RESUMO
AIMS: We sought to evaluate the effects of overfeeding during lactation on the feeding behavior and expression of specific regulatory genes in brain areas associated with food intake in 22- and 60-day old male rats. METHODS: We evaluated body weight, food intake of standard and palatable diet, and mRNA expression of dopamine receptor D1 (DDR1), dopamine receptor (DDR2), melanocortin 4 receptor (MC4R), the µ-opioid receptor (MOR), neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocortin (POMC), cocaine-and amphetamine-regulated transcript (CART), serotonin (5-hydroxytryptamine; 5-HT) transporter (SERT), 5-hydroxytryptamine receptor 1B (5-HT1B), 5-hydroxytryptamine receptor 2C receptor (5-HT2C), Clock (CLOK), cryptochrome protein 1 (Cry1) and period circadian protein homolog 2 (Per2) in the striatum, hypothalamus and brainstem of male rats at post-natal days (PND) 22 and 60. KEY FINDINGS: Overfeeding resulted in significantly increased body weight through PND60, and a 2-fold increase in palatable food intake at PND22, but not at PND60. We observed significant increases in DDR1, DDR2, and MC4R gene expression in the striatum and brainstem and POMC/CART in the hypothalamus of the OF group at PND22 that were reversed by PND60. Hypothalamic levels of 5-HT1B, 5-HT2C and NPY/AGRP on the other hand were decreased at PND22 and increased at PND60 in OF animals. Clock genes were unaffected by OF at PND22, but were significantly elevated at PND60. SIGNIFICANCE: Overfeeding during early development of the rat brain results in obesity and altered feeding behavior in early adulthood. The altered behavior might be the consequence of the changes in food intake and reward gene expression.
Assuntos
Peso Corporal , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Comportamento Alimentar , Hipernutrição/fisiopatologia , Animais , Proteínas CLOCK/metabolismo , Criptocromos/metabolismo , Ingestão de Alimentos , Feminino , Lactação , Masculino , Proteínas de Ligação a RNA/metabolismo , Ratos , Ratos Wistar , Receptor 5-HT1B de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismoRESUMO
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 JovemRESUMO
G-protein-coupled receptors (GPCRs) play a major role in psychiatric disorders and are the targets of several current therapeutic approaches in this field. A number of studies have now shown that GPCRs can assemble as high molecular weight homo- and hetero-oligomers, which could affect ligand binding, intracellular signalling or trafficking. This information could be critical in design of new drugs to treat neurological and psychiatric disorders. This chapter describes a sequential co-immunoprecipitation and immunoblot protocol for determining oligomerisation of the 5-hydroxytryptamine (HT)1A receptor with other GPCRs in co-transfected HEK-293 cells.
Assuntos
Western Blotting/métodos , Cromatografia de Afinidade/métodos , Imunoprecipitação/métodos , Receptores Acoplados a Proteínas G/análise , Células HEK293 , Humanos , Oligopeptídeos , Multimerização Proteica , Proteínas Proto-Oncogênicas c-myc , Receptor 5-HT1A de Serotonina/análise , Receptor 5-HT1A de Serotonina/química , Receptor 5-HT1B de Serotonina/análise , Receptor 5-HT1B de Serotonina/química , Receptor 5-HT1D de Serotonina/análise , Receptor 5-HT1D de Serotonina/química , Receptores Acoplados a Proteínas G/química , Proteínas Recombinantes de Fusão/análise , Proteínas Recombinantes de Fusão/química , TransfecçãoRESUMO
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 JovemRESUMO
Objective: To explore the association of three polymorphisms of the serotonin receptor 1Dβ 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
Humanos , Masculino , Feminino , Adolescente , Adulto , Adulto Jovem , Anorexia Nervosa/genética , Polimorfismo de Nucleotídeo Único , Receptor 5-HT1B de Serotonina/genética , Bulimia Nervosa/genética , Estudos de Associação Genética/métodos , Ansiedade/complicações , Ansiedade/fisiopatologia , Escala de Ansiedade Frente a Teste , Índice de Gravidade de Doença , Família , Anorexia Nervosa/fisiopatologia , Valor Preditivo dos Testes , Fatores de Risco , Depressão/complicações , Depressão/fisiopatologia , Bulimia Nervosa/fisiopatologia , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Técnicas de Genotipagem , Frequência do GeneRESUMO
Serotonin (5-HT) participates in pain modulation by interacting with different 5-HT receptors. The role of 5-HT5A receptor in neuropathic pain has not previously studied. The purpose of this study was to investigate: A) the role of 5-HT5A receptors in rats subjected to spinal nerve injury; B) the expression of 5-HT5A receptors in dorsal spinal cord and dorsal root ganglia (DRG). Neuropathic pain was induced by L5/L6 spinal nerve ligation. Tactile allodynia in neuropathic rats was assessed with von Frey filaments. Western blot methodology was used to determine 5-HT5A receptor protein expression. Intrathecal administration (on day 14th) of 5-HT (10-100 nmol) or 5-carboxamidotryptamine (5-CT, 0.03-0.3 nmol) reversed nerve injury-induced tactile allodynia. Intrathecal non-selective (methiothepin, 0.1-0.8 nmol) and selective (SB-699551, 1-10 nmol) 5-HT5A receptor antagonists reduced, by ~60% and ~25%, respectively, the antiallodynic effect of 5-HT (100 nmol) or 5-CT (0.3 nmol). Moreover, both selective 5-HT1A and 5-HT1B/1D receptor antagonists, WAY-100635 (0.3-1 nmol) and GR-127935 (0.3-1 nmol), respectively, partially diminished the antiallodynic effect of 5-HT or 5-CT by about 30%. Injection of antagonists, by themselves, did not affect allodynia. 5-HT5A receptors were expressed in the ipsilateral dorsal lumbar spinal cord and DRG and L5/L6 spinal nerve ligation did not modify 5-HT5A receptor protein expression in those sites. Results suggest that 5-HT5A receptors reduce pain processing in the spinal cord and that 5-HT and 5-CT reduce neuropathic pain through activation of 5-HT5A and 5-HT1A/1B/1D receptors. These receptors could be an important part of the descending pain inhibitory system.
Assuntos
Neuralgia/metabolismo , Receptores 5-HT1 de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Medula Espinal/metabolismo , Nervos Espinhais/lesões , Analgésicos/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Vértebras Lombares , Metiotepina/farmacologia , Neuralgia/tratamento farmacológico , Oxidiazóis/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1B de Serotonina/metabolismo , Receptor 5-HT1D de Serotonina/metabolismo , Serotonina/análogos & derivados , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Medula Espinal/efeitos dos fármacos , TatoRESUMO
AIMS: The present study analyzed the potential antinociceptive effect of the antimigraine drugs sumatriptan, dihydroergotamine or methysergide in rats submitted to the formalin test. Moreover, by using selective antagonists, the role of 5-HT1B/1D serotonergic receptors was investigated in the antinociception induced by these antimigraine drugs. MAIN METHODS: The formalin test was used to assess the nociceptive activity. Overt pain-like behavior (flinching, 1h) and evoked nociception (long-lasting secondary mechanical allodynia and hyperalgesia, 6 days) were determined in the same rat. KEY FINDINGS: Ipsilateral, but not contralateral, pre-treatment (in µg/paw) with sumatriptan (10-300), methysergide (1-30) or dihydroergotamine (1-30) significantly prevented flinching behavior (at 1h) as well as secondary allodynia and hyperalgesia (at day 6) induced by formalin. Interestingly, the antinociceptive (flinching), antiallodynic and antihyperalgesic effects of sumatriptan were completely prevented by peripheral pre-treatment with selective antagonists at the 5-HT1B (SB 224289; 100) or 5-HT1D (BRL 15572; 100) receptors. In contrast, the acute antinociceptive effects of methysergide and dihydroergotamine were partially prevented by SB 224289 and BRL 15572. The antiallodynic and antihyperalgesic effects of both drugs were completely prevented by BRL 15572 and partially prevented by SB 224289. Given alone, SB 224289 or BRL 15572 did not modify per se the long-lasting secondary allodynia and hyperalgesia. SIGNIFICANCE: The above findings suggest that: (i) the antimigraine drugs sumatriptan, methysergide and dihydroergotamine reduce the acute and chronic nociception induced by formalin; and (ii) this antinociceptive effect results from activation of peripheral 5-HT1B/1D serotonergic receptors.
Assuntos
Hiperalgesia/metabolismo , Dor Nociceptiva/tratamento farmacológico , Receptor 5-HT1B de Serotonina/fisiologia , Receptor 5-HT1D de Serotonina/fisiologia , Antagonistas da Serotonina/uso terapêutico , Dor Aguda , Animais , Compostos de Bifenilo/uso terapêutico , Dor Crônica , Di-Hidroergotamina/uso terapêutico , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Formaldeído/toxicidade , Hiperalgesia/induzido quimicamente , Metisergida/uso terapêutico , Dor Nociceptiva/induzido quimicamente , Dor Nociceptiva/metabolismo , Piperazinas/uso terapêutico , Piperidonas/uso terapêutico , Ratos , Ratos Wistar , Compostos de Espiro/uso terapêutico , Sumatriptana/uso terapêuticoRESUMO
This study measured the effects of the preferential 5-HT1D/1B receptor agonist sumatriptan in healthy volunteers who performed the Simulated Public Speaking Test (SPST), which recruits the neural network involved in panic disorder and social anxiety disorder. In a double-blind, randomised experiment, 36 males received placebo (12), 50 mg (12) or 100 mg (12) of sumatriptan 2 h before the SPST. Subjective, physiological and hormonal measures were taken before, during and after the test. The dose of 100 mg of sumatriptan increased speech-induced fear more than either a 50mg dose of the drug or placebo. The largest dose of sumatriptan also enhanced vigilance more than placebo, without any change in blood pressure, heart rate or electrical skin conductance. Sumatriptan decreased plasma levels of prolactin. A significant but moderate increase in plasma cortisol after SPST occurred, independent of treatment. Because sumatriptan decreases 5-HT release into the extracellular space, the potentiation of SPST-induced fear caused by the drug supports the hypothesis that 5-HT attenuates this emotional state. As acute administration of antidepressants has also been shown to enhance speaking fear and increase plasma prolactin, in contrast to sumatriptan, the 5-HT regulation of stress-hormone release is likely to be different from that of emotion.
Assuntos
Medo/efeitos dos fármacos , Prolactina/sangue , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Sumatriptana/farmacologia , Adulto , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Resposta Galvânica da Pele/fisiologia , Frequência Cardíaca/fisiologia , Humanos , Masculino , Rede Nervosa/fisiologia , Receptor 5-HT1B de Serotonina/efeitos dos fármacos , Receptor 5-HT1B de Serotonina/metabolismo , Receptor 5-HT1D de Serotonina/efeitos dos fármacos , Receptor 5-HT1D de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Fala/fisiologia , Sumatriptana/administração & dosagem , Adulto JovemRESUMO
Pathological gambling (PG) has become a growing public health problem in many countries around the world. PG is an impulse control disorder and its behavior and psychopathology present similarities with substance abuse disorders. Evidence from twin studies supports a significant genetic predisposition to PG, but the precise genetic loci still remain unclear. The present study investigates the allele and genotype distribution of polymorphisms of the serotonin transporter, serotonin receptor 1B and 2A genes in 140 sib-pairs discordant for the diagnosis of PG. A significant association of the C/C genotype of the serotonin receptor 2A T102C (rs 6313) polymorphism and the PG phenotype was observed [OR = 1.7 (1.1-3.4)]. This preliminary result is consistent with the hypothesis that the serotonin system is associated with addiction behavior and similar results have been reported for nicotine and alcohol dependence.
Assuntos
Jogo de Azar/genética , Receptor 5-HT2A de Serotonina/fisiologia , Serotonina/fisiologia , Adulto , Alelos , Substituição de Aminoácidos , Brasil , Éxons/genética , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Mutação INDEL , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT2A de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , IrmãosRESUMO
It has been suggested that during a migraine attack trigeminal nerves release calcitonin gene-related peptide (CGRP), producing central nociception and vasodilatation of cranial arteries, including the extracranial branches of the external carotid artery. Since trigeminal inhibition may prevent this vasodilatation, the present study has investigated the effects of intrathecal dihydroergotamine on the external carotid vasodilatation to capsaicin, α-CGRP and acetylcholine. Anaesthetized vagosympathectomized dogs were prepared to measure blood pressure, heart rate and external carotid conductance. A catheter was inserted into the right common carotid artery for the continuous infusion of phenylephrine (to restore the carotid vascular tone), whereas the corresponding thyroid artery was cannulated for one-min intracarotid infusions of capsaicin, α-CGRP and acetylcholine (which dose-dependently increased the external carotid conductance). Another cannula was inserted intrathecally (C(1)-C(3)) for the administration of dihydroergotamine, the α(2)-adrenoceptor antagonist rauwolscine or the serotonin 5-HT(1B/1D) receptor antagonist GR127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1-biphenyl]-4-carboxamide hydrochloride monohydrate). Intrathecal dihydroergotamine (10, 31 and 100µg) inhibited the vasodilatation to capsaicin, but not that to α-CGRP or acetylcholine. This inhibition was: (i) unaffected by 10µg GR127935 or 100µg rauwolscine, but abolished by 31µg GR127935 or 310µg rauwolscine at 10µg dihydroergotamine; and (ii) abolished by the combination 10µg GR127935+100µg rauwolscine at 100µg dihydroergotamine. Thus, intrathecal (C(1)-C(3)) dihydroergotamine seems to inhibit the external carotid vasodilatation to capsaicin by spinal activation of serotonin 5-HT(1B/1D) (probably 5-HT(1B)) receptors and α(2) (probably α(2A/2C))-adrenoceptors.
Assuntos
Capsaicina/farmacologia , Artérias Carótidas/efeitos dos fármacos , Di-Hidroergotamina/farmacologia , Oxidiazóis/farmacologia , Piperazinas/farmacologia , Receptor 5-HT1B de Serotonina/metabolismo , Vasodilatação/efeitos dos fármacos , Ioimbina/farmacologia , Acetilcolina/farmacologia , Animais , Circulação Sanguínea/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Artérias Carótidas/metabolismo , Artérias Carótidas/fisiologia , Di-Hidroergotamina/administração & dosagem , Cães , Relação Dose-Resposta a Droga , Hemodinâmica/efeitos dos fármacos , Injeções Espinhais , Masculino , Propilenoglicol/administração & dosagem , Propilenoglicol/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Vasodilatadores/farmacologiaRESUMO
BACKGROUND: Animal and human studies have suggested that the serotonergic system plays an important role in alcohol consumption and abuse, mainly due to the serotonin receptor 1B (5-HT(1B)) function in the mesolimbic reward pathway. Association studies between the HTR1B gene variants and alcoholism have found significant results. There is also evidence for a complex balancing regulation of the gene by two functional variants in the promoter region (rs11568817 and rs130058), which are in linkage disequilibrium. METHODS: The aim of this study is to investigate the role of the most relevant variants (rs11568817, rs130058, rs6296 and rs13212041) of the HTR1B gene in the susceptibility to alcohol dependence. The sample comprised 136 Brazilian alcoholics of European descendent and 237 controls. RESULTS: The results suggest an association between a functional variant of the gene (rs11568817) and alcohol dependence (p=0.001). In addition, this association could also be confirmed in an independent sample using imputed data from a GWAS, where marginal significant association (p=0.03, one-tailed) with the same allele was obtained. The pattern of distribution of haplotypes was significantly different between patients and controls (p<0.0001), which is consistent with the role of the two functional variants of the promoter region. CONCLUSION: In conclusion, our findings point to an association between functional variants in the promoter region of the HTR1B gene and alcohol dependence, supporting previous neurobiological evidences of the involvement of HTR1B variations in alcohol-related phenotypes.
Assuntos
Alcoolismo/genética , Predisposição Genética para Doença , Haplótipos , Polimorfismo Genético , Receptor 5-HT1B de Serotonina/genética , Adulto , Alelos , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
While the role of 5-hydroxytryptamine (5-HT, serotonin) in the nociceptive processing has been widely investigated in the central nervous system, information regarding its role in peripheral tissues is still lacking. Noteworthy, 5-HT induces phenotypic changes of nociceptors and peripheral injection induces pain in humans and nociceptive response in rodents. However, local receptors involved in 5-HT effects are not well characterized. Thus, we aimed to investigate the role of 5-HT and some of its receptors in the peripheral nociceptive processing in mice. Intraplantar injection of 5-HT (10, 20 or 40 µg) into the hind-paw of mice induced paw licking behavior, which was inhibited by previous intraplantar treatment with cyproheptadine (5-HT(1) and 5-HT(2) antagonist; 0.5 or 5 µg), mianserin (5-HT(2) and 5-HT(6) antagonist; 0.1 µg), isamoltane (5-HT(1B) antagonist; 0.5 or 5 µg) and ketanserin (5-HT(2A) antagonist; 0.1 or 1 µg), but not by BRL 15572 (5-HT(1D) antagonist; 1 or 10 µg), ondansetron (5-HT(3) antagonist; 1, 5, 10 or 20 µg) and SB 269970 (5-HT(7) antagonist; 2.5 and 25 µg). Altogether, these results indicate the local involvement of 5-HT(1), 5-HT(2) and 5-HT(6), especially 5-HT(1B) and 5-HT(2A), in the nociceptive response induced by 5-HT in mice, thus contributing to a better understanding of 5-HT role in the peripheral nociceptive processing. In addition, they also point to important species differences and the need of a wide evaluation of the peripheral nociceptive processing in mice as these animals have been increasingly used in studies investigating the cellular and molecular mechanisms mediating the nociceptive response.
Assuntos
Nociceptores/efeitos dos fármacos , Dor/psicologia , Receptor 5-HT1B de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Serotonina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologiaRESUMO
Serotonin (5-HT) is involved in the fine adjustments at several brain centers including the core of the mammal circadian timing system (CTS) and the hypothalamic suprachiasmatic nucleus (SCN). The SCN receives massive serotonergic projections from the midbrain raphe nuclei, whose inputs are described in rats as ramifying at its ventral portion overlapping the retinohypothalamic and geniculohypothalamic fibers. In the SCN, the 5-HT actions are reported as being primarily mediated by the 5-HT1 type receptor with noted emphasis for 5-HT(1B) subtype, supposedly modulating the retinal input in a presynaptic way. In this study in a New World primate species, the common marmoset (Callithrix jacchus), we showed the 5-HT(1B) receptor distribution at the dorsal SCN concurrent with a distinctive location of 5-HT-immunoreactive fibers. This finding addresses to a new discussion on the regulation and synchronization of the circadian rhythms in recent primates.
Assuntos
Receptor 5-HT1B de Serotonina/metabolismo , Núcleo Supraquiasmático/metabolismo , Animais , Callithrix/anatomia & histologia , Toxina da Cólera/metabolismo , Diagnóstico por Imagem , Masculino , Vias Visuais/metabolismoRESUMO
RATIONALE: 5-HT(1A) and 5-HT(1B) receptor agonists effectively reduce aggressive behavior in males that has been escalated by social instigation. Important sites of action for these drugs are the receptors in dorsal raphé nuclei (DRN) and the ventral-orbital prefrontal cortex (VO PFC). DRN and VO PFC areas are particularly relevant in the inhibitory control of escalated aggressive and impulsive behavior. OBJECTIVES: The objectives of this study are to assess the anti-aggressive effects of 5-HT(1A) (8-OH-DPAT) and 5-HT(1B) (CP-93,129) receptor agonists microinjected into DRN and VO PFC, respectively, and to study the aggressive behavior in postpartum female Wistar rats using the social instigation protocol to increase aggression. METHODS AND RESULTS: 8-OH-DPAT (0.56 µg) in the DRN increased aggressive behavior in postpartum female rats. By contrast, CP-93,129 (1.0 µg) microinjected into VO PFC decreased the number of attack bites and lateral threats. 5-HT(1A) and 5-HT(1B) receptor agonists differed in their effects on non-aggressive activities, the former decreasing rearing and grooming and the latter increasing these acts. When 8-OH-DPAT was microinjected into DRN and CP-93,129 was microinjected into VO PFC in female rats at the same time, maternal aggression decreased. Specific participation of 5-HT(1B) receptors was verified by reversal of the anti-aggressive effects using the selective antagonist SB-224,289 (1.0 µg). CONCLUSIONS: The decrease in maternal aggressive behavior after microinjections of 5-HT(1B) receptor agonists into the VO PFC and DRN of female postpartum rats that were instigated socially supports the hypothesis that activation of these receptors modulates high levels of aggression in a behaviorally specific manner, due to activation of 5-HT(1B) receptors at the soma and terminals.
Assuntos
Agressão , Período Pós-Parto , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1B de Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Feminino , Córtex Pré-Frontal/metabolismo , Piridinas/farmacologia , Pirróis/farmacologia , Núcleos da Rafe/metabolismo , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT1B de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Hypothalamic serotonin inhibits food intake and stimulates energy expenditure. High-fat feeding is obesogenic, but the role of polyunsaturated fats is not well understood. This study examined the influence of different high-PUFA diets on serotonin-induced hypophagia, hypothalamic serotonin turnover, and hypothalamic protein levels of serotonin transporter (ST), and SR-1B and SR-2C receptors. Male Wistar rats received for 9 weeks from weaning a diet high in either soy oil or fish oil or low fat (control diet). Throughout 9 weeks, daily intake of fat diets decreased such that energy intake was similar to that of the control diet. However, the fish group developed heavier retroperitoneal and epididymal fat depots. After 12 h of either 200 or 300 µg intracerebroventricular serotonin, food intake was significantly inhibited in control group (21-25%) and soy group (37-39%) but not in the fish group. Serotonin turnover was significantly lower in the fish group than in both the control group (-13%) and the soy group (-18%). SR-2C levels of fish group were lower than those of control group (50%, P = 0.02) and soy group (37%, P = 0.09). ST levels tended to decrease in the fish group in comparison to the control group (16%, P = 0.339) and the soy group (21%, P = 0.161). Thus, unlike the soy-oil diet, the fish-oil diet decreased hypothalamic serotonin turnover and SR-2C levels and abolished serotonin-induced hypophagia. Fish-diet rats were potentially hypophagic, suggesting that, at least up to this point in its course, the serotonergic impairment was either compensated by other factors or not of a sufficient extent to affect feeding. That fat pad weight increased in the absence of hyperphagia indicates that energy expenditure was affected by the serotonergic hypofunction.
Assuntos
Gorduras Insaturadas na Dieta/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Óleos de Peixe/farmacologia , Serotonina/metabolismo , Tecido Adiposo/anatomia & histologia , Animais , Dieta , Óleos de Peixe/administração & dosagem , Humanos , Ácido Hidroxi-Indolacético/química , Ácido Hidroxi-Indolacético/metabolismo , Hipotálamo/química , Hipotálamo/metabolismo , Infusões Intraventriculares , Masculino , Tamanho do Órgão , Distribuição Aleatória , Ratos , Ratos Wistar , Receptor 5-HT1B de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Serotonina/administração & dosagem , Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Óleo de Soja/administração & dosagem , Óleo de Soja/farmacologiaRESUMO
The importance of calcitonin gene-related peptide (CGRP) in the regulation of vascular tone has been widely documented. Indeed, stimulation of the perivascular sensory outflow in pithed rats results in vasodepressor responses, which are mediated by CGRP release. These vasodepressor responses are inhibited by clonidine via prejunctional alpha(2A/2C)-adrenoceptors, but no study has yet reported the role of prejunctional 5-hydroxytryptamine (5-HT) receptors in this experimental model. Since activation of prejunctional 5-HT(1) receptors results in inhibition of neurotransmitter release, this study sets out to investigate as an initial approach the role of 5-HT(1B) receptors in the inhibition of the vasodepressor sensory outflow in pithed rats. Male Wistar pithed rats were pretreated with hexamethonium (2mg/kg.min) followed by i.v. continuous infusions of methoxamine (20 microg/kg min), and then by saline (0.02 ml/min) or CP-93,129 (a rodent 5-HT(1B) receptor agonist; 0.1, 1 and 10 microg/kg min). Under these conditions, electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the spinal cord (T(9)-T(12)) resulted in frequency-dependent decreases in diastolic blood pressure. The infusions of CP-93,129, as compared to those of saline, inhibited the vasodepressor responses induced by electrical stimulation without affecting those to i.v. bolus injections of exogenous alpha-CGRP (0.1, 0.18, 0.31, 0.56 and 1 microg/kg). This inhibition by CP-93,129 was abolished by the antagonists GR127935 (5-HT(1B/1D)) or SB224289 (5-HT(1B)), but not by BRL15572 (5-HT(1D)). The above results suggest that CP-93,129-induced inhibition of the vasodepressor (perivascular) sensory outflow in pithed rats is mainly mediated by activation of prejunctional 5-HT(1B) receptors.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina , Vasoconstritores/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estimulação Elétrica , Frequência Cardíaca/efeitos dos fármacos , Hexametônio/farmacologia , Infusões Intravenosas , Masculino , Metoxamina/farmacologia , Piperidonas/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Wistar , Receptor 5-HT1B de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Cloreto de Sódio/farmacologia , Medula Espinal , Compostos de Espiro/farmacologia , Fatores de Tempo , Vasoconstritores/administração & dosagem , Vasoconstritores/farmacologiaRESUMO
The effects of CP-94253, a selective 5-HT(1B) receptor agonist, and of SB 224-289, a selective 5-HT(1B) receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. The 5-HT(1B) receptor ligands were microinjected directly into the dorsal raphe nucleus (DRN) during the light period of the 12-h light/12-h dark cycle. Infusion of CP-94253 (1-4 mM) into the DRN induced a significant reduction of rapid-eye-movement sleep (REMS) and of the mean duration of REM episodes. On the other hand, SB 224-289 (0.25-0.5 mM) decreased REMS and the number of REM periods. Pretreatment with SB 224-289 (0.125-0.25 mM) antagonized the CP-94253 (4 mM)-induced reduction of REMS and of the mean duration of REM periods. Administration of the GABA(A) receptor agonist muscimol (1.5mM), which by itself did not significantly affect sleep variables, prevented the effect of CP-94253 (4 mM) on REMS suppression. It is proposed that the suppression of REMS after microinjection of CP-94253 into the DRN is related to the inhibition of GABAergic interneurons that make synaptic contacts with serotonergic cells. The resultant increase of serotonin release at postsynaptic sites involved in the induction and maintenance of REMS would induce the suppression of the behavioral state.
Assuntos
Núcleos da Rafe/efeitos dos fármacos , Receptor 5-HT1B de Serotonina/fisiologia , Sono REM/efeitos dos fármacos , Análise de Variância , Animais , Cateteres de Demora , Relação Dose-Resposta a Droga , Eletrodos Implantados , Eletroencefalografia , Eletromiografia , Agonistas GABAérgicos/farmacologia , Masculino , Microinjeções , Muscimol/farmacologia , Piperidonas/farmacologia , Piridinas/farmacologia , Núcleos da Rafe/fisiologia , Ratos , Ratos Wistar , Receptores de GABA-A/fisiologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Sono REM/fisiologia , Compostos de Espiro/farmacologiaRESUMO
This study assessed the possible antinociceptive role of peripheral 5-HT(1) receptor subtypes in the rat formalin test. Rats were injected into the dorsum of the hind paw with 50 microl of diluted formalin (1%). Nociceptive behavior was quantified as the number of flinches of the injected paw. Reduction of flinching was considered as antinociception. Ipsilateral, but not contralateral, peripheral administration of the 5-HT(1) receptor agonists R(+)-UH-301 (5-HT(1A); 0.1-3 microg/paw), CGS-12066A (5-HT(1B); 0.01-0.3 microg/paw), GR46611 (5-HT(1B/1D); 0.3-10 microg/paw), BRL54443 (5-HT(1E/1F); 3-300 microg/paw) or LY344864 (5-HT(1F); 3-300 microg/paw) significantly reduced formalin-induced flinching. The corresponding vehicle was devoid of any effect by itself. The local antinociceptive effect of R(+)-UH-301 (0.3 microg/paw) was significantly reduced by WAY-100635 (30-100 microg/paw; a 5-HT(1A) receptor antagonist). Moreover, the antagonists GR55562 (30-100 microg/paw; 5-HT(1B/D)) or SB224289 (30-100 microg/paw; 5-HT(1B)) dose-dependently reduced the antinociceptive effect of CGS-12066A (0.3 microg/paw) whereas GR55562 (30-100 microg/paw) or BRL15572 (30-100 microg/paw, 5-HT(1D)) reduced the antinociceptive effect of GR46611 (0.3 microg/paw). Interestingly, the effects of BRL54443 and LY344864 (300 microg/paw each) were partially reduced by methiothepin, but not by the highest doses of WAY-100635, SB224289 or BRL15572. The above antagonists did not produce any effect by themselves. These results suggest that peripheral activation of the 5-HT(1A,) 5-HT(1B), 5-HT(1D), 5-HT(1F) and, probably, 5-HT(1E) receptor subtypes leads to antinociception in the rat formalin test. Thus, the use of selective 5-HT(1) receptor agonists could be a therapeutic strategy to reduce inflammatory pain.
Assuntos
Dor/tratamento farmacológico , Dor/metabolismo , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Formaldeído , Lateralidade Funcional , Membro Posterior/efeitos dos fármacos , Membro Posterior/metabolismo , Dor/induzido quimicamente , Medição da Dor , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1B de Serotonina/metabolismo , Receptor 5-HT1D de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/administração & dosagem , Receptor 5-HT1F de SerotoninaRESUMO
Several evidences suggested that the serotonin 5-HT1B receptor gene (HRT1B) might be involved in the susceptibility to attention deficit/hyperactivity disorder (ADHD). Prior studies reported excess transmissions of the HRT1B gene 861G allele to affected ADHD children and of a haplotype block containing this variant and two functional promoter SNPs to probands with ADHD-inattentive subtype. However, some investigations did not replicate these findings. Therefore, we tested for biased transmissions of haplotypes derived from the 861G > C, -161A > T, and -261T > G SNPs from parents to 343 families with ADHD children. We also sought to replicate findings from the literature that the association between HTR1B is preferentially with ADHD-Inattentive subtype. Using a transmission disequilibrium test we found evidence for an excess transmission of haplotype. -261G/-161T/861G (P = 0.014) for affected children in the total sample. When the analysis was repeated with 143 families with ADHD-Inattentive subtype no significant associations were observed. Our results provide additional evidence that HRT1B gene may be an important risk factor for the development of ADHD, but this effect seems not to be attributable to inattentive cases.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Polimorfismo de Nucleotídeo Único , Receptor 5-HT1B de Serotonina/genética , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Família , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pais , Fatores de Risco , Análise de Sequência de DNARESUMO
BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is an important psychiatric condition in terms of its prevalence and impact on quality of life. It has one of the highest heritabilities found in psychiatric disorders. A number of association studies exploring several candidate genes in different populations around the world have been carried out. The objective of the present study was to carry out a meta-analysis for 8 common variants located in 5 top candidate genes for ADHD (BDNF, HTR1B, SLC6A2, SLC6A4 and SNAP25); these genes are known to be involved in synaptic transmission and plasticity. METHODS: We performed a search for published genetic association studies that analyzed the candidate polymorphisms in different populations, and we applied state-of-the-art meta-analytical procedures to obtain pooled odds ratios (ORs) and to evaluate potential basis of heterogeneity. We included 75 genetic association studies in these meta-analyses. RESULTS: A major part of the previously postulated associations were nonconsistent in the pooled odds ratios. We observed a weak significant association with a single nucleotide polymorphism (SNP) located in the 3' UTR region of the SNAP25 gene (rs3746544, T allele, OR 1.15, 95% confidence interval 1.01-1.31, p = 0.028, I(2) = 0%). In addition to the low coverage of genetic variability given by these variants, phenotypic heterogeneity between samples (ADHD subtypes, comorbidities) and genetic background may explain these differences. LIMITATIONS: Limitations of our study include the retrospective nature of our meta-analysis with the incorporation of study-level data from published articles. CONCLUSION: To our knowledge, the present study is the largest meta-analysis carried out for ADHD genetics; previously proposed cumulative associations with common polymorphisms in SLC6A4 and HTR1B genes were not supported. We identified a weak consistent association with a common SNP in the SNAP25 gene, a molecule that is known to be central for synaptic transmission and plasticity mechanisms.