Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 230
Filtrar
1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
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
8.
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
9.
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
10.
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
11.
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
12.
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
13.
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
14.
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
15.
Neuropsychopharmacology ; 41(12): 2941-2950, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27353308

RESUMO

The effects of serotonin (5-HT) on anxiety and depression are mediated by a number of 5-HT receptors, including autoreceptors that act to inhibit 5-HT release. While the majority of anxiety and depression-related research has focused on the 5-HT1A receptor, the 5-HT1B receptor has a lesser known role in modulating emotional behavior. 5-HT1B receptors are inhibitory GPCRs located on the presynaptic terminal of both serotonin and non-serotonin neurons, where they act to inhibit neurotransmitter release. The autoreceptor population located on the axon terminals of 5-HT neurons is a difficult population to study due to their diffuse localization throughout the brain that overlaps with 5-HT1B heteroreceptors (receptors located on non-serotonergic neurons). In order to study the contribution of 5-HT1B autoreceptors to anxiety and depression-related behaviors, we developed a genetic mouse model that allows for selective ablation of 5-HT1B autoreceptors. Mice lacking 5-HT1B autoreceptors displayed the expected increases in extracellular serotonin levels in the ventral hippocampus following administration of a selective serotonin reuptake inhibitor. In behavioral studies, they displayed decreased anxiety-like behavior in the open field and antidepressant-like effects in the forced swim and sucrose preference tests. These results suggest that strategies aimed at blocking 5-HT1B autoreceptors may be useful for the treatment of anxiety and depression.


Assuntos
Ansiedade/metabolismo , Autorreceptores/metabolismo , Depressão/metabolismo , Hipocampo/metabolismo , Receptor 5-HT1B de Serotonina/deficiência , Animais , Animais Recém-Nascidos , Ansiedade/genética , Autorreceptores/genética , Depressão/genética , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Preferências Alimentares/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Isótopos de Iodo/farmacocinética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pindolol/análogos & derivados , Pindolol/farmacocinética , Receptor 5-HT1B de Serotonina/genética , Receptores 5-HT1 de Serotonina/genética , Receptores 5-HT1 de Serotonina/metabolismo , Antagonistas da Serotonina/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
16.
J Neural Transm (Vienna) ; 123(11): 1347-1354, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27324805

RESUMO

Pharmacogenetic approach to antidepressant (AD) response is a promising avenue toward individualizing AD treatment. This is particularly relevant in pediatric populations because of concerns about the suicide risk of serotonin selective reuptake inhibitors (SSRIs), resulting in a black-box warning. However, to date, no specific gene or polymorphism has been consistently implicated as a marker of AD side effect (SE) in the pediatric population. The aim of this study was to examine the association between polymorphisms in genes related to the serotonergic system and citalopram SE's in children and adolescents with major depressive disorder (MDD)/dysthymia and/or anxiety disorders. Outpatients (N = 87, 44 % males), aged 7-18 years with a DSM-IV-TR diagnosis of MDD/dysthymia and/or an anxiety disorder were treated in an 8-week open trial with 20-40 mg/day of citalopram. SE's were rated using a questionnaire devised specifically for this study. Association analysis between known/candidate genetic variants in three genes (5-HTR2A, 5-HTR1Dß, 5-HTR2C) and SE's was conducted. Agitation was more common in boys than girls (male:female 42.1 vs. 18.7 %, χ 2 = 5.61, df = 1, p = 0.018). Subjects with 5-HTR1Dß CC genotype showed more agitation vs. both CG and GG genotypes (CC:CG:GG 71.4 vs. 33.3 vs. 18.1 %, χ 2 = 8.99, df = 2, p = 0.011). The 5-HTR1Dß CC genotype was associated with more reports of agitation. It has been suggested that agitation may be an intermediate phenotype to suicidal behavior. Thus, it seems that 5-HTR1Dß polymorphism may be involved in citalopram-related agitation in children and adolescents treated for depression and/or anxiety.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/genética , Citalopram/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Inibidores de Captação de Serotonina/efeitos adversos , Adolescente , Criança , Citalopram/uso terapêutico , Transtorno Distímico/tratamento farmacológico , Transtorno Distímico/genética , Feminino , Humanos , Masculino , Variantes Farmacogenômicos , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2C de Serotonina/genética , Inibidores de Captação de Serotonina/uso terapêutico , Fatores Sexuais
17.
J Alzheimers Dis ; 53(1): 349-61, 2016 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-27163814

RESUMO

Serotonin (5-HT) plays a central role in the integrity of different brain functions. The 5-HT homeostasis is regulated by many factors, including serotonin transporter (SERT), monoamine oxidase enzyme (MAO), and several 5-HT receptors, including the 5-HT1B. There is little knowledge how the dynamics of this system is affected by the amyloid-ß (Aß) burden of Alzheimer's disease (AD) pathology. SH-SY5Y neuroblastoma cells transfected with the amyloid precursor protein (APP) gene containing the Swedish mutations causing familial AD (APPswe), were used as a model to explore the effect of Aß pathology on 5-HT1B and related molecules including the receptor adaptor protein (p11), SERT and MAOA gene expression, and MAOA activity after treatment with selective serotonin reuptake inhibitor (SSRI) (sertraline), and a 5-HT1B receptor antagonist. Sertraline led more than 70 fold increase of 5-HT1B gene expression (p < 0.001), an increased serotonin turnover in both APPswe and control cells and reduced intracellular serotonin levels by 75% in APPswe cells but not in controls (p > 0.05). Treatment with the 5-HT1B receptor antagonist increased SERT gene-expression in control cells but not in the APPswe cells. 5-HT and 5-HT1B antagonist treatment resulted in different p11 expression patterns in APPswe cells compared to controls. Although MAOA gene expression was not changed by APPswe overexpression, adding 5-HT lead to a significant increase in MAOA gene expression in APPswe but not control cells. These findings suggest that the sensitivity of the 5-HT1B receptor and related systems is affected by APPswe overexpression, with potential relevance for pharmacologic intervention in AD. This may at least partly explain the lack of effect of SSRIs in patients with AD and depression.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Receptor 5-HT1B de Serotonina/metabolismo , Serotoninérgicos/farmacologia , Serotonina/metabolismo , Precursor de Proteína beta-Amiloide/genética , Linhagem Celular Tumoral , Cromatografia Líquida , Técnicas Eletroquímicas , Regulação da Expressão Gênica/genética , Humanos , Ácido Hidroxi-Indolacético/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Monoaminoxidase/metabolismo , Mutação/genética , Neuroblastoma/patologia , Fosforilação/efeitos dos fármacos , Piperidonas/farmacologia , RNA Mensageiro/metabolismo , Receptor 5-HT1B de Serotonina/genética , Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Compostos de Espiro/farmacologia , Estatísticas não Paramétricas , Transfecção
18.
Nutr Diabetes ; 6: e204, 2016 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-27110685

RESUMO

OBJECTIVE: This study examined the proteomic profile of the hypothalamus in mice exposed to a high-fat diet (HFD) or with the anorexia of acute illness. This comparison could provide insight on the effects of these two opposite states of energy balance on appetite regulation. METHODS: Four to six-week-old male C56BL/6J mice were fed a normal (control 1 group; n=7) or a HFD (HFD group; n=10) for 8 weeks. The control 2 (n=7) and lipopolysaccharide (LPS) groups (n=10) were fed a normal diet for 8 weeks before receiving an injection of saline and LPS, respectively. Hypothalamic regions were analysed using a quantitative proteomics method based on a combination of techniques including iTRAQ stable isotope labeling, orthogonal two-dimensional liquid chromatography hyphenated with nanospray ionization and high-resolution mass spectrometry. Key proteins were validated with quantitative PCR. RESULTS: Quantitative proteomics of the hypothalamous regions profiled a total of 9249 protein groups (q<0.05). Of these, 7718 protein groups were profiled with a minimum of two unique peptides for each. Hierachical clustering of the differentiated proteome revealed distinct proteomic signatures for the hypothalamus under the HFD and LPS nutritional conditions. Literature research with in silico bioinformatics interpretation of the differentiated proteome identified key biological relevant proteins and implicated pathways. Furthermore, the study identified potential pharmacologic targets. In the LPS groups, the anorexigen pro-opiomelanocortin was downregulated. In mice with obesity, nuclear factor-κB, glycine receptor subunit alpha-4 (GlyR) and neuropeptide Y levels were elevated, whereas serotonin receptor 1B levels decreased. CONCLUSIONS: High-precision quantitative proteomics revealed that under acute systemic inflammation in the hypothalamus as a response to LPS, homeostatic mechanisms mediating loss of appetite take effect. Conversely, under chronic inflammation in the hypothalamus as a response to HFD, mechanisms mediating a sustained 'perpetual cycle' of appetite enhancement were observed. The GlyR protein may constitute a novel treatment target for the reduction of central orexigenic signals in obesity.


Assuntos
Anorexia/genética , Regulação do Apetite , Hipotálamo/metabolismo , Obesidade/genética , Proteoma/metabolismo , Animais , Anorexia/sangue , Anorexia/induzido quimicamente , Biologia Computacional , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Regulação para Baixo , Inflamação/induzido quimicamente , Inflamação/genética , Insulina/sangue , Resistência à Insulina , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Obesidade/sangue , Obesidade/induzido quimicamente , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT1B de Serotonina/metabolismo , Receptores da Glicina/genética , Receptores da Glicina/metabolismo
19.
Curr Biol ; 26(7): 981-6, 2016 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-27020741

RESUMO

Anxiety helps us anticipate and assess potential danger in ambiguous situations [1-3]; however, the anxiety disorders are the most prevalent class of psychiatric illness [4-6]. Emotional states are shared between humans and other animals [7], as observed by behavioral manifestations [8], physiological responses [9], and gene conservation [10]. Anxiety research makes wide use of three rodent behavioral assays-elevated plus maze, open field, and light/dark box-that present a choice between sheltered and exposed regions [11]. Exposure avoidance in anxiety-related defense behaviors was confirmed to be a correlate of rodent anxiety by treatment with known anxiety-altering agents [12-14] and is now used to characterize anxiety systems. Modeling anxiety with a small neurogenetic animal would further aid the elucidation of its neuronal and molecular bases. Drosophila neurogenetics research has elucidated the mechanisms of fundamental behaviors and implicated genes that are often orthologous across species. In an enclosed arena, flies stay close to the walls during spontaneous locomotion [15, 16], a behavior proposed to be related to anxiety [17]. We tested this hypothesis with manipulations of the GABA receptor, serotonin signaling, and stress. The effects of these interventions were strikingly concordant with rodent anxiety, verifying that these behaviors report on an anxiety-like state. Application of this method was able to identify several new fly anxiety genes. The presence of conserved neurogenetic pathways in the insect brain identifies Drosophila as an attractive genetic model for the study of anxiety and anxiety-related disorders, complementing existing rodent systems.


Assuntos
Ansiedade/metabolismo , Vias Neurais , Animais , Ansiedade/tratamento farmacológico , Ansiedade/genética , Diazepam/farmacologia , Drosophila , Luz , Camundongos , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT1B de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
20.
Alcohol Clin Exp Res ; 40(2): 284-90, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26842247

RESUMO

BACKGROUND: The roles of GABA, serotonin, dopamine, and alcohol metabolism pathways in alcohol dependence (AD) are evident from animal models and human studies. Aims of this study were to investigate associations between genes in the 4 pathways and AD. METHODS: Male subjects from 2 independent samples of Taiwanese Han descent, a family sample of 179 trios and a case-control sample of 262 AD cases and 273 normal controls, were included in this study. The Schedules for Clinical Assessment in Neuropsychiatry was used for phenotype assessment of AD. We genotyped 282 single nucleotide polymorphisms (SNPs) located in 61 candidate genes involving alcohol metabolism, serotonin, and GABA systems among the family sample and replicated the top hits in the case-control sample. RESULTS: Fifteen SNPs located in 10 genes showed signals of associations (FBAT test p < 0.05) with AD in the family sample. Three SNPs, rs1229984 in ADH1B, rs671 in ALDH2, and rs2000292 in HTR1B, were significantly replicated in the case-control sample (p = 5.87 × 10(-14) , 5.12 × 10(-14) , and 0.0051, respectively). In the combined meta-analysis, these 3 SNPs and 1 additional SNP, rs698 in ADH1C, showed significant association after correcting for multiple comparisons, and rs1229984 and rs671 showed the strongest association (p < 10(-16) ). Logistic regression conditioning on rs1229984 and rs671 in the case-control sample showed that rs2000292 in HTR1B remained nominally significant. CONCLUSIONS: Genes in alcohol metabolism pathway, especially ADH1B and ALDH2, conferred the major genetic risk for AD in Taiwanese Han population. Some genes in GABA and serotonin pathways showed nominal association with AD.


Assuntos
Alcoolismo/genética , Dopamina/metabolismo , Etanol/metabolismo , Redes e Vias Metabólicas/genética , Polimorfismo de Nucleotídeo Único/genética , Serotonina/metabolismo , Ácido gama-Aminobutírico/metabolismo , Adulto , Álcool Desidrogenase/genética , Álcool Desidrogenase/fisiologia , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/fisiologia , Aldeído-Desidrogenase Mitocondrial , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/fisiologia , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT1B de Serotonina/fisiologia , Taiwan
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA