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1.
Zoolog Sci ; 37(1): 50-60, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32068374

RESUMO

The labial palps of bivalves are thought to be involved in suspension feeding. However, the function of their muscular movements and neural regulation are still unclear. In semi-intact preparations of Mytilus, in which one valve was removed, suspended particles were removed from the labial palps following two kinds of compound movements: torsional and rotational. Both of these compound movements are therefore thought to function in rejection during feeding. These movements were observed in reduced preparations of isolated labial palps with intact cerebral ganglia, and were maintained even after removal of the cerebral ganglia, suggesting that they are generated by the peripheral neural network. Stimulation of the anterior pallial nerve elicited tetanic contraction of the labial palp, followed by secondary responses, including torsional movement. Secondary responses were dramatically reduced by a high concentration of divalent cations, in which polysynaptic pathways were inhibited. Hence, the cerebral ganglia may play an excitatory role within the peripheral neural network and the labial palp musculature via the anterior pallial nerve. Administration of serotonin induced repetitive muscular movements, whereas dopamine did not induce muscular movements. Serotonin-induced muscular movements were not elicited under a high concentration of divalent cation condition. In histochemical experiments, both the serotonergic and dopaminergic neural processes and cell body-like structures were widely observed inside the labial palp, the anterior pallial nerve, and the cerebral ganglia. Serotonin may thus contribute to activation of polysynaptic peripheral pathways, which are involved in regulating compound movements.


Assuntos
Comportamento Alimentar , Músculos/inervação , Mytilus/fisiologia , Animais , Dopamina/farmacologia , Gânglios , Movimento/efeitos dos fármacos , Músculos/efeitos dos fármacos , Serotonina/farmacologia
2.
Cell Physiol Biochem ; 54(1): 126-141, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32017483

RESUMO

BACKGROUND/AIMS: Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter and hormone with important physiological functions in many organs, including the intestine. We have previously shown that 5-HT activates the aryl hydrocarbon receptor (AhR) in intestinal epithelial cells (IECs) via a serotonin transporter (SERT)-dependent mechanism. AhR is a nuclear receptor that binds a variety of molecules including tryptophan (TRP) metabolites to regulate physiological processes in the intestine including xenobiotic detoxification and immune modulation. We hypothesized that 5-HT activates AhR indirectly by interfering with metabolic clearance of AhR ligands by cytochrome P450 1A1 (CYP1A1). METHODS: Inhibition of CYP1A1 activity by 5-HT was assessed in the human intestinal epithelial cell line Caco-2 and recombinant CYP1A1 microsomes using both luciferase and LC-MS/MS. Degradation of 5-HT by recombinant CYP1A1 was measured by LC-MS/MS. For in vitro studies, CYP1A1 and CYP1B1 mRNA expression levels were measured by RT-PCR and CYP1A1 activity was measured by ethoxyresorufin-O-deethylase (EROD) assays. For in vivo studies, AhR ligands were administered to SERT KO mice and WT littermates and intestinal mucosa CYP1A1 mRNA was measured. RESULTS: We show that 5-HT inhibits metabolism of both the pro-luciferin CYP1A1 substrate Luc-CEE as well as the high affinity AhR ligand 6-formylindolo[3,2-b] carbazole (FICZ). Recombinant CYP1A1 assays revealed that 5-HT is metabolized by CYP1A1 in an NADPH dependent manner. Treatment with 5-HT in TRP-free medium, which is devoid of trace AhR ligands, showed that 5-HT requires the presence of AhR ligands to activate AhR. Cotreatment with 5-HT and FICZ confirmed that 5-HT potentiates induction of AhR target genes by AhR ligands. However, this was only true for ligands which are CYP1A1 substrates such as FICZ. Administration of ß-napthoflavone by gavage or indole-3-carbinol via diet to SERT KO mice revealed that lack of SERT impairs intestinal AhR activation. CONCLUSION: Our studies provide novel evidence of crosstalk between serotonergic and AhR signaling where 5-HT can influence the ability of AhR ligands to activate the receptor in the intestine.


Assuntos
Citocromo P-450 CYP1A1/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Serotonina/farmacologia , Transcrição Genética/efeitos dos fármacos , Animais , Células CACO-2 , Carbazóis/farmacologia , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Humanos , Ligantes , Masculino , Camundongos , Camundongos Knockout , RNA Mensageiro/metabolismo , Receptores de Hidrocarboneto Arílico/química , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/deficiência , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Transdução de Sinais/efeitos dos fármacos , Especificidade por Substrato , beta-Naftoflavona/administração & dosagem
3.
J Steroid Biochem Mol Biol ; 195: 105470, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31509772

RESUMO

Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via maternal blood, and we have previously shown that SRIs alter feto-placental steroidogenesis in an in vitro co-culture model. More specifically, serotonin (5-HT) regulates the estrogen biosynthetic enzyme aromatase (cytochrome P450 19; CYP19), which is disrupted by fluoxetine and its active metabolite norfluoxetine in BeWo choriocarcinoma cells. Based on molecular simulations, the present study illustrates that the SRIs fluoxetine, norfluoxetine, paroxetine, sertraline, citalopram and venlafaxine exhibit binding affinity for the active-site pocket of CYP19, suggesting potential competitive inhibition. Using BeWo cells and primary villous trophoblast cells isolated from normal term placentas, we compared the effects of the SRIs on CYP19 activity. We observed that paroxetine and sertraline induce aromatase activity in BeWo cells, while venlafaxine, fluoxetine, paroxetine and sertraline decrease aromatase activity in primary villous trophoblast. The effects of paroxetine and sertraline in primary villous trophoblasts were observed at the lower doses tested. We also showed that 5-HT and the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) induced CYP19 activity. An increase in phosphorylation of serine and tyrosine and a decrease in threonine phosphorylation of CYP19 was also associated with DOI treatment. Our results contribute to better understanding how 5-HT and SRIs interact with CYP19 and may affect estrogen production. Moreover, this study suggests that alteration of placental 5-HT levels due to depression and/or SRI treatment during pregnancy may be associated with disruption of placental estrogen production.


Assuntos
Aromatase/metabolismo , Placenta/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacologia , Serotonina/farmacologia , Células Cultivadas , Citalopram/farmacologia , Feminino , Fluoxetina/análogos & derivados , Fluoxetina/farmacologia , Humanos , Simulação de Acoplamento Molecular , Paroxetina/farmacologia , Placenta/metabolismo , Gravidez , Sertralina/farmacologia , Trofoblastos/efeitos dos fármacos , Trofoblastos/metabolismo , Cloridrato de Venlafaxina/farmacologia
4.
Anim Reprod Sci ; 208: 106122, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31405473

RESUMO

The vitellogenesis-inhibiting hormone (VIH), also known as gonad-inhibiting hormone, is a neuropeptide hormone in crustaceans that belongs to the crustacean hyperglycemic hormone (CHH)-family peptide. There is regulation vitellogenesis by VIH during gonad maturation in crustaceans. A full-length Scylla olivacea VIH (Scyol-VIH) was identified through reverse transcription polymerase chain reaction and rapid amplification of cDNA ends. The open reading frame consists of 378 nucleotides, which encodes a 126-amino acid precursor protein, including a 22-residue signal peptide and a 103-amino acid mature peptide in which 6 highly conserved cysteine residues are present. There was expression of the Scyol-VIH gene in immature female Scylla olivacea in the eyestalk, brain and ventral nerve cord. The Scyol-VIH gene expression was localized to the eyestalk X-organ, brain neuronal clusters 6 and 11, and in multiple neuronal clusters of the ventral nerve cord. The relative abundance of Scyol-VIH mRNA transcript in the eyestalk was relatively greater in immature stage females, then decreased as ovarian maturation progressed. Furthermore, eyestalk Scyol-VIH increased after dopamine (5 µg/g BW) injection. The present research provides fundamental information about Scyol-VIH and its potential effect in controlling reproduction.


Assuntos
Braquiúros/fisiologia , Dopamina/farmacologia , Hormônios de Invertebrado/metabolismo , Ovário/crescimento & desenvolvimento , RNA Mensageiro/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Braquiúros/genética , Clonagem Molecular , Dopamina/administração & dosagem , Dopaminérgicos/farmacologia , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios de Invertebrado/genética , Ovário/metabolismo , Filogenia , RNA Mensageiro/genética , Serotonina/administração & dosagem , Serotonina/farmacologia , Serotoninérgicos/administração & dosagem , Serotoninérgicos/farmacologia , Maturidade Sexual , Espiperona/administração & dosagem , Espiperona/farmacologia , Fatores de Tempo
5.
Molecules ; 24(17)2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443581

RESUMO

Epidermal inflammation is caused by various bacterial infectious diseases that impair the skin health. Feruloylserotonin (FS) belongs to the hydroxycinnamic acid amides of serotonin, which mainly exists in safflower seeds and has been proven to have anti-inflammatory and antioxidant activities. Human epidermis mainly comprises keratinocytes whose inflammation causes skin problems. This study investigated the protective effects of FS on the keratinocyte with lipopolysaccharides (LPS)-induced human HaCaT cells and elucidated its underlying mechanisms of action. The mechanism was investigated by analyzing cell viability, PGE2 levels, cell apoptosis, nuclear factor erythroid 2-related factor 2 (Nrf2) translocation, and TLR4/NF-κB pathway. The anti-inflammatory effects of FS were assessed by inhibiting the inflammation via down-regulating the TLR4/NF-κB pathway. Additionally, FS promoted Nrf2 translocation to the nucleus, indicating that FS showed anti-oxidative activities. Furthermore, the antioxidative and anti-inflammatory effects of FS were found to benefit each other, but were independent. Thus, FS can be used as a component to manage epidermal inflammation due to its anti-inflammatory and anti-oxidative properties.


Assuntos
Substâncias Protetoras/farmacologia , Serotonina/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Oxirredução/efeitos dos fármacos , Transporte Proteico , Serotonina/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
6.
Mol Cell Biochem ; 461(1-2): 57-64, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31352610

RESUMO

Metabolic syndrome (MetS) is associated with alterations in coronary vascular smooth muscle and endothelial function. The current study examined the contractile response of the isolated coronary arterioles to serotonin in pigs with and without MetS and investigated the signaling pathways responsible for serotonin-induced vasomotor tone. The MetS pigs (8-weeks old) were fed with a hyper-caloric, fat/cholesterol diet and the control animals (lean) were fed with a regular diet for 12 weeks (n = 6/group). The coronary arterioles (90-180 µm in diameter) were dissected from the harvested pig myocardial tissues and the in vitro coronary arteriolar response to serotonin was measured in the presence of pharmacological inhibitors. The protein expressions of phospholipase A2 (PLA2), TXA2 synthase, and the thromboxane-prostanoid (TP) receptor in the pigs' left ventricular tissue samples were measured using Western blotting. Serotonin (10-9-10-5 M) induced dose-dependent contractions of coronary-resistant arterioles in both non-MetS control (lean) and MetS pigs. This effect was more pronounced in the MetS vessels compared with those of non-MetS controls (lean, P < 0.05]. Serotonin-induced contraction of the MetS vessels was significantly inhibited in the presence of the selective PLA2 inhibitor quinacrine (10-6 M), the COX inhibitor indomethacin (10-5 M), and the TP receptor antagonist SQ29548 (10-6 M), respectively (P < 0.05). MetS exhibited significant increases in tissue levels of TXA2 synthase and TP receptors (P < 0.05 vs. lean), respectively. MetS is associated with increased contractile response of porcine coronary arterioles to serotonin, which is in part via upregulation/activation of PLA2, COX, and subsequent TXA2, suggesting that alteration of vasomotor function may occur at an early stage of MetS and juvenile obesity.


Assuntos
Arteríolas/fisiopatologia , Vasos Coronários/fisiopatologia , Síndrome Metabólica/fisiopatologia , Serotonina/farmacologia , Vasoconstrição/efeitos dos fármacos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Animais , Arteríolas/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Vasos Coronários/efeitos dos fármacos , Modelos Animais de Doenças , Ácidos Graxos Insaturados/farmacologia , Hidrazinas/farmacologia , Indometacina/farmacologia , Masculino , Fosfolipases A2/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Quinacrina/farmacologia , Receptores de Tromboxanos/metabolismo , Suínos , Tromboxano A2/metabolismo
7.
Exp Brain Res ; 237(10): 2573-2584, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31352493

RESUMO

Patients with eating disorders exhibit problems with appetitive impulse control. Interactions between dopamine and serotonin (5-HT) neuron in this setting are poorly characterized. Here we examined 5-HT receptor-mediated changes in extracellular dopamine during impulsive appetitive behavior in rats. Rats were trained to perform a cued lever-press (LP) task for a food reward such that they stopped experiencing associated dopamine increases. Trained rats were administered the mixed 5-HT1B/2C-receptor antagonist metergoline, the 5-HT2A/2C-receptor antagonist ketanserin, and p-chlorophenylalanine (PCPA). We measured dopamine changes in the ventral striatum using voltammetry and examined the number of premature LPs, reaction time (RT), and reward acquisition rate (RAR). Compared with controls, metergoline increased premature LPs and shortened RT significantly; ketanserin decreased premature LPs and lengthened RT significantly; and PCPA decreased premature LPs, lengthened RT, and decreased RAR significantly. Following metergoline administration, rats exhibited a fast phasic dopamine increase for 0.25-0.75 s after a correct LP, but only during LP for an incorrect LP. No dopamine increases were detected with ketanserin or PCPA, or in controls. After LP task completion, metergoline also caused dopamine to increase slowly and remain elevated; in contrast, ketanserin caused dopamine to increase slowly and decrease rapidly. No slow dopamine increase occurred with PCPA. Inhibition of 5-HT1B- and 5-HT2C-receptors apparently induced dual modes of extracellular dopamine increase: fast phasic, and slow long-lasting. These increases may be associated with the suppression of acquired prediction learning and retention of high motivation for reward, leading to impulsive excessive premature LPs.


Assuntos
Comportamento Animal/efeitos dos fármacos , Dopamina/farmacologia , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Serotonina/farmacologia , Animais , Sinais (Psicologia) , Dopamina/metabolismo , Comportamento Impulsivo/efeitos dos fármacos , Ketanserina/farmacologia , Aprendizagem/efeitos dos fármacos , Ratos , Tempo de Reação , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/fisiologia , Serotonina/metabolismo
8.
Nat Commun ; 10(1): 3225, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324772

RESUMO

Serotonin receptor (5-HT3AR) is the most common therapeutic target to manage the nausea and vomiting during cancer therapies and in the treatment of irritable bowel syndrome. Setrons, a class of competitive antagonists, cause functional inhibition of 5-HT3AR in the gastrointestinal tract and brainstem, acting as effective anti-emetic agents. Despite their prevalent use, the molecular mechanisms underlying setron binding and inhibition of 5-HT3AR are not fully understood. Here, we present the structure of granisetron-bound full-length 5-HT3AR solved by single-particle cryo-electron microscopy to 2.92 Å resolution. The reconstruction reveals the orientation of granisetron in the orthosteric site with unambiguous density for interacting sidechains. Molecular dynamics simulations and electrophysiology confirm the granisetron binding orientation and the residues central for ligand recognition. Comparison of granisetron-bound 5-HT3AR with the apo and serotonin-bound structures, reveals key insights into the mechanism underlying 5-HT3AR inhibition.


Assuntos
Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Serotonina/farmacologia , Animais , Antieméticos/farmacologia , Sítios de Ligação , Tronco Encefálico , Microscopia Crioeletrônica , Trato Gastrointestinal , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutação , Receptores 5-HT3 de Serotonina/genética , Xenopus laevis/genética
9.
Acta Neurobiol Exp (Wars) ; 79(2): 217-224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31342957

RESUMO

The aim of the current study was to analyse the augmentation of minocycline with bupropion in treating depression. 'Saline' (10 ml/kg), 'minocycline per se' (25 mg/kg), 'minocycline per se' (50 mg/kg), 'bupropion per se' (5 mg/kg), 'bupropion per se' (10 mg/kg) and 'bupropion + minocycline' (5 mg/kg + 25 mg/kg each) were administered to mice via the intraperitoneal route. In the forced swim and tail suspension test, the immobility period was analysed after 30 min of the treatment. Monoamines like dopamine, norepinephrine and serotonin levels were analysed in brain areas such as the whole brain, hippocampus and cerebral cortex using an HPLC-fluorescence detector. Euthanasia of mice was performed 1 h after treatment. Comparison between the control group and combination therapy and other standard drug groups showed a significant decrease in immobility in both antidepressant animal models. The combination of bupropion and minocycline showed greater benefits with respect to a reduction in the immobility time period and enhancement of dopamine, serotonin, and norepinephrine levels in the cerebral cortex, hippocampus and the whole brain when compared to the monotherapy treated groups. Hence, the side effects may be reduced drastically through this combination by a reduction in the bupropion/minocycline dosage.


Assuntos
Antidepressivos/uso terapêutico , Encéfalo/efeitos dos fármacos , Bupropiona/farmacologia , Minociclina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Dopamina/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Serotonina/farmacologia
10.
Int J Mol Sci ; 20(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336820

RESUMO

Among serotonin receptors, the 5-HT6 subtype is the most controversial and the least known in the field of molecular mechanisms. The 5-HT6R ligands can be pivotal for innovative treatment of cognitive impairment, but none has reached pharmacological market, predominantly, due to insufficient "druglikeness" properties. Recently, 1,3,5-triazine-piperazine derivatives were identified as a new chemical family of potent 5-HT6R ligands. For the most active triazine 5-HT6R agents found (1-4), a wider binding profile and comprehensive in vitro evaluation of their drug-like parameters as well as behavioral studies and an influence on body mass in vivo were investigated within this work. Results indicated the most promising pharmacological/druglikeness profiles for 4-((1H-indol-3-yl)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) and 4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (4), which displayed a significant procognitive action and specific anxiolytic-like effects in the behavioral tests in vivo together with satisfied pharmaceutical and safety profiles in vitro. The thymol derivative (4) seems to be of higher importance as a new lead candidate, due to the innovative, non-indole and non-sulfone structure with the best 5-HT6R binding properties.


Assuntos
Receptores de Serotonina/química , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Triazinas/química , Triazinas/farmacologia , Animais , Disfunção Cognitiva/tratamento farmacológico , Dopamina/química , Dopamina/farmacologia , Células HEK293 , Humanos , Ligantes , Masculino , Memória/efeitos dos fármacos , Redes e Vias Metabólicas , Estrutura Molecular , Ratos , Receptores de Serotonina/metabolismo , Serotonina/química , Serotonina/farmacologia , Agonistas do Receptor de Serotonina/uso terapêutico
11.
Int J Mol Sci ; 20(12)2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31208068

RESUMO

Migraine is a disorder affecting an increasing number of subjects. Currently, this disorder is not entirely understood, and limited therapeutic solutions are available. Migraine manifests as a debilitating headache associated with an altered sensory perception that may compromise the quality of life. Animal models have been developed using chemical, physical or genetic modifications, to evoke migraine-like hallmarks for the identification of novel molecules for the treatment of migraine. In this context, experimental models based on the use of chemicals as nitroglycerin or inflammatory soup were extensively used to mimic the acute state and the chronicity of the disorder. This manuscript is aimed to provide an overview of murine models used to investigate migraine pathophysiology. Pharmacological targets as 5-HT and calcitonin gene-related peptide (CGRP) receptors were evaluated for their relevance in the development of migraine therapeutics. Drug delivery systems using nanoparticles may be helpful for the enhancement of the brain targeting and bioavailability of anti-migraine drugs as triptans. In conclusion, the progresses in migraine management have been reached with the development of emerging agonists of 5-HT receptors and novel antagonists of CGRP receptors. The nanoformulations may represent a future perspective in which already known anti-migraine drugs showed to better exert their therapeutic effects.


Assuntos
Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/etiologia , Animais , Biomarcadores , Humanos , Transtornos de Enxaqueca/metabolismo , Modelos Animais , Modelos Teóricos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Serotonina/farmacologia
12.
Biol Pharm Bull ; 42(6): 1048-1053, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155582

RESUMO

Previous research has indicated that high insulin affects vascular function. Equol is an active metabolite of daidzein, an isoflavone produced from soy by intestinal microbial flora, with beneficial effects on the vascular system. This study investigated whether equol was beneficial for vascular function under high insulin conditions. Using organ culture techniques, rat carotid arteries were treated for 23 ± 1 h with a vehicle, high insulin (100 nM), or equol (100 µM) plus high insulin (100 nM). Vascular isometric forces were measured by the organ bath technique. In each endothelium-intact ring, the contractions induced by high-K+, noradrenaline, or by serotonin (5-HT) were similar for the vehicle, insulin, and equol + insulin treatments. Contractions induced by a selective 5-HT2A receptor agonist (TCB2) increased with insulin treatment (vs. vehicle), but less so with equol + insulin. Under basal conditions, a selective 5-HT2B receptor agonist (BW723C86) did not induce contraction; following precontraction by a thromboxane analog, it induced contraction but not relaxation. These responses were similar across the three treatments. Acetylcholine-induced relaxations were also similar for the three treatments. In the endothelium-denuded preparations, 5-HT-induced contraction was augmented with insulin treatment (vs. vehicle) but less so by equol + insulin treatment. These differences in 5-HT-induced contractions were eliminated by iberiotoxin, a large-conductance calcium-activated K+ channel (BKCa) inhibitor. These results suggest that equol exerts a preventive effect on the enhancement of 5-HT-induced contraction by high insulin (possibly mediated by the 5-HT2A receptor), and that these effects may be attributed to the activation of BKCa channels in vascular smooth muscle.


Assuntos
Artérias Carótidas/efeitos dos fármacos , Equol/farmacologia , Insulina/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Artérias Carótidas/fisiologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/fisiologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Norepinefrina/farmacologia , Fitoestrógenos/farmacologia , Potássio/farmacologia , Ratos Wistar , Serotonina/farmacologia
13.
Neuroscience ; 411: 150-163, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31153963

RESUMO

Silent angina is a critical phenomenon in the clinic and is more commonly associated with women patients suffering from myocardial ischemia. Its underlying cause remains mysterious in medicine. With our recent discovery of female-specific Ah-type baroreceptor neurons (BRNs), we hypothesize that cardiac analgesia is due to the direct activation of Ah-type BRNs by elevated levels of circulating serotonin (5-HT) myocardial infarction (MI) patients. Electromyography and the tail-flick reflex were assessed in control and MI-model rats to evaluate 5-HT-mediated BP regulation as well as peripheral and cardiac nociception. 5-HT or a 5-HT receptor agonist was microinjected into the nodose ganglion to confirm the involvement of the afferent pathway of the baroreflex arc. An inward current was observed in identified BRNs by applying a whole-cell patch-clamp technique in conjunction with qRT-PCR to verify the afferent-specific action of 5-HT and the expression of 5-HT receptors. Although the tail-flick reflex and mean arterial pressure were dramatically reduced in female MI rats with elevated serum 5-HT, intrapericardial capsaicin-evoked muscular discharges were significantly inhibited in comparing with those of males, which were mimicked by microinjection of 5-HT or SR57227A into the nodose. Ah-type BRNs displayed robust inward currents at lower concentrations of 5-HT than the C-type or the A-type, with significantly increased expression and cellular distribution of 5-HT3AR but not 5-HT3BR compared to the A- and C-types. Activation of 5-HT3AR in Ah-type BRNs by 5-HT contributes significantly to cardiac analgesia, which may suggest the pathogenic condition that silent angina occurs mainly in female patients.


Assuntos
Angina Pectoris/metabolismo , Pressão Sanguínea/fisiologia , Infarto do Miocárdio/metabolismo , Nociceptividade/fisiologia , Pressorreceptores/metabolismo , Serotonina/metabolismo , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Gânglio Nodoso/efeitos dos fármacos , Gânglio Nodoso/metabolismo , Ratos , Receptores de Serotonina/metabolismo , Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
14.
Horm Behav ; 114: 104542, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31226329

RESUMO

Aggression is a behavioral strategy for securing limited resources and its expression is strongly influenced by their presence and value. In particular, males are generally thought to guard females after mating to ward off other males, but the underlying control mechanisms are unknown. Here, we investigated the role of amines on male courtship behavior and its subsequent effect on male-male aggression in crickets (Gryllus bimaculatus). Contrary to the guarding hypothesis, female presence alone had no immediate effect on male-male aggression. Furthermore, confirming studies on other species, prior female contact, but not necessarily courtship or copulation, promoted subsequent male-male aggression in subordinate, but not socially naive crickets. This promoting effect of female contact is transient and slowly wanes after her removal. Selective aminergic receptor antagonists revealed that the promoting effect of prior female contact on male-male aggression is mediated by octopamine (OA), as well as by serotonin (5HT) acting most likely via 5HT1 and/or 5HT7 like receptors. This contrasts the role of 5HT2-like receptors in maintaining reduced aggressiveness after social defeat. Furthermore, while dopamine (DA) is necessary for the recovery of aggression in subordinates after defeat, it appears to play no part in female induced aggression. Male courtship, on the other hand, is selectively promoted by DA and 5HT, again most likely via 5HT1 and/or 5HT7 like receptors, but not by OA. We conclude that OA, DA and 5HT each differentially modulate different aspects of courtship and aggressive behavior in a context specific fashion.


Assuntos
Agressão/efeitos dos fármacos , Corte , Dopamina/farmacologia , Gryllidae/fisiologia , Octopamina/farmacologia , Serotonina/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Feminino , Masculino
15.
Folia Med (Plovdiv) ; 61(1): 120-126, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31237846

RESUMO

BACKGROUND: Intra-abdominal hypertension is known as a factor affecting cerebral haemodynamics. Sustainably elevated abdominal pressure may disturb the balance of intracranial/blood pressure ratio, eventually developing perfusion pressure to drop. AIM: The aim of this study is to investigate the influence of artificially elevated intra-abdominal pressure upon brain pial vessels condition and contractile reactivity of isolated rat arteria carotis communis and vena jugularis to norepinephrine and serotonin. MATERIALS AND METHODS: The abdominal pressure of rats anaesthetized with xylazine 10 mg/kg and ketamine 100 mg/kg was increased up to 25 mm Hg by insufflation of air through venflon cannula and maintained for period of 1 to 3 hours. Craniotomy of left parietal area was carried out by micro drill. Open scull and cranial window techniques were applied. Outer diameters of superficial pial vessels were measured by USB digital microcamera (magnification up to 400x). Contractile reactivity of smooth muscle preparations from arteria carotis communis and vena jugularis of euthanized abdominal-hypertensive (AH) rats was registered isometrically. RESULTS: Increased smooth muscle reactivity of a. carotis communis from AH rats to serotonin (10-8-10-4 mol/l) but not to norepinephrine compared to controls was registered. The changes tended to be higher in long lasting (3 hours) exposure of AH rats. Increase in outer diameter of pial vessels during maintenance of abdominal hypertension in both open scull and cranial window techniques was found. CONCLUSIONS: The increased intra-abdominal pressure causes dilatation of small superficial cerebral blood vessels and increases the smooth muscle reactivity of isolated arteria carotis communis to 5-HT.


Assuntos
Hipertensão/fisiopatologia , Músculo Liso Vascular/fisiologia , Pia-Máter/irrigação sanguínea , Animais , Masculino , Ratos , Ratos Wistar , Serotonina/farmacologia , Vasoconstrição
16.
Dokl Biol Sci ; 484(1): 5-9, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31016495

RESUMO

When studying a preparation of the isolated spinal cord segment of an adult frog, damaged and intact lumbar motoneurons were found to differ significantly in the membrane potential, input resistance and the action potential properties (amplitude, duration, fast and medium phases of the afterhyperpolarization, and the frequency of spikes). Serotonin (5-HT) reduced the amplitude of afterpolarization and increased the frequency of the spikes of the intact neurons, while in the damaged motoneurons, 5-HT increased the amplitude of afterpolarization and had no effect on the frequency of discharges.


Assuntos
Neurônios Motores/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/farmacologia , Traumatismos da Medula Espinal/fisiopatologia , Medula Espinal/efeitos dos fármacos , Potenciais de Ação , Animais , Neurônios Motores/fisiologia , Ranidae , Medula Espinal/fisiopatologia
17.
Am J Chin Med ; 47(2): 369-383, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30827154

RESUMO

This study examined whether serotonin and two of its derivatives, N -feruloylserotonin and N -( p -coumaroyl) serotonin, have a renoprotective effect in a mouse model of cisplatin-induced acute renal failure. Cisplatin (20 mg/kg body weight) was administered by intraperitoneal injection to male BALB/c mice that had received oral serotonin, N -feruloylserotonin or N -( p -coumaroyl) serotonin (7.5 mg/kg body weight per day) during the preceding 2 days. At 3 days after the cisplatin injection, serum and renal biochemical factors, oxidative stress, inflammation and apoptosis-related protein expression were evaluated, and histological examinations were performed. Cisplatin caused reduction in body weight and an increase in kidney weight; however, N -( p -coumaroyl) serotonin and N -feruloylserotonin attenuated these effects. Moreover, the serotonin derivatives significantly decreased serum urea nitrogen and creatinine levels. They also significantly reduced the level of reactive oxygen species and upregulated the expression of glutathione peroxidase in the kidney. Furthermore, the serotonin derivatives improved the abnormal expression of mitogen-activated protein kinases activation-dependent inflammation- and apoptosis-related protein and caused less renal damage. These results provide important evidence that N -( p -coumaroyl) serotonin and N -feruloylserotonin exert a pleiotropic effect on several parameters related to oxidative stress, inflammation and apoptosis. The derivatives also have a renoprotective effect in cisplatin-treated mice; however, this effect is higher with N -( p -coumaroyl) serotonin.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/prevenção & controle , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Fitoterapia , Serotonina/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Nitrogênio da Ureia Sanguínea , Carthamus tinctorius/química , Creatinina/sangue , Modelos Animais de Doenças , Expressão Gênica , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Inflamação/genética , Injeções Intraperitoneais , Rim/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Serotonina/administração & dosagem , Serotonina/farmacologia
18.
Handb Exp Pharmacol ; 250: 145-180, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30838456

RESUMO

This chapter covers antidepressants that fall into the class of serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors. That is, they bind to the 5-HT and NE transporters with varying levels of potency and binding affinity ratios. Unlike the selective serotonin (5-HT) reuptake inhibitors (SSRIs), most of these antidepressants have an ascending rather than a flat dose-response curve. The chapter provides a brief review of the chemistry, pharmacology, metabolism, safety and adverse effects, clinical use, and therapeutic indications of each antidepressant. Venlafaxine, a phenylethylamine, is a relatively weak 5-HT and weaker NE uptake inhibitor with a 30-fold difference in binding of the two transporters. Therefore, the drug has a clear dose progression, with low doses predominantly binding to the 5-HT transporter and more binding of the NE transporter as the dose ascends. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine (ODV; desvenlafaxine) by CYP2D6, and it therefore is subject to significant inter-individual variation in blood levels and response dependent on variations in CYP2D6 metabolism. The half-life of venlafaxine is short at about 5 h, with the ODV metabolite being 12 h. Both parent compound and metabolite have low protein binding and neither inhibit CYP enzymes. Therefore, both venlafaxine and desvenlafaxine are potential options if drug-drug interactions are a concern, although venlafaxine may be subject to drug-drug interactions with CYP2D6 inhibitors. At low doses, the adverse effect profile is similar to an SSRI with nausea, diarrhea, fatigue or somnolence, and sexual side effects, while venlafaxine at higher doses can produce mild increases in blood pressure, diaphoresis, tachycardia, tremors, and anxiety. A disadvantage of venlafaxine relative to the SSRIs is the potential for dose-dependent blood pressure elevation, most likely due to the NE reuptake inhibition caused by higher doses; however, this adverse effect is infrequently observed at doses below 225 mg per day. Venlafaxine also has a number of potential advantages over the SSRIs, including an ascending dose-antidepressant response curve, with possibly greater overall efficacy at higher doses. Venlafaxine is approved for MDD as well as generalized anxiety disorder, social anxiety disorder, and panic disorder. Desvenlafaxine is the primary metabolite of venlafaxine, and it is also a relatively low-potency 5-HT and NE uptake inhibitor. Like venlafaxine it has a favorable drug-drug interaction profile. It is subject to CYP3A4 metabolism, and it is therefore vulnerable to enzyme inhibition or induction. However, the primary metabolic pathway is direct conjugation. It is approved in the narrow dose range of 50-100 mg per day. Duloxetine is a more potent 5-HT and NE reuptake inhibitor with a more balanced profile of binding at about 10:1 for 5HT and NE transporter binding. It is also a moderate inhibitor of CYP2D6, so that modest dose reductions and careful monitoring will be needed when prescribing duloxetine in combination with drugs that are preferentially metabolized by CYP2D6. The most common side effects identified in clinical trials are nausea, dry mouth, dizziness, constipation, insomnia, asthenia, and hypertension, consistent with its mechanisms of action. Clinical trials to date have demonstrated rates of response and remission in patients with major depression that are comparable to other marketed antidepressants reviewed in this book. In addition to approval for MDD, duloxetine is approved for diabetic peripheral neuropathic pain, fibromyalgia, and musculoskeletal pain. Milnacipran is marketed as an antidepressant in some countries, but not in the USA. It is approved in the USA and some other countries as a treatment for fibromyalgia. It has few pharmacokinetic and pharmacodynamic interactions with other drugs. Milnacipran has a half-life of about 10 h and therefore needs to be administered twice per day. It is metabolized by CYP3A4, but the major pathway for clearance is direct conjugation and renal elimination. As with other drugs in this class, dysuria is a common, troublesome, and dose-dependent adverse effect (occurring in up to 7% of patients). High-dose milnacipran has been reported to cause blood pressure and pulse elevations. Levomilnacipran is the levorotary enantiomer of milnacipran, and it is pharmacologically very similar to the racemic compound, although the side effects may be milder within the approved dosing range. As with other NE uptake inhibitors, it may increase blood pressure and pulse, although it appears to do so less than some other medications. All medications in the class can cause serotonin syndrome when combined with MAOIs.


Assuntos
Antidepressivos/farmacologia , Succinato de Desvenlafaxina/química , Cloridrato de Duloxetina/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina , Serotonina , Antidepressivos/química , Cloridrato de Duloxetina/química , Humanos , Serotonina/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia
19.
Proc Natl Acad Sci U S A ; 116(14): 7107-7112, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30872487

RESUMO

Feeding is vital for animal survival and is tightly regulated by the endocrine and nervous systems. To study the mechanisms of humoral regulation of feeding behavior, we investigated serotonin (5-HT) and octopamine (OA) signaling in Caenorhabditis elegans, which uses pharyngeal pumping to ingest bacteria into the gut. We reveal that a cross-modulation mechanism between 5-HT and OA, which convey feeding and fasting signals, respectively, mainly functions in regulating the pumping and secretion of both neuromodulators via ADF/RIC/SIA feedforward neurocircuit (consisting of ADF, RIC, and SIA neurons) and ADF/RIC/AWB/ADF feedback neurocircuit (consisting of ADF, RIC, AWB, and ADF neurons) under conditions of food supply and food deprivation, respectively. Food supply stimulates food-sensing ADFs to release more 5-HT, which augments pumping via inhibiting OA secretion by RIC interneurons and, thus, alleviates pumping suppression by OA-activated SIA interneurons/motoneurons. In contrast, nutrient deprivation stimulates RICs to secrete OA, which suppresses pumping via activating SIAs and maintains basal pumping and 5-HT production activity through excitation of ADFs relayed by AWB sensory neurons. Notably, the feedforward and feedback circuits employ distinct modalities of neurosignal integration, namely, disinhibition and disexcitation, respectively.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Octopamina/farmacologia , Serotonina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Proteínas de Caenorhabditis elegans/fisiologia , Ingestão de Alimentos/fisiologia , Jejum/fisiologia , Privação de Alimentos/fisiologia , Interneurônios/patologia , Neurônios Motores/fisiologia , Células Receptoras Sensoriais/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
20.
J Pharmacol Exp Ther ; 369(1): 98-106, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30728250

RESUMO

Serotonin [5-hydroxytryptamine (5-HT)] exerts multiple central and peripheral functions. High concentrations of 5-HT have been found in the epididymis, a ductal organ that plays pivotal roles in sperm transport and maturation. The contraction of the epididymal smooth muscle is essential for sperm transport and emission during ejaculation. The contributions of the epididymal 5-HT system to these events are poorly understood. Here, we assessed the contractile function of 5-HT in the rat cauda epididymis (CE), pharmacologically targeting the receptor(s) and the reuptake mechanism involved in this system. Segments of CE duct from adult Wistar rats were set up in an organ bath system for isometric tension recordings, and concentration-response curves to 5-HT and norepinephrine were obtained. 5-HT elicited concentration-dependent contractions of the CE duct (pEC50 = 6.5 ± 0.1) that were potentiated with high potency by the norepinephrine transporter (NET) inhibitor desipramine and with low potency by the highly selective serotonin transporter inhibitor paroxetine, indicating that the NET is the major mediator of 5-HT reuptake in vitro. CE contractions to 5-HT were antagonized by the α 1-adrenoceptor (α 1-AR) antagonist prazosin (pA 2 ≅ 8.9), 5-HT2A/2C antagonists ketanserin (pA 2 ≅ 9.4) and fluoxetine (pA 2 ≅ 7.4), and 5-HT1A ligands WAY 100635 (pA 2 ≅ 8.9) and buspirone (pA 2 ≅ 7.3). Reverse transcriptase polymerase chain reaction analysis demonstrated that 5-HT1A and 5-HT2A transcripts are highly abundant in the cauda epididymis, whereas 5-HT2C transcript was not found. Altogether, our results reveal that contractions of the CE duct to 5-HT encompasses at least activation of α 1-ARs and 5-HT1A and 5-HT2A receptors, providing new insights into the roles of 5-HT on the epididymal function.


Assuntos
Epididimo/efeitos dos fármacos , Epididimo/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Serotonina/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores Adrenérgicos/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo
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