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1.
Genes (Basel) ; 10(10)2019 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-31614865

RESUMO

This study identified a transcription factor that might bind to the 5' regulatory region of the HTR1A and explored the potential effect on 5-HT1A receptor expression. Based on JASPAR predictions, the binding of the transcription factor was demonstrated using the electrophoretic mobility shift assay (EMSA). Vectors over-expressing the transcription factor were co-transfected into HEK-293 and SK-N-SH cells with the recombinant pGL3 vector, and relative fluorescence intensity was measured to determine regulatory activity. Additionally, the qRT-PCR and Western blot were also used to identify whether the transcription factor modulated the endogenous expression of 5-HT1A receptor. The results suggest that the transcription factor CCAA/T enhancer binding protein beta (CEBPB) likely binds to the -1219 to -1209 bp (ATG+1) region of the HTR1A. Two sequences located in the -722 to -372 bp and -119 to +99 bp were also identified. Although the effect of CEBPB on endogenous 5-HT1A receptor expression was not significant, it exhibited the strong inhibition on the relative fluorescence intensity and the mRNA level of HTR1A. CEBPB inhibited the human HTR1A expression by binding to the sequence -1219 - -1209 bp. This is useful and informative for ascertaining the regulation of 5-HT1A receptor and mental diseases.


Assuntos
Região 5'-Flanqueadora , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Receptor 5-HT1A de Serotonina/genética , Regulação da Expressão Gênica , Células HEK293 , Humanos , Receptor 5-HT1A de Serotonina/metabolismo , Sequências Reguladoras de Ácido Nucleico
2.
Nat Commun ; 10(1): 3924, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477731

RESUMO

The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD). Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains, and identified ZDHHC21 as a major palmitoyl acyltransferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression-like behavior show reduced brain ZDHHC21 expression and attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in the murine forebrain induced depression-like behavior. We also identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. Through analysis of the post-mortem brain samples in individuals with MDD that died by suicide we find that miR-30e expression is increased, while ZDHHC21 expression, as well as palmitoylation of 5-HT1AR, are reduced within the prefrontal cortex. Our study suggests that downregulation of 5-HT1AR palmitoylation is a mechanism involved in depression, making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of MDD.


Assuntos
Encéfalo/fisiopatologia , Depressão/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Receptor 5-HT1A de Serotonina/metabolismo , Aciltransferases/genética , Aciltransferases/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Depressão/genética , Depressão/metabolismo , Transtorno Depressivo Maior/genética , Regulação da Expressão Gênica , Humanos , Lipoilação , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Ratos Wistar , Receptor 5-HT1A de Serotonina/genética
3.
Psychiatr Danub ; 31(2): 256-262, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291234

RESUMO

BACKGROUND: Post-traumatic stress disorder (PTSD) is a stress related disorder which can occur in an individual after exposure to a traumatic event. It most commonly co-occurs with depression. The two disorders share not only overlapping symptoms, but also genetic diathesis. The aim of this study was to investigate the potential role of single nucleotide polymorphisms (SNPs) of the two serotonergic candidate genes 5-hydroxytryptamine receptor 1A (HTR1A) and tryptophan hydroxylase 2 (TPH2) in the pathogenesis of PTSD and comorbid psychopathology. SUBJECTS AND METHODS: 719 (487 males, 232 females) participants who had experienced war-related trauma between 1991 and 1999 in Bosnia and Herzegovina, Kosovo and Croatia were included in the study. The Sociodemographic questionnaire, Mini International Neuropsychiatric Interview (M.I.N.I.), Clinician Administered PTSD Scale (CAPS) and Brief Symptom Inventory (BSI) were used to collect clinical data. The SNPs rs6295 (HTR1A), rs11178997 and rs1386494 (TPH2) were investigated for their association with PTSD and comorbid psychopathology. RESULTS: A nominal significant association was found between the BSI total score in Lifetime PTSD with the SNP rs6295 of the HTR1A gene. The best result was seen in the dominant model (P=0.018), with the minor allele (C) being the risk allele. Several BSI subscores were also associated with the minor (C) allele in Lifetime PTSD. No association was found for the TPH2 SNPs rs11178997 and rs1386494 in relation to PTSD or comorbid psychopathology. CONCLUSIONS: Our findings suggest that rs6295 in the HTR1A gene may contribute to the psychopathology of PTSD.


Assuntos
Alelos , Receptor 5-HT1A de Serotonina/genética , Transtornos de Estresse Pós-Traumáticos/genética , Triptofano Hidroxilase/genética , Conflitos Armados/psicologia , Bósnia e Herzegóvina , Croácia , Feminino , Humanos , Kosovo , Masculino , Pessoa de Meia-Idade
4.
Asian J Psychiatr ; 43: 184-188, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31228794

RESUMO

INTRODUCTION: Major Depressive Disorder (MDD) is a broad heterogeneous diagnostic construct. Previous studies have shown that it can be resolved into several symptom-clusters which are proposed to be associated with single nucleotide polymorphisms (SNPs) of the serotonergic pathway (5-HTTLPR, 5HTR1A, 5-HTR2A). METHODS AND MATERIAL: In a cross-sectional study conducted at a tertiary level mental health care set-up in north India, 80 out-patients with MDD were evaluated with Montgomery Asberg Depression Rating Scale (MADRS) and then genotyping was done. The different clinical and genetic variables were compared across the factor structures of MADRS. Also, the comparison of the genetic data of cases was done with the pre-existing database of the non-blood related healthy ethnically-matched controls. RESULTS: There was no significant association between age, gender, other clinical variables, SNPs like 5-HTTLPR SS/SL, rs6295 CC/CG/GG, rs6311GG/GA/AA, rs6313 CC/CT/TT and different factor-structures like 'detachment' consisting of items like concentration difficulty, lassitude, inability to feel; 'psychic anxiety' consisting of suicidal thoughts and inner tension; 'mood-pessimism' consisting of symptoms like apparent sadness, reported sadness, pessimistic thoughts and 'vegetative symptoms' like decreased sleep, poor appetite. Neither there was any association between genotype of the cases compared with the controls. CONCLUSIONS: No significant association was obtained between the four-factor structures of depression in MADRS and serotonin transporter and receptor SNPs in a study with a small sample size. This study evaluates whether depression symptom-clusters have distinct genotypic determinants and necessitates more comprehensive studies for unravelling the genetic determinants of depression.


Assuntos
Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/fisiopatologia , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT2A de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto , Estudos Transversais , Transtorno Depressivo Maior/classificação , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
5.
Mol Biol Evol ; 36(7): 1418-1429, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31045220

RESUMO

Serotonin is a neurotransmitter that plays an important role in regulating behavior and personality in humans and other mammals. Polymorphisms in genes coding for the serotonin receptor subtype 1A (HTR1A), the serotonin transporter (SLC6A4), and the serotonin degrading enzyme monoamine oxidase A (MAOA) are associated with anxiety, impulsivity, and neurotic personality in humans. In primates, previous research has largely focused on SLC6A4 and MAOA, with few studies investigating the role of HTR1A polymorphic variation on behavior. Here, we examined variation in the coding region of HTR1A across apes, and genotyped polymorphic coding variation in a sample of 214 chimpanzees with matched measures of personality and behavior. We found evidence for positive selection at three amino acid substitution sites, one in chimpanzees-bonobos (Thr26Ser), one in humans (Phe33Val), and one in orangutans (Ala274Gly). Investigation of the HTR1A coding region in chimpanzees revealed a polymorphic site, where a C/A single nucleotide polymorphism changes a proline to a glutamine in the amino acid sequence (Pro248Gln). The substitution is located in the third intracellular loop of the receptor, a region important for serotonin signal transduction. The derived variant is the major allele in this population (frequency 0.67), and is associated with a reduction in anxiety, decreased rates of male agonistic behavior, and an increase in socio-positive behavior. These results are the first evidence that the HTR1A gene may be involved in regulating social behavior in chimpanzees and encourage further systematic investigation of polymorphic variation in other primate populations with corresponding data on behavior.


Assuntos
Comportamento Agonístico , Ansiedade/genética , Pan troglodytes/genética , Receptor 5-HT1A de Serotonina/genética , Sequência de Aminoácidos , Animais , Feminino , Variação Genética , Masculino , Pan troglodytes/psicologia , Personalidade/genética
6.
Food Funct ; 10(5): 2720-2728, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31033966

RESUMO

Piperine is the crucial alkaloid component of black pepper (Piper nigrum Linn.) and has neuroprotective effects. Because inhibition of glutamatergic excitatory neurotransmission is a possible mechanism involved in neuroprotection, we investigated the effect of piperine on the 4-aminopyridine (4-AP)-evoked release of glutamate from rat hippocampal synaptosomes. Piperine inhibited 4-AP-evoked glutamate release, and the inhibition was prevented by the chelation of extracellular Ca2+ ions and a vesicular transporter inhibitor. Piperine reduced the 4-AP-evoked elevation of intrasynaptosomal Ca2+ levels but did not affect the synaptosomal membrane potential. In the presence of ω-conotoxin MVIIC, an N- and P/Q-type channel blocker, the piperine-mediated inhibition of 4-AP-evoked glutamate release was markedly reduced; however, dantrolene and CGP37157, which are intracellular Ca2+-release inhibitors, did not alter the piperine effect. In addition, immunocytochemical analysis confirmed the presence of presynaptic 5-hydroxytryptamine 1A (5-HT1A) receptor proteins. The glutamate release-inhibiting effect of piperine was discovered to be prevented by the 5-HT1A receptor antagonist WAY100635 and the G protein ßγ subunit inhibitor gallein; however, it was unaffected by the adenylate cyclase inhibitor SQ22536 or the protein kinase A inhibitor PKI622. These results suggest that piperine inhibits glutamate release from rat hippocampal nerve terminals by reducing Ca2+ influx through N- and P/Q-type Ca2+ channels and that the activation of presynaptic 5-HT1A receptors and the G protein ßγ subunit is involved in this effect.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Cálcio/metabolismo , Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , 4-Aminopiridina/metabolismo , Animais , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Subunidades beta da Proteína de Ligação ao GTP/genética , Subunidades gama da Proteína de Ligação ao GTP/genética , Hipocampo/efeitos dos fármacos , Masculino , Piper nigrum/química , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/genética , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo
7.
Biochem Biophys Res Commun ; 511(2): 440-446, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30808545

RESUMO

The association between dysregulated serotonergic activity and major depressive disorder (MDD) is well known. However, the various mechanisms underlying serotonergic dysregulation in MDD remain unclear. Previous research on serotonergic (5-HT) neurons identified microRNA-26a (miR-26a) targeting of the serotonin autoreceptor, 5-HT receptor 1A (HTR1A). Reporter assays with the Htr1a 5'UTR sequence were performed in vitro. Adult transgenic mouse models altering miR-26a-2 and Htr1a expression were used for chronic social defeat, antidepressant treatment, and in vivo lentiviral experiments. Mice were tested for anxiety-like behavior using the elevated plus-maze, dark-light transfer, and open-field tests, and for depression-like behavior using the forced-swim test. We confirmed that miR-26a-2 downregulates Htr1a expression in 5-HT neurons in vitro. miR-26a-2 levels were significantly upregulated in the mouse dorsal raphe nucleus (DRN) following antidepressant therapy. The transgenic murine model overexpressing miR-26a-2 in serotonergic neurons displayed improved behavioral resiliency to social defeat. These effects were abrogated by the addition of Htr1a overexpression. In contrast, the transgenic murine model with miR-26a-2 knockdown in serotonergic neurons displayed increased anxious behavior and weakened antidepressant response. These effects were rescued by silencing Htr1a expression. Our findings suggest that miR-26a-2 functions as an endogenous antidepressant by targeting HTR1A in serotonergic neurons.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , MicroRNAs/genética , Receptor 5-HT1A de Serotonina/genética , Animais , Ansiedade/complicações , Ansiedade/genética , Ansiedade/patologia , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/patologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Regulação para Cima/efeitos dos fármacos
8.
Circ Arrhythm Electrophysiol ; 12(1): e006884, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30636478

RESUMO

BACKGROUND: Several studies suggest that vasovagal syncope has a genetic origin, but this is unclear. We assessed whether plausible gene variants associate with vasovagal syncope. METHODS: We studied 160 subjects in 9 kindreds comprising 82 fainters and 78 controls. The diagnosis was ascertained with the Calgary Syncope Score. Common genetic variants were genotyped for 12 genes for vascular signaling, potassium channels, the HTR1A(serotonin 5-HT1A receptor), SLC6A4(serotonin reuptake transporter), and COMT(catecholamine O-methyltransferase). Sex-specific associations between genotypes and phenotypes were tested. RESULTS: In 9 out of 12 variants, there was no significant association between genotype and phenotype. However, the HTR1A(-1019) G alleles associated with syncope in males, but not in females ( P=0.005). CC and GG males had 9% versus 77% likelihoods of syncope. The SLC6A4 promoter L alleles associated with decreased syncope in males but increased in females ( P=0.059). The LL and SS males had 25% and 47% syncope likelihoods, whereas females had 75% and 50% syncope likelihoods. The COMT c.472 A alleles associated with decreased syncope in males but increased in females ( P=0.017). The GG and AA males had 50% and 15% syncope likelihoods, whereas females had 52% and 73% syncope likelihoods. CONCLUSIONS: There is a sex-dependent effect of alleles of serotonin signaling and vasovagal syncope, supporting the serotonin hypothesis of the physiology of vasovagal syncope.


Assuntos
Catecol O-Metiltransferase/genética , Polimorfismo de Nucleotídeo Único , Receptor 5-HT1A de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Síncope Vasovagal/genética , Adulto , Alberta , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Linhagem , Fenótipo , Medição de Risco , Fatores de Risco , Fatores Sexuais , Síncope Vasovagal/diagnóstico , Síncope Vasovagal/fisiopatologia
9.
PLoS One ; 14(1): e0210949, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30677060

RESUMO

We show that in an animal model of anxiety the overall excitation, particularly in the infralimbic region of the medial prefrontal cortex (IL), is increased and that the activity ratio between excitatory pyramidal neurons and inhibitory interneurons (AR PN/IN) is shifted towards excitation. The same change in AR PN/IN is evident for wildtype mice, which have been exposed to an anxiety stimulus. We hypothesize, that an elevated activity and the imbalance of excitation (PN) and inhibition (IN) within the neuronal microcircuitry of the prefrontal cortex is responsible for anxiety behaviour and employed optogenetic methods in freely moving mice to verify our findings. Consistent with our hypothesis elevation of pyramidal neuron activity in the infralimbic region of the prefrontal cortex significantly enhanced anxiety levels in several behavioural tasks by shifting the AR PN/IN to excitation, without affecting motor behaviour, thus revealing a novel mechanism by which anxiety is facilitated.


Assuntos
Ansiedade/patologia , Ansiedade/fisiopatologia , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Células Piramidais/patologia , Células Piramidais/fisiologia , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/fisiopatologia , Animais , Ansiedade/etiologia , Transtornos de Ansiedade/etiologia , Transtornos de Ansiedade/patologia , Transtornos de Ansiedade/fisiopatologia , Modelos Animais de Doenças , Núcleo Dorsal da Rafe/patologia , Núcleo Dorsal da Rafe/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Optogenética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptor 5-HT1A de Serotonina/deficiência , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT1A de Serotonina/fisiologia , Serotonina/fisiologia , Transmissão Sináptica
10.
Brain Behav ; 9(2): e01140, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30656852

RESUMO

OBJECTIVE: From an evolutionary perspective, emotions emerged as rapid adaptive reactions that increase survival rates. Current psychobiology includes the consideration that genetic changes affecting neuroendocrine and neurotransmission pathways may also be affecting mood states. Following this hypothesis, abnormal levels of any of the aminergic neurotransmitters would be of considerable importance in the development of a pathophysiological state. MATERIALS AND METHODS: A total of 668 students from the School of Medicine of the University of Malaga (Average = 22.41 ± 3; 41% men) provided self-report measures of mood states using POMS and GHQ-28 questionnaires and buccal cells for genotyping 19 polymorphisms from 14 selected neurotransmitter pathways genes (HTR1A; HTR2A; HTR2C; HTR3B; TPH1; SLC18A1; SLC18A2; COMT; MAOA; MAOB) and neuroendocrine system (AVPR1B; OPRM1; BDNF; OXTR). RESULTS: MAOA rs3788862 genotype correlates with decreasing levels of Tension among females (beta = -0.168, p-value = 0.003) but it is neutral among males in this subscale. On the contrary, it correlates with lower GHQ-28 depression scores among males (beta = -0.196, p-value = 0.008). Equivalently, SLC18A1 and HTR2A variants correlated with anger and vigor scores, only among males. From the neuroendocrine system, OPRM1 rs1799971 correlated increasing levels of female's Anxiety, depression and Social Dysfunction scores. CONCLUSION: Our findings suggest that these polymorphisms contribute to define general population mood levels, although exhibiting a clear sexual dimorphism.


Assuntos
Emoções/fisiologia , Voluntários Saudáveis/psicologia , Monoaminoxidase/genética , Receptor 5-HT1A de Serotonina/genética , Transmissão Sináptica/genética , Proteínas Vesiculares de Transporte de Monoamina/genética , Adulto , Feminino , Genótipo , Humanos , Masculino , Sistemas Neurossecretores/metabolismo , Polimorfismo Genético , Técnicas Psicológicas , Fatores Sexuais , Estudantes/psicologia , Inquéritos e Questionários
11.
Transl Psychiatry ; 9(1): 5, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30664620

RESUMO

Alterations of the 5-HT1A receptor and BDNF have consistently been associated with affective disorders. Two functional single nucleotide polymorphisms (SNPs), rs6295 of the serotonin 1A receptor gene (HTR1A) and rs6265 of brain-derived neurotrophic factor gene (BDNF), may impact transcriptional regulation and expression of the 5-HT1A receptor. Here we investigated interaction effects of rs6295 and rs6265 on 5-HT1A receptor binding. Forty-six healthy subjects were scanned with PET using the radioligand [carbonyl-11C]WAY-100635. Genotyping was performed for rs6265 and rs6295. Subjects showing a genotype with at least three risk alleles (G of rs6295 or A of rs6265) were compared to control genotypes. Cortical surface binding potential (BPND) was computed for 32 cortical regions of interest (ROI). Mixed model was applied to study main and interaction effects of ROI and genotype. ANOVA was used for post hoc analyses. Individuals with the risk genotypes exhibited an increase in 5-HT1A receptor binding by an average of 17% (mean BPND 3.56 ± 0.74 vs. 2.96 ± 0.88). Mixed model produced an interaction effect of ROI and genotype on BPND and differences could be demonstrated in 10 ROI post hoc. The combination of disadvantageous allelic expression of rs6295 and rs6265 may result in a 5-HT1A receptor profile comparable to affective disorders as increased 5-HT1A receptor binding is a well published phenotype of depression. Thus, epistasis between BDNF and HTR1A may contribute to the multifactorial risk for affective disorders and our results strongly advocate further research on this genetic signature in affective disorders.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Transtorno Depressivo/genética , Epistasia Genética , Receptor 5-HT1A de Serotonina/metabolismo , Adulto , Alelos , Encéfalo/diagnóstico por imagem , Fator Neurotrófico Derivado do Encéfalo/genética , Estudos Transversais , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/metabolismo , Polimorfismo de Nucleotídeo Único , Tomografia por Emissão de Pósitrons , Piridinas/metabolismo , Receptor 5-HT1A de Serotonina/genética
12.
Int J Neurosci ; 129(3): 264-272, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30232922

RESUMO

OBJECTIVE: There have been controversial results in the literature on the association between HTR1A polymorphisms (rs10042486, C-1019G, and Gly272Asp) and obsessive-compulsive disorder (OCD). Here, the plausibility for such genetic and pharmacogenetic association was investigated by assessing a sample of Iranian OCD patients. METHOD: OCD patients had fulfilled the criteria for DSM-IV-TR with Y-BOCS scores higher than 9. A total of 207 controls and 205 patients' blood samples were genotyped by means of PCR-RFLP. RESULTS: The results showed that there was no association between these three SNPs and the treatment response. The distribution of rs10042486 genotypes was significantly different in the patients compared to the controls. The association analyses of the C-1019G showed significant differences in the genotypic frequency of the patients with or without a positive family history of psychiatric disorders. Similar differences in female patients were also observed. We found that the age of onset also associates with the C-1019G polymorphism but only in the female patients. No association of Gly272Asp polymorphism and OCD was observed in this study. CONCLUSION: We concluded that among the HTR1A polymorphisms, only the association of rs10042486 CT genotype and OCD was statistically significant. The association of C-1019G with OCD by considering the age of onset and family history was just significant in the female patients. No significant association between the studied HTR1A SNPs with treatment response was observed. Acquiring both positive and negative pharmacogenetic outcomes in each population helps to select the appropriate medication for a particular patient with fewer side effects.


Assuntos
Fluvoxamina/farmacologia , Transtorno Obsessivo-Compulsivo/genética , Receptor 5-HT1A de Serotonina/genética , Inibidores de Captação de Serotonina/farmacologia , Adulto , Idade de Início , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Adulto Jovem
13.
Food Chem Toxicol ; 123: 125-141, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30366073

RESUMO

Serotonin syndrome is an adverse reaction due to increased serotonin (5-hydroxytryptophan: 5-HT) concentrations in the central nervous system (CNS). The full 5-HT1A receptor (5-HT1AR) agonist (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) has been recognized to elicit traditional serotonergic behaviors. Treatment with 8-OH-DPAT selectively increased PKCδ expression out of PKC isoforms and 5-HT turnover rate in the hypothalamus of wild-type mice. Treatment with 8-OH-DPAT resulted in oxidative burdens, co-immunoprecipitation of 5-HT1AR and PKCδ, and phosphorylation and membrane translocation of p47phox. Importantly, p47phox also interacted with 5-HT1AR or PKCδ in the presence of 8-OH-DPAT. Consistently, the interaction and oxidative burdens were attenuated by 5-HT1AR antagonism (i.e., WAY100635), PKCδ inhibition (i.e., rottlerin and genetic depletion of PKCδ), or NADPH oxidase/p47phox inhibition (i.e., apocynin and genetic depletion of p47phox). However, WAY100635, apocynin, or rottlerin did not exhibit any additive effects against the protective effect by inhibition of PKCδ or p47phox. Furthermore, apocynin, rottlerin, or WAY100635 also significantly protected from pro-inflammatory/pro-apoptotic changes induced by 8-OH-DPAT. Therefore, we suggest that 8-OH-DPAT-induced serotonergic behaviors requires oxidative stress, pro-inflammatory, and pro-apoptotic changes, that PKCδ or p47phox mediates the serotonergic behaviors induced by 8-OH-DPAT, and that the inhibition of PKCδ-dependent p47phox activation is critical for protecting against serotonergic behaviors.


Assuntos
NADPH Oxidases/metabolismo , Proteína Quinase C-delta/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Síndrome da Serotonina/tratamento farmacológico , Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina , Animais , Comportamento Animal/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidases/genética , Fosforilação/efeitos dos fármacos , Ligação Proteica , Proteína Quinase C-delta/genética , Receptor 5-HT1A de Serotonina/genética , Síndrome da Serotonina/genética , Síndrome da Serotonina/metabolismo , Síndrome da Serotonina/psicologia
14.
J Mol Neurosci ; 67(1): 89-96, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30519864

RESUMO

Autism spectrum disorder (ASD) is characterized by repetitive stereotypic behaviors, restricted interests, social withdrawal, and communication deficits. Aggression and insensitivity to pain are largely unexplained in these cases. We analyzed nine mRNA expressions of the candidate genes related to aggression and insensitivity to pain in the peripheral blood of patients with ASD. Whole blood samples were obtained from 40 autistic patients (33 boys, 7 girls) and 50 age- and sex-matched controls (37 boys and 13 girls) to isolate RNA. Gene expression was assessed by quantitative Real-Time PCR (qRT-PCR) in the Erciyes University Genome and Stem Cell Center (GENKOK). All of the gene expressions except CRHR1 and SLC6A4 were found to be statistically different between the ASD patients and controls. Gene expression also differed according to gender. Alterations in the mRNA expression patterns of the HTR1E, OPRL1, OPRM1, TACR1, PRKG1, SCN9A and DRD4 genes provide further evidence for a relevant effect of the respective candidate genes on the pathophysiology of ASD. Future studies may determine the sensitivity of these candidate markers in larger samples including further neuropsychiatric diagnosis.


Assuntos
Transtorno do Espectro Autista/genética , Canal de Sódio Disparado por Voltagem NAV1.7/genética , RNA Mensageiro/sangue , Receptor 5-HT1A de Serotonina/genética , Receptores de Dopamina D4/genética , Receptores Opioides/genética , Agressão , Transtorno do Espectro Autista/sangue , Transtorno do Espectro Autista/fisiopatologia , Biomarcadores/sangue , Pré-Escolar , Proteína Quinase Dependente de GMP Cíclico Tipo I/genética , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Feminino , Humanos , Masculino , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Percepção da Dor , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D4/metabolismo , Receptores Opioides/metabolismo
15.
Life Sci ; 218: 139-146, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30594665

RESUMO

AIMS: Methylphenidate (MPD) widely prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), is a psychostimulant and can produce addiction in patients treated with it. In view of growing increase in the use of drug by general population as a cognitive enhancer, the present study is designed to investigate reinforcing and cognition enhancing effects of MPD in rats. Associated changes in serotonin-1A receptor expression are investigated as a potential molecular mechanism involved. METHODS: Learning acquisition and memory retention in Morris water-maze test were used to assess cognitive effects of MPD. Reinforcing effects were evaluated in conditioned place-preference (CPP) paradigm. The expression of 5-hydroxytryptamine (5-HT; serotonin)-1A receptor in the nucleus accumbens and prefrontal cortex of repeated MPD treated animals was determined by qRT-PCR. FINDINGS: Lower doses (0.5 and 2.5 mg/kg) of MPD enhanced learning acquisition and memory retention but higher doses (5 mg/kg) impaired these. The drug administered repeatedly at a dose of 2.5 mg/kg was reinforcing in CPP test, but sensitization like effects of this dose were only transient. These animals tested in water-maze test exhibited improved memory retention but no effect occurred on learning acquisition. The expression of 5-HT-1A receptor was markedly attenuated in the nucleus accumbens; attenuation in the prefrontal cortex was not significant. SIGNIFICANCE: The findings suggest that clinically relevant doses of MPD can produce drug addiction, but effects of the drug on memory retention are retained. A downregulation of 5-HT-1A receptor in the nucleus accumbens seems important in the reinforcing effects of MPD.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Metilfenidato/farmacologia , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Regulação para Baixo , Masculino , Metilfenidato/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Receptor 5-HT1A de Serotonina/química , Receptor 5-HT1A de Serotonina/genética
16.
BMC Genet ; 19(1): 115, 2018 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-30594152

RESUMO

BACKGROUND: The serotonin neurotransmitter (5-HT) and its receptors have important roles in neuropsychiatric disorders such as schizophrenia. The aim of this study was to investigate the functional sequences of the 5' regulation region of the human HTR1A gene to explore the effects on the expression of the 5-HT1A receptor. METHODS: Fourteen recombinant pGL3-basic vectors containing deletion fragments of the HTR1A gene regulatory region were transfected with HEK-293 and SK-N-SH cells. The relative chemiluminescence intensities of different length fragments were analyzed. The JASPAR software was used for the prediction of transcription factors. RESULTS: In the HEK-293 cells, the relative chemiluminescence intensity of the - 1649 bp to - 1550 bp (ATG + 1) fragment was significantly different. Two inhibitory activity regions were found in the - 1409 bp to - 1381 bp and - 1196 bp to - 1124 bp fragments, which might be bound to the GATA or SOX10 transcription factors as predicted by the JASPAR software. In addition, the fragments located from - 1124 bp to - 1064 bp and from - 908 bp to - 722 bp up-regulated protein expression. Only the sequence from - 1550 bp to - 1409 bp demonstrated a difference in luciferase expression in the both cell lines. According to the results of the 5'-UTR truncated vectors, there was a repression region at the distal end of the 5'-UTR, an enhancer region might be present at the proximal end of the transcription start site. CONCLUSIONS: Although the functional sequences of the HTR1A gene regulatory region were confirmed, the regulatory factors and functional components require further investigation.


Assuntos
Receptor 5-HT1A de Serotonina/genética , Regiões 5' não Traduzidas , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Genes Reporter , Células HEK293 , Humanos , Receptor 5-HT1A de Serotonina/metabolismo , Elementos Reguladores de Transcrição , Esquizofrenia/genética , Esquizofrenia/patologia , Deleção de Sequência , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Transfecção
17.
J Psychopharmacol ; 32(12): 1379-1384, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30324842

RESUMO

BACKGROUND: Research interest has grown around the potential therapeutic use of cannabidiol in mood-related disorders, due to its anxiolytic and antidepressant-like effects. These have been partially attributed to its action as an allosteric modulator of 5-HTR1A. However, the exact mechanism supporting cannabidiol properties remains unclear. AIMS: To assess the effects of cannabidiol on different targets of the hypothalamus-pituitary-adrenal axis under baseline and stress conditions. METHODS: We administered cannabidiol (5 mg/kg, 15 mg/kg or 30 mg/kg, intraperitoneally) or vehicle to male C57BL/6J mice 90 min before single restraint stress exposure (20 min). Using real-time polymerase chain reaction analysis, we measured alterations in the relative gene expression of corticotropin-releasing factor in the paraventricular nucleus, pro-opiomelanocortin in the arcuate nucleus of the hypothalamus, glucocorticoid receptor in the hippocampus, and serotonin 5-HTR1A receptor in the hippocampus and amygdala. RESULTS: Under baseline conditions, cannabidiol did not modify any element of the hypothalamus-pituitary-adrenal axis. In contrast, all doses induced alterations in 5-HTR1A in the amygdala and hippocampus. Interestingly, cannabidiol at low (5 mg/kg) and intermediate doses (15 mg/kg) successfully blocked the effects induced by acute stress on corticotropin-releasing factor, pro-opiomelanocortin and glucocorticoid receptor gene expression. Also, restraint stress induced the opposite effects in 5-HTR1A gene expression in the hippocampus and amygdala, an effect not seen in mice treated with cannabidiol at low doses. CONCLUSIONS: Taken together, these data suggest the ability of cannabidiol to regulate acute stress hypothalamus-pituitary-adrenal axis activation might be explained, at least in part, by its action on 5-HTR1A receptors.


Assuntos
Canabidiol/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Canabidiol/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Hipófise-Suprarrenal/metabolismo , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT1A de Serotonina/metabolismo , Restrição Física , Estresse Psicológico/fisiopatologia
18.
J Neurosci ; 38(38): 8200-8210, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30093565

RESUMO

The serotonin-1A (5-HT1A) receptor is a key regulator of serotonergic activity and is implicated in mood and emotion. However, its post-transcriptional regulation has never been studied in humans. In the present study, we show that the "intronless" human 5-HT1A gene (HTR1A) is alternatively spliced in its 3'-UTR, yielding two novel splice variants. These variants lack a ∼1.6 kb intron, which contains an microRNA-135 (miR135) target site. Unlike the human HTR1A, the mouse HTR1A lacks the splice donor/accepter sites. Thus, in the mouse HTR1A, splicing was not detected. The two spliced mRNAs are extremely stable, are resistant to miR135-induced downregulation, and have greater translational output than the unspliced variant. Moreover, alternative HTR1A RNA splicing is oppositely regulated by the splice factors PTBP1 and nSR100, which inhibit or enhance its splicing, respectively. In postmortem human brain tissue from both sexes, HTR1A mRNA splicing was prevalent and region-specific. Unspliced HTR1A was expressed more strongly in the hippocampus and midbrain versus the prefrontal cortex (PFC), and correlated with reduced levels of nSR100. Importantly, HTR1A RNA splicing and nSR100 levels were reduced in the PFC of individuals with major depression compared with controls. Our unexpected findings uncover a novel mechanism to regulate HTR1A gene expression through alternative splicing of microRNA sites. Altered levels of splice factors could contribute to changes in regional and depression-related gene expression through alternative splicing.SIGNIFICANCE STATEMENT Alternative splicing, which is prevalent in brain tissue, increases gene diversity. The serotonin-1A receptor gene (HTR1A) is a regulator of serotonin, which is implicated in mood and emotion. Here we show that human HTR1A RNA is alternately spliced. Splicing removes a microRNA site to generate ultrastable RNA and increase HTR1A expression. This splicing varies in different brain regions and is reduced in major depression. We also identify specific splice factors for HTR1A RNA, showing they are also reduced in depression. Thus, we describe a novel mechanism to regulate gene expression through splicing. Altered levels of splice factors could contribute to depression by changing gene expression.


Assuntos
Processamento Alternativo , Transtorno Depressivo Maior/metabolismo , Hipocampo/metabolismo , Mesencéfalo/metabolismo , Estabilidade de RNA/fisiologia , Receptor 5-HT1A de Serotonina/metabolismo , Adulto , Transtorno Depressivo Maior/genética , Feminino , Células HEK293 , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Receptor 5-HT1A de Serotonina/genética
19.
J Mol Neurosci ; 66(1): 59-67, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30091081

RESUMO

The atypical antipsychotic drug iloperidone has high affinity for a wide range of neurotransmitter receptors, including serotonin and adrenoceptors. We examined the long-term effects of multiple doses of iloperidone (0.5, 1.5, or 5 mg/kg) on serotonin (5-HT) 5-HT1A, 5-HT2A receptor subtypes, and adrenoceptors α1 and α2 subtypes. Rats received daily intraperitoneal injections of different doses of iloperiodone or vehicle for 4 weeks. Receptor autoradiography quantified the levels of 5-HT and adrenoceptors in medial prefrontal cortex (MPC), dorsolateral frontal cortex (DFC), caudate putamen (CPu), nucleus accumbens (NAc), and hippocampal CA1 (HIP-CA1) and CA3 (HIP-CA3) regions. Four weeks of iloperidone treatment significantly and dose-dependently increased 5-HT1A and decreased 5-HT2A receptors in the MPC and DFC. Higher doses of iloperidone (1.5 and 5 mg/kg) increased 5-HT1A and decreased 5-HT2A receptors in HIP-CA1 and HIP-CA3 regions. In addition, repeated iloperidone treatment produced significant increases in α1- and α2-adrenoceptors in MPC, DFC, HIP-CA1, and HIP-CA3 regions. No changes in 5-HT and adrenoceptors were observed in other brain regions examined. These results suggest that long-term iloperidone treatment exerts region- and dose-specific effects on forebrain 5-HT and adrenoceptors, which may contribute to its therapeutic benefits in improving positive and negative symptoms of schizophrenia as well as maintaining a benign safety profile.


Assuntos
Antipsicóticos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Isoxazóis/farmacologia , Piperidinas/farmacologia , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT2A de Serotonina/genética , Receptores Adrenérgicos alfa/genética , Animais , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Córtex Cerebral/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptores Adrenérgicos alfa/metabolismo
20.
Biophys Chem ; 240: 34-41, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29885563

RESUMO

G protein-coupled receptors (GPCRs) are major signaling proteins in eukaryotic cells and are important drug targets. In spite of their role in GPCR function, the extramembranous regions of GPCRs are relatively less appreciated. The third intracellular loop (ICL3), which connects transmembrane helices V and VI, is important in this context since its crucial role in signaling has been documented for a number of GPCRs. Unfortunately, the structure of this loop is generally not visualized in x-ray crystallographic studies since this flexible loop is either stabilized using a monoclonal antibody or replaced with lysozyme. In this work, we expressed and purified the ICL3 region of the serotonin1A receptor and monitored its motional restriction and organization utilizing red edge excitation shift (REES) of its sole tryptophan and circular dichroism (CD) spectroscopy. Our results show that the tryptophan in ICL3 exhibits REES of 4 nm, implying that it is localized in a restricted microenvironment. These results are further supported by wavelength-selective changes in fluorescence anisotropy and lifetime. This constrained dynamics was relaxed upon denaturation of the peptide, thereby suggesting the involvement of the peptide secondary structure in the observed motional restriction, as evident from CD spectroscopy and apparent rotational correlation time. To the best of our knowledge, these results constitute one of the first measurements of motional constraint in the ICL3 region of GPCRs. Our results are relevant in the context of the reported intrinsically disordered nature of ICL3 and its role in providing functional diversity to GPCRs due to conformational plasticity.


Assuntos
Receptor 5-HT1A de Serotonina/química , Triptofano/química , Sequência de Aminoácidos , Dicroísmo Circular , Polarização de Fluorescência , Humanos , Desnaturação Proteica , Domínios Proteicos , Estrutura Secundária de Proteína , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT1A de Serotonina/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação
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