicated in larger sample and different population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Receptor 5-HT1B de Serotonina/genética , Síndrome de Tourette/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , China/epidemiologia , Feminino , Humanos , Masculino , Polimorfismo Genético , Síndrome de Tourette/epidemiologia , Adulto Jovem
16.
Genes Brain Behav ; 16(3): 328-341, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27749013

RESUMO

Although exercise is critical for health, many lack the motivation to exercise, and it is unclear how motivation might be increased. To uncover the molecular underpinnings of increased motivation for exercise, we analyzed the transcriptome of the striatum in four mouse lines selectively bred for high voluntary wheel running and four non-selected control lines. The striatum was dissected and RNA was extracted and sequenced from four individuals of each line. We found multiple genes and gene systems with strong relationships to both selection and running history over the previous 6 days. Among these genes were Htr1b, a serotonin receptor subunit and Slc38a2, a marker for both glutamatergic and γ-aminobutyric acid (GABA)-ergic signaling. System analysis of the raw results found enrichment of transcriptional regulation and kinase genes. Further, we identified a splice variant affecting the Wnt-related Golgi signaling gene Tmed5. Using coexpression network analysis, we found a cluster of interrelated coexpression modules with relationships to running behavior. From these modules, we built a network correlated with running that predicts a mechanistic relationship between transcriptional regulation by nucleosome structure and Htr1b expression. The Library of Integrated Network-Based Cellular Signatures identified the protein kinase C δ inhibitor, rottlerin, the tyrosine kinase inhibitor, Linifanib and the delta-opioid receptor antagonist 7-benzylidenenaltrexone as potential compounds for increasing the motivation to run. Taken together, our findings support a neurobiological framework of exercise motivation where chromatin state leads to differences in dopamine signaling through modulation of both the primary neurotransmitters glutamate and GABA, and by neuromodulators such as serotonin.


Assuntos
Cromatina/genética , Corpo Estriado/fisiologia , Motivação/genética , Atividade Motora/genética , Esforço Físico/genética , Receptores de Amina Biogênica/genética , Corrida/fisiologia , Animais , Monoaminas Biogênicas/metabolismo , Cromatina/metabolismo , Corpo Estriado/metabolismo , Dopamina/genética , Dopamina/metabolismo , Regulação da Expressão Gênica , Masculino , Camundongos , RNA não Traduzido/genética , Receptor 5-HT1B de Serotonina/biossíntese , Receptor 5-HT1B de Serotonina/genética , Receptores de Amina Biogênica/biossíntese , Seleção Genética , Transcriptoma
17.
Neurosci Lett ; 638: 204-210, 2017 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-28007644

RESUMO

Serotonin receptors, also known as 5-hydroxytryptamine receptors (HTRs), play a role in individuals' vulnerability to major depressive disorders (MDDs) and/or suicide attempts. In the first part of the study, we recruited 789 Taiwanese participants, which included 285 MDD patients, 191 MDD patients with a history of suicide attempts (MS), and 313 controls. The three groups were genotyped to identify HTR single nucleotide polymorphisms (SNPs) and we analyzed the correlations among the three groups. In the second part of the study, which involved a functional test of HTR1B allelic and haplotype variants, another 113 MDD patients were recruited. The rs6298-T allele was more frequent in the MS group than in the control group. The rs1923885-T allele occurred more frequently in the MS group than in the MDD group. Carriers of haplotype GT were estimated to have a 1.774-fold higher risk of suicide attempts. Younger age, alleles rs6296-C, rs6298-T and rs1923885-C, and haplotype CT were associated with a greater risk of MDD. Haplotypes GC and GT were directly associated with a lower risk of suicidal ideation. Haplotypes GC and GT also associated with higher levels of HTR1B mRNA, and haplotype GC was associated with extraversion, which caused a lower risk of suicidal ideation. The rs6296-C allele have directly and indirectly influenced a greater risk of suicidal ideation, which mediated by its negative effect on extraversion. Haplotype GT can be used to identify patients with a higher risk of suicide attempts. The rs6296-C allele lowered the level of HTR1B mRNA, causing individuals with MDD to display more hostility and aggressive behavior, which may lead to suicidal ideation.


Assuntos
Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/psicologia , Receptor 5-HT1B de Serotonina/genética , Ideação Suicida , Alelos , Estudos de Casos e Controles , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Heterozigoto , Humanos , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Receptor 5-HT1B de Serotonina/metabolismo , Risco
18.
Artigo em Inglês | MEDLINE | ID: mdl-28025020

RESUMO

The serotonin 1B receptor (5-HT1B) is important to both the pathogenesis of major depressive disorder and the antidepressant effects of selective serotonin reuptake inhibitors. Although fluoxetine has been shown to be effective and safe in children and adolescents, not all patients experience a proper clinical response, which has led to further study into the main factors involved in this inter-individual variability. Our aim was to study the effect of epigenetic and genetic factors that could affect 5-hydroxytryptamine receptor 1B (HTR1B) gene expression, and thereby response to fluoxetine. A total of 83 children and adolescents were clinically assessed 12weeks after of initiating an antidepressant treatment with fluoxetine for the first time. We evaluated the influence of single nucleotide polymorphisms (SNPs) specifically located in transcription factor binding sites (TFBSs) on their clinical improvement. A combined genetic analysis considering the significant SNPs together with the functional variant rs130058 previously associated in our population was also performed. Moreover, we assessed, for the first time in the literature, whether methylation levels of the HTR1B promoter region could be associated with the pharmacological response. Two, rs9361233 and rs9361235, were significantly associated with clinical improvement after treatment with fluoxetine. The heterozygous genotype combination analysis showed a negative correlation with clinical improvement. The lowest improvement was experienced by patients who were heterozygous for all three SNPs. Moreover, a negative correlation was found between clinical improvement and the average methylation level of the HTR1B promoter. These results give new evidence for the role of epigenetic and genetic factors which could modulate HTR1B expression in the pharmacological response to antidepressants.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Fluoxetina/uso terapêutico , Farmacogenética , Polimorfismo de Nucleotídeo Único/genética , Receptor 5-HT1B de Serotonina/genética , Adolescente , Transtornos de Ansiedade/dietoterapia , Transtornos de Ansiedade/genética , Criança , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Relação Dose-Resposta a Droga , Epigênese Genética/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Estatística como Assunto , Resultado do Tratamento
19.
Pharmacogenet Genomics ; 26(11): 487-496, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27660918

RESUMO

OBJECTIVE: Pharmacogenetic studies of fluoxetine in children and adolescents are scarce. After reporting the effect of genetic variants in genes related to the fluoxetine pharmacokinetics on clinical response in a pediatric population, we now evaluate the impact of genetic markers involved in its pharmacodynamics. PATIENTS AND METHODS: The assessment was performed in 83 patients after 12 weeks of fluoxetine treatment. The genetic association analysis included a total of 316 validated single nucleotide polymorphisms in 45 candidate genes involved in six different pathways. RESULTS: Clinical improvement after treatment with fluoxetine in our pediatric population was associated significantly with two polymorphisms located in genes related to the serotonergic system: the 5-hydroxytryptamine receptor 1B (HTR1B) and the tryptophan 5-hydroxylase 2 (TPH2). CONCLUSION: Although a wide range of candidate genes related to different pathways were assessed, the results show that genetic markers directly related to serotonin have an important effect on fluoxetine response.


Assuntos
Fluoxetina/farmacocinética , Transtornos Mentais/tratamento farmacológico , Variantes Farmacogenômicos , Receptor 5-HT1B de Serotonina/genética , Inibidores de Captação de Serotonina/farmacocinética , Triptofano Hidroxilase/genética , Adolescente , Transtornos de Ansiedade/tratamento farmacológico , Criança , Transtorno Depressivo/tratamento farmacológico , Feminino , Fluoxetina/administração & dosagem , Fluoxetina/farmacologia , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Testes Farmacogenômicos/métodos , Inibidores de Captação de Serotonina/administração & dosagem , Resultado do Tratamento
20.
Braz J Psychiatry ; 38(3): 239-42, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27579596

RESUMO

OBJECTIVE: To explore the association of three polymorphisms of the serotonin receptor 1Dß 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.


Assuntos
Anorexia Nervosa/genética , Bulimia Nervosa/genética , Estudos de Associação Genética/métodos , Polimorfismo de Nucleotídeo Único , Receptor 5-HT1B de Serotonina/genética , Adolescente , Adulto , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Anorexia Nervosa/fisiopatologia , Ansiedade/complicações , Ansiedade/fisiopatologia , Bulimia Nervosa/fisiopatologia , Depressão/complicações , Depressão/fisiopatologia , Família , Feminino , Frequência do Gene , Técnicas de Genotipagem , Humanos , Masculino , Valor Preditivo dos Testes , Fatores de Risco , Índice de Gravidade de Doença , Escala de Ansiedade Frente a Teste , Adulto Jovem
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