RESUMO
INTRODUCTION: Serotonin is highly implicated in the regulation of emotional state and the execution of cognitive tasks, so much so that the serotonin transporter genes (5-HTT, SLC6A4) and the serotonin receptor genes (HTR1A, HTR1B, HTR2A) have become the perfect candidates when studying the effects that these genes and their polymorphic variations have on depression characteristics. OBJECTIVE: A review of research reports that have studied the effects of variations in the serotonin transporter and receptor genes on different clinical features of depression. METHODS: A search of the Scopus, Web of Science and PubMed databases was conducted using the keywords ("depression" AND "polymorphism"). CONCLUSIONS: According to the review of 54 articles, the short allele of the 5-HTTLPR polymorphism was found to be the most reported risk factor related to the development of depression and its severity. Variations in the genes studied (SLC6A4, HTR1A, HTR2A) can generate morphological alterations of brain structures.
Assuntos
Depressão , Proteínas da Membrana Plasmática de Transporte de Serotonina , Humanos , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Depressão/genética , Polimorfismo Genético , Serotonina/genética , AlelosRESUMO
Various animal models, especially rodents, are used to study pain, due to the difficulty of studying it in humans. Many drugs that produce analgesia have been studied and there is evidence among which NSAIDs deserve to be highlighted. Dexketoprofen (DEX) provides a broad antinociceptive profile in different types of pain; therefore, this study was designed to evaluate the profile of antinociceptive potency in mice. Analgesic activity was evaluated using the acetic acid abdominal constriction test (writhing test), a chemical model of visceral pain. Dose-response curves for i.p. DEX administration (1, 3, 10, 30 and 100 mg/kg), using at least six mice in each of at least five doses, was obtained before and 30 min after pre-treatment with different pharmacological agents. Pretreatment of the mice with opioid receptor antagonists was not effective; however, the serotonin receptor antagonist and nitric oxide synthase inhibitor produce a significant increase in DEX-induced antinociception. The data from the present study shows that DEX produces antinociception in the chemical twisting test of mice, which is explained with difficulty by the simple inhibition of COX. This effect appears to be mediated by other mechanisms in which the contribution of the NO and 5-HT pathways has an important effect on DEXinduced antinociception.
Assuntos
Cetoprofeno/análogos & derivados , Receptores Opioides/genética , Receptores de Serotonina/genética , Trometamina/farmacologia , Dor Visceral/tratamento farmacológico , Ácido Acético/farmacologia , Analgesia/métodos , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Relação Dose-Resposta a Droga , Humanos , Cetoprofeno/farmacologia , Camundongos , Antagonistas de Entorpecentes/farmacologia , Óxido Nítrico/genética , Serotonina/genética , Antagonistas da Serotonina/farmacologia , Dor Visceral/genética , Dor Visceral/patologiaRESUMO
Traits that undergo massive natural selection pressure, with multiple events of positive selection, are hard to find. Social behaviour, in social animals, is crucial for survival, and genetic networks involved in behaviour, such as those of serotonin (5-HT) and other neurotransmitters, must be the target of natural selection. Here, we used molecular analyses to search for signals of positive selection in the 5-HT system and found such signals in the M3-M4 intracellular domain of the 5-HT3A serotonin receptor subunit (HTR3A) in primates. We detected four amino acid sites with signs of putatively positive selection (398, 403, 432 and 416); the first three showed indications of being selected in New World monkeys (NWM, Platyrrhini), specifically in the Callitrichinae branch. Additionally, we searched for associations of these amino acid variants with social behavioural traits (i.e. sex-biased dispersal, dominance and social monogamy) using classical and Bayesian methods, and found statistically significant associations for unbiased sex dispersal (398L and 416S), unbiased sex dominance (416S) and social monogamy (416S), as well as significant positive correlation between female dispersal and 403G. Furthermore, we found putatively functional protein motifs determined by three selected sites, of which we highlight a ligand motif to GSK3 in the 416S variant, appearing only in Platyrrhini. 5-HT, 5-HT3A receptor and GSK3 are part of a network that participates in neurodevelopment and regulates behaviour, among other functions. We suggest that these genetic variations, together with those found in other neurotransmitter systems, must contribute to adaptive behaviours and consequently to fitness in NWMs.
Assuntos
Comportamento Animal/fisiologia , Platirrinos/genética , Platirrinos/fisiologia , Seleção Genética , Serotonina/metabolismo , Animais , Evolução Molecular , Regulação da Expressão Gênica/fisiologia , Filogenia , Serotonina/genéticaRESUMO
AIMS: Pancreatic ß-cells synthesize and release serotonin (5 hydroxytryptamine, 5HT); however, the role of 5HT receptors on glucose stimulated insulin secretion (GSIS) and the mechanisms mediating this function is not fully understood. The aims of this study were to determine the expression profile of 5HT receptors in murine MIN6 ß-cells and to examine the effects of pharmacological activation of 5HT receptor Htr2b on GSIS and mitochondrial function. MATERIALS AND METHODS: mRNA levels of 5HT receptors in MIN6 cells were quantified by RT qPCR. GSIS was assessed in MIN6 cells in response to global serotonergic activation with 5HT and pharmacological Htr2b activation or inhibition with BW723C86 or SB204741, respectively. In response to Htr2b activation also was evaluated the mRNA and protein levels of PGC1α and PPARy by RT-qPCR and western blotting and mitochondrial function by oxygen consumption rate (OCR) and ATP cellular content. RESULTS: We found that mRNA levels of most 5HT receptors were either very low or undetectable in MIN6 cells. By contrast, Htr2b mRNA was present at moderate levels in these cells. Preincubation (6 h) of MIN6 cells with 5HT or BW723C86 reduced GSIS and the effect of 5HT was prevented by SB204741. Preincubation with BW723C86 increased PGC1α and PPARy mRNA and protein levels and decreased mitochondrial respiration and ATP content in MIN6 cells. CONCLUSIONS: Our results indicate that prolonged Htr2b activation in murine ß-cells decreases glucose-stimulated insulin secretion and mitochondrial activity by mechanisms likely dependent on enhanced PGC1α/PPARy expression.
Assuntos
Insulina/metabolismo , PPAR gama/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Receptores de Serotonina/genética , Serotonina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Humanos , Indóis/farmacologia , Insulina/genética , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Consumo de Oxigênio/genética , PPAR gama/biossíntese , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/biossíntese , Receptores de Serotonina/biossíntese , Serotonina/genética , Serotonina/farmacologia , Tiofenos/farmacologia , Ureia/análogos & derivados , Ureia/farmacologiaRESUMO
Psychiatric comorbidities are frequent in temporal lobe epilepsy (TLE). It is plausible that variance in serotonin-related genes is involved in the susceptibility of these associations. We report here the results on the association of tryptophan hydroxylase 2 (TPH2) gene polymorphisms with psychiatric comorbidities in TLE. A cohort study was conducted on 163 patients with TLE. We assessed the influence of the rs4570625 and rs17110747 polymorphisms in the TPH2 gene on psychiatric comorbidities in TLE. In patients with TLE, the presence of the T allele in the rs4570625 polymorphism was associated with psychotic disorders (OR=6.28; 95% CI=1.27-17.54; p=0.02), while the presence of the A allele in the rs17110747 polymorphism was associated with alcohol abuse (OR=20.33; 95% CI=1.60-258.46; p=0.02). Moreover, we identified male gender (OR=11.24; 95% CI=1.68-76.92; p=0.01) and family history of psychiatric disorder (OR=15.87; 95% CI=2.46-100; p=0.004) as factors also associated with alcohol abuse in TLE. Conversely, a family history of epilepsy was inversely associated with alcohol abuse (OR=0.03; 95% CI=0.001-0.60; p=0.02). Tryptophan hydroxylase 2 gene allele variants might be risk factors for psychiatric conditions in TLE. More specifically, we observed that the T allele in the rs4570625 polymorphism was associated with psychotic disorders, and the A allele in the rs17110747 TPH2 polymorphism was associated with alcohol abuse in patients with TLE. We believe that this study may open new research venues on the influence of the serotonergic system associated with psychiatric comorbidities in epilepsy.
Assuntos
Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/psicologia , Transtornos Mentais/epidemiologia , Serotonina/genética , Triptofano Hidroxilase/genética , Adulto , Alelos , Estudos de Coortes , Comorbidade , Epilepsia do Lobo Temporal/epidemiologia , Feminino , Genótipo , Humanos , Masculino , Transtornos Mentais/genética , Pessoa de Meia-Idade , Polimorfismo Genético , Receptores de Serotonina/metabolismo , Serotonina/administração & dosagem , Serotoninérgicos/uso terapêutico , Agonistas do Receptor de Serotonina/administração & dosagem , Fatores SexuaisRESUMO
Data suggest that the serotonin (5-hydroxytryptamine, 5-HT) system is implicated in the pathogenesis of multiple neuropsychiatric disorders and may also be involved in smoking behaviour since nicotine increases brain serotonin secretion. It is known that smoking behaviour is influenced by both genetic and environmental factors. The present review examines the role of the serotonin transporter gene (5-HTT) in smoking behaviour and investigating studies that showed association of 5-HTT gene with smoking. This study discusses a polymorphism which has been investigated by many researchers, as the bi-allelic insertion/deletion polymorphism in the 5'- flanking promoter region (5-HTTLPR). This gene has received considerable attention in attempts to understand the molecular determinants of smoking. Therefore, in the present study, the relationship between genetic polymorphism of serotonin transporter in smoking behaviour is reviewed considering the interactive effect of genetic factors.
Assuntos
Comportamento Aditivo/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Fumar/genética , Regiões 5' não Traduzidas/genética , Estudos de Associação Genética , Humanos , Mutação INDEL , Neurônios/metabolismo , Polimorfismo Genético , Regiões Promotoras Genéticas/genética , Serotonina/genética , Transmissão Sináptica/genéticaRESUMO
BACKGROUND: The occurrence of mania during antidepressant treatment is a key issue in the clinical management of bipolar disorder (BD). The serotonin transporter gene is a candidate to be associated with antidepressant-associated mania (AAM) in some patients. This gene has a polymorphism within the promoter region (5-HTTLPR) with two allelic forms, the long (L) and the short (S) variants. METHODS: We performed a case-control study to compare 5-HTTLPR genotype and allelic frequencies between 43 patients with a DSM-IV diagnosis of BD, with at least one manic/hypomanic episode associated with treatment with proserotonergic antidepressants (AAM+) and 69 unrelated, matched bipolar patients, who had been exposed to proserotonergic antidepressants without development of manic symptoms (AAM-(*)). Furthermore, we performed this comparison between a subgroup of 23 AAM+ patients that, when they presented AAM, were not using mood stabilizer (AAM+(*)) and 25 AAM- patients who used antidepressant without the concomitant use of a mood stabilizer (AAM-(*)). 5-HTTLPR genotyping was performed using PCR. RESULTS: No significant differences were found between AAM+ and AAM-. Within the subgroups, our results show that S-carriers (LS+SS Genotypes) are more prone to make a manic/hypomanic episode associated with antidepressant (P=0.017). LIMITATIONS: Our study is retrospective. CONCLUSIONS: The 5-HTTLPR polymorphism may be considered a predictor of abnormal response to antidepressant in patients with BP, but this action is influenced by the presence of a mood stabilizer. Such observations reinforce that a correct diagnosis of bipolarity before the beginning of the treatment is essential, mainly for S-carriers patients.
Assuntos
Antidepressivos/efeitos adversos , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto , Anticonvulsivantes/uso terapêutico , Antidepressivos/uso terapêutico , Estudos de Casos e Controles , Quimioterapia Combinada , Feminino , Predisposição Genética para Doença/genética , Variação Genética , Genótipo , Heterozigoto , Humanos , Compostos de Lítio/uso terapêutico , Masculino , Farmacogenética/estatística & dados numéricos , Reação em Cadeia da Polimerase/métodos , Regiões Promotoras Genéticas/genética , Estudos Retrospectivos , Serotonina/genética , Serotonina/metabolismoRESUMO
Early-life events influence brain development and evoke long-lasting behavioral consequences. Postweaning social isolation in rodents induces emotional and neurochemical alterations similar to those observed among some human psychopathologies. Central serotonergic neurotransmission is intimately involved in the observed adjustments, but the impact of social deprivation on serotonergic gene expression is unknown. We investigated the effects of prolonged early social isolation on emotion-related behaviors and 5-hydroxytryptamine (5-HT)-related gene transcription in mice. After weaning, male C57BL/6J mice were reared singly or in groups of four for 6 weeks. Gene expression of 5-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT(2C), 5-HT(3A), 5-HT(6) and 5-HT(7) receptors and of 5-HT transporter and tryptophan hydroxylase-2 was determined by quantitative real-time polymerase chain reaction in distinct brain areas. Single-housed mice were hyperactive in a novel environment and showed signs of aggressive behavior. Housing condition did not alter weight gain or body temperature. Isolation markedly reduced transcription of all postsynaptic 5-HT receptors in the prefrontal cortex and reduced 5-HT(1B), 5-HT(2A) and 5-HT(2C) in both hypothalamus and midbrain. In contrast, the only alteration in the hippocampus was 5-HT(6) overexpression. Neither 5-HT transporter nor synthetic enzyme gene transcription differed between housing conditions. In conclusion, early social isolation in mice induces robust changes in postsynaptic 5-HT receptors gene transcription, motor hyperactivity and behavioral disinhibition. The overall pattern of decreased gene expression in the prefrontal cortex highlights its high vulnerability to environment. Furthermore, this is the first study to present a general representation of 5-HT-related gene expression in specific brain areas after social isolation and identifies novel candidates that may be critical for underlying molecular mechanisms.
Assuntos
Encéfalo/metabolismo , Atividade Motora/fisiologia , Serotonina/metabolismo , Isolamento Social , Agressão/fisiologia , Animais , Comportamento Exploratório/fisiologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hipocampo/metabolismo , Hipotálamo/metabolismo , Masculino , Mesencéfalo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , RNA/análise , RNA Mensageiro/análise , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismoRESUMO
UNLABELLED: Burning mouth syndrome (BMS) is a chronic pain syndrome that encompasses all forms of burning sensations in the oral cavity when the oral mucosa is clinically normal. Neural, psychologic, and cytokine factors may be implicated in the pathogenesis of BMS. There are no studies of genetic factors associated with psychologic behavior and cytokine pain sensitivity in BMS patients. The purpose of the present study was to investigate a possible association between functional genetic polymorphisms, +3,954 (C/T) interleukin-1beta, and the polymorphic site on promoter region of the serotonin transporter gene (5-HTTLPR) in a sample of Brazilian patients. Thirty patients affected by BMS and 31 healthy volunteers were genotyped for 5-HTTLPR and IL-1beta gene. The chi-squared test was used for statistical analysis. There was no statistical difference in 5-HTTLPR genotypes between the case and control groups (P = .60), however a significant increase was observed in the IL-1beta high production genotype CT in BMS subjects (P = .005). In conclusion, the present study shows association between BMS and IL-1beta high producer genotype. PERSPECTIVE: This article shows evidence that genetic polymorphisms associated with IL-1beta high production genotype are implicated on the pathogenesis of BMS. The modulation of IL1beta production may be an interesting tool in BMS management.
Assuntos
Síndrome da Ardência Bucal/genética , Predisposição Genética para Doença/genética , Interleucina-1/genética , Polimorfismo Genético/genética , Serotonina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Síndrome da Ardência Bucal/imunologia , Síndrome da Ardência Bucal/fisiopatologia , Análise Mutacional de DNA , Transtorno Depressivo/genética , Transtorno Depressivo/imunologia , Transtorno Depressivo/fisiopatologia , Feminino , Marcadores Genéticos/genética , Testes Genéticos , Genótipo , Humanos , Interleucina-1/imunologia , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Serotonina/imunologiaRESUMO
OBJECTIVE: There is compelling evidence that a serotonergic dysfunction may play a major role in suicide behaviour and it has also been demonstrated that suicide is, at least partially, genetically determined. Thus, the serotonin-related genes are the major candidates. Previously a functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was identified and the presence of the short allele (S) was found to be associated with a lower level of expression of the gene and lower levels of 5-HT uptake when compared with the long allele (L). The purpose of this study was to evaluate the association between family suicide behaviour history and probands' suicide attempt (SA) history, SA characteristics and 5-HTTLPR genotype. METHOD: We genotyped 237 probands (major depressed or schizophrenic patients) and used a semistructured interview to determine probands' SA characteristics and first- and second-degree family suicidal behaviour. RESULTS: An association between suicidal family history and proband's SA but not with SA characteristics and probands genotype was found. CONCLUSION: Our results suggest that multiple biological and environmental factors underlie familial transmission of suicidal behaviour.