RESUMO
BACKGROUND: This study examines the complex relationships among the neuroendocrine axis, gut microbiome, inflammatory responses, and gastrointestinal symptoms in patients with irritable bowel syndrome (IBS). The findings provide new insights into the pathophysiology of IBS and suggest potential therapeutic targets for improving patient outcomes. AIM: To investigate the interactions between the neuroendocrine axis, gut microbiome, inflammation, and gastrointestinal symptoms in patients with IBS. METHODS: Patients diagnosed with IBS between January 2022 and January 2023 were selected for the study. Healthy individuals undergoing routine check-ups during the same period served as the control group. Data were collected on neuroendocrine hormone levels, gut microbiome profiles, inflammatory biomarkers, and gastrointestinal symptomatology to analyze their interrelations and their potential roles in IBS pathogenesis. RESULTS: IBS patients exhibited significant dysregulation of the neuroendocrine axis, with altered levels of cortisol, serotonin, and neuropeptides compared to healthy controls. The gut microbiome of IBS patients showed reduced diversity and specific alterations in bacterial genera, including Bifidobacterium, Lactobacillus, and Faecalibacterium, which were associated with neuroendocrine disturbances. Additionally, elevated levels of inflammatory markers, such as C-reactive protein, interleukin-6, and tumor necrosis factor-α, were observed and correlated with the severity of gastrointestinal symptoms like abdominal pain, bloating, and altered bowel habits. CONCLUSION: The findings suggest that targeting the neuroendocrine axis, gut microbiome, and inflammatory pathways may offer novel therapeutic strategies to alleviate symptoms and improve the quality of life in IBS patients.
Assuntos
Biomarcadores , Microbioma Gastrointestinal , Síndrome do Intestino Irritável , Sistemas Neurossecretores , Humanos , Síndrome do Intestino Irritável/microbiologia , Síndrome do Intestino Irritável/imunologia , Síndrome do Intestino Irritável/fisiopatologia , Microbioma Gastrointestinal/imunologia , Feminino , Adulto , Masculino , Sistemas Neurossecretores/fisiopatologia , Pessoa de Meia-Idade , Biomarcadores/sangue , Estudos de Casos e Controles , Inflamação/imunologia , Inflamação/microbiologia , Dor Abdominal/microbiologia , Dor Abdominal/etiologia , Dor Abdominal/imunologia , Serotonina/sangue , Serotonina/metabolismo , Adulto JovemRESUMO
The optimization of brain circuit connectivity based on initial environmental input occurs during critical periods characterized by sensory experience-dependent, temporally restricted, and transiently reversible synapse elimination. This precise, targeted synaptic pruning mechanism is mediated by glial phagocytosis. Serotonin signaling has prominent, foundational roles in the brain, but functions in glia, or in experience-dependent brain circuit synaptic connectivity remodeling, have been relatively unknown. Here, we discover that serotonergic signaling between glia is essential for olfactory experience-dependent synaptic glomerulus pruning restricted to a well-defined Drosophila critical period. We find that experience-dependent serotonin signaling is restricted to the critical period, with both (1) serotonin production and (2) 5-HT2A receptors specifically in glia, but not neurons, absolutely required for targeted synaptic glomerulus pruning. We discover that glial 5-HT2A receptor signaling limits the experience-dependent synaptic connectivity pruning in the critical period and that conditional reexpression of 5-HT2A receptors within adult glia reestablishes "critical period-like" experience-dependent synaptic glomerulus pruning at maturity. These results reveal an essential requirement for glial serotonergic signaling mediated by 5-HT2A receptors for experience-dependent synapse elimination.
Assuntos
Neuroglia , Receptor 5-HT2A de Serotonina , Serotonina , Transdução de Sinais , Sinapses , Animais , Neuroglia/metabolismo , Sinapses/metabolismo , Sinapses/fisiologia , Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Plasticidade Neuronal/fisiologia , Drosophila melanogaster/metabolismo , Drosophila/metabolismoRESUMO
Serotonin has been implicated in the neurobiology of attention-deficit/hyperactivity disorder (ADHD) due to its association with impulsivity, attention, and emotional regulation. Many compounds with serotonergic properties have been evaluated in ADHD, but few have been approved by regulatory authorities. Utilizing a search of public databases, we identified interventions studied in ADHD. Prescribing information and peer-reviewed and gray literature helped us to determine which compounds had an underlying mechanism of action associated with changing serotonin levels. Of the 24 compounds that met the search criteria, 16 had either failed clinical studies in an ADHD population or had been discontinued from future development. The available evidence was assessed to identify the developmental history of drugs with serotonergic activity and the outlook for new ADHD drug candidates targeting serotonin. Several treatment candidates floundered due to an inability to balance effectiveness with safety, underscoring the potential importance of potency, and selectivity. Ongoing drug development includes compounds with multimodal mechanisms of action targeting neurotransmission across serotonin, norepinephrine, and dopamine pathways; it appears likely that treatment which balances competing and complementary monoamine effects may provide improved outcomes for patients. It is hoped that continuing research into ADHD treatment will produce new therapeutic options targeting the serotonergic system, which can positively impact a wide range of symptoms, including mood, anxiety, and sleep as well as attention and hyperactivity.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Serotoninérgicos , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Serotoninérgicos/farmacologia , Desenvolvimento de Medicamentos , Serotonina/metabolismo , AnimaisRESUMO
Omeprazole, a drug of choice for the management of gastric hyperacidity, influences serotonergic neurotransmission in brain regions and its long-term use is known to cause stress-related behavioral deficits including anxiety. Aim of the current study was to explore the effects of omeprazole treatment on immobilization-induced anxiety in rats, specifically on the role of serotonin (5-HT). In view of the role of serotonin-1A (5-HT1A) autoreceptor in the availability of 5-HT in brain regions, mRNA expression of this autoreceptor was performed in raphe nuclei. Similarly, because of the role of hippocampal 5-HT neurotransmission in anxiety-like disorders, expression of the 5-HT1A heteroreceptors was determined in this region. We found that the treatment with omeprazole reduces anxiety-like behavior in rats, increases the expression of 5-HT1A autoreceptor in the raphe and decreases the hippocampal expression of 5-HT1A heteroreceptor. This suggests a role of 5-HT1A receptor types in omeprazole-induced behavioral changes. It also indicates a potential role of omeprazole in the management of serotonergic disorders.
Assuntos
Ansiedade , Modelos Animais de Doenças , Hipocampo , Omeprazol , Receptor 5-HT1A de Serotonina , Estresse Psicológico , Animais , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Omeprazol/farmacologia , Masculino , Ratos , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/tratamento farmacológico , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Ratos Wistar , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Serotonina/metabolismo , Núcleos da Rafe/metabolismo , Núcleos da Rafe/efeitos dos fármacos , RNA Mensageiro/metabolismo , Restrição Física , ImobilizaçãoRESUMO
Proper fetal development requires tight regulation of serotonin concentrations within the fetoplacental unit. This homeostasis is partly maintained by the placental transporter OCT3/SLC22A3, which takes up serotonin from the fetal circulation. Metformin, an antidiabetic drug commonly used to treat gestational diabetes mellitus, was shown to inhibit OCT3. We, therefore, hypothesized that its use during pregnancy could disrupt placental serotonin homeostasis. This hypothesis was tested using three experimental model systems: primary trophoblast cells isolated from the human term placenta, fresh villous human term placenta fragments, and rat term placenta perfusions. Inhibition of serotonin transport by metformin at three concentrations (1⯵M, 10⯵M, and 100⯵M) was assessed in all three models. The OCT3 inhibitor decynium-22 (100⯵M) and paroxetine (100⯵M), a dual inhibitor of SERT and OCT3, were used as controls. In primary trophoblasts, paroxetine exhibited the strongest inhibition of serotonin uptake, followed by decynium-22. Metformin showed a concentration-dependent effect, reducing serotonin uptake by up to 57â¯% at the highest concentration. Its inhibitory effect was less pronounced in fresh villous fragments but remained statistically significant at all concentrations. In the perfused rat placenta, metformin demonstrated a concentration-dependent effect, reducing placental serotonin uptake by 44â¯% at the highest concentration tested. Our findings across all experimental models show inhibition of placental OCT3 by metformin, resulting in reduced serotonin uptake by the trophoblast. This sheds light on mechanisms that may underpin metformin-mediated effects on fetal development.
Assuntos
Metformina , Placenta , Serotonina , Trofoblastos , Metformina/farmacologia , Feminino , Gravidez , Animais , Serotonina/metabolismo , Placenta/metabolismo , Placenta/efeitos dos fármacos , Humanos , Trofoblastos/metabolismo , Trofoblastos/efeitos dos fármacos , Ratos , Transporte Biológico/efeitos dos fármacos , Fator 3 de Transcrição de Octâmero/metabolismo , Hipoglicemiantes/farmacologia , Células Cultivadas , Ratos Wistar , Proteínas de Transporte de Cátions OrgânicosRESUMO
Postprandial dyslipidemia is commonly present in people with type 2 diabetes and obesity and is characterized by overproduction of apolipoprotein B48-containing chylomicron particles from the intestine. Peripheral serotonin is emerging as a regulator of energy homeostasis with profound implications for obesity; however, its role in dietary fat absorption and chylomicron production is unknown. Chylomicron production was assessed in Syrian golden hamsters by administering an olive oil gavage and IP poloxamer to inhibit lipoprotein clearance. Administration of serotonin or selective serotonin reuptake inhibitor, fluoxetine, increased postprandial plasma triglyceride (TG) and TG-rich lipoproteins. Conversely, inhibiting serotonin synthesis pharmacologically by p-chlorophenylalanine (PCPA) led to a reduction in both the size and number of TG-rich lipoprotein particles, resulting in lower plasma TG and apolipoprotein B48 levels. The effects of PCPA occurred independently of gastric emptying and vagal afferent signaling. Inhibiting serotonin synthesis by PCPA led to increased TG within the intestinal lumen and elevated levels of TG and cholesterol in the stool when exposed to a high-fat/high-cholesterol diet. These findings imply compromised fat absorption, as evidenced by reduced lipase activity in the duodenum and lower levels of serum bile acids, which are indicative of intestinal bile acids. During the postprandial state, mRNA levels for serotonin receptors (5-HTRs) were upregulated in the proximal intestine. Administration of cisapride, a 5-HT4 receptor agonist, alleviated reductions in postprandial lipemia caused by serotonin synthesis inhibition, indicating that serotonin controls dietary fat absorption and chylomicron secretion via 5-HT4 receptor.
Assuntos
Quilomícrons , Gorduras na Dieta , Mesocricetus , Receptores 5-HT4 de Serotonina , Serotonina , Triglicerídeos , Animais , Masculino , Quilomícrons/metabolismo , Serotonina/metabolismo , Receptores 5-HT4 de Serotonina/metabolismo , Gorduras na Dieta/farmacologia , Triglicerídeos/metabolismo , Triglicerídeos/sangue , Cricetinae , Fenclonina/farmacologia , Absorção Intestinal/efeitos dos fármacos , Fluoxetina/farmacologia , Período Pós-Prandial/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Serotonin (5-HT) is a biogenic monoamine that acts as a neurotransmitter in the central nervous system and as a paracrine, exocrine, or endocrine messenger in peripheral tissues. In this study, we hypothesized that inhibition of serotonin signaling using 5-HT receptor 2B (HTR2B) inhibitors could potentially impede the progression of CRC. We treated CT26 and COLO-205 cells with SB204741, an inhibitor of HTR2B, and evaluated CRC cell proliferation and migration. We then evaluated the effects of HTR2B inhibition in a xenograft mouse model of human colorectal cancer. We also evaluated the role of a novel inhibitor, GM-60186, using both in vitro and in vivo models. RNA sequencing analysis was performed to elucidate the underlying mechanism of the anti-tumor effects of pharmacological inhibition of HTR2B on CRC. In both CRC cell lines and xenograft mouse models, we show that pharmacological inhibition of HTR2B with SB204741 and GM-60186 significantly inhibits CRC cell proliferation and migration. HTR2B inhibition leads to the suppression of extracellular signal-regulated kinase (ERK) signaling, a critical pathway in CRC pathogenesis. Notably, transcriptomic analysis reveals distinct gene expression changes associated with HTR2B inhibition, providing insight into its therapeutic potential. In this study, we found that pharmacological inhibition of HTR2B suppressed CRC proliferation via ERK signaling. In addition, we proposed a novel HTR2B inhibitor for the treatment of CRC. This study highlights the potential role of HTR2B signaling in CRC. These inhibitors may contribute to new therapeutics for CRC treatment.
Assuntos
Movimento Celular , Proliferação de Células , Neoplasias Colorretais , Sistema de Sinalização das MAP Quinases , Receptor 5-HT2B de Serotonina , Serotonina , Animais , Neoplasias Colorretais/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Humanos , Proliferação de Células/efeitos dos fármacos , Receptor 5-HT2B de Serotonina/metabolismo , Linhagem Celular Tumoral , Serotonina/metabolismo , Serotonina/farmacologia , Movimento Celular/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , Camundongos Endogâmicos BALB C , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
When an organism encounters a pathogen, the host innate immune system activates to defend against pathogen colonization and toxic xenobiotics produced. C. elegans employ multiple defense systems to ensure survival when exposed to Pseudomonas aeruginosa including activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtype C. elegans quickly learn to avoid pathogens, here we describe a peculiar apathy-like behavior towards PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave and continue to feed on the pathogen even when a non-pathogenic and healthspan-promoting food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display the typical pathogen-induced intestinal distension and eventual demise. SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling that is required from both neurons and non-neuronal tissues. Serotonin depletion from SKN-1 activation limits pathogen defenses capacity, drives the pathogen-associated apathy behaviors and induces a synthetic sensitivity to selective serotonin reuptake inhibitors. Taken together, our work reveals interesting insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Proteínas de Ligação a DNA , Pseudomonas aeruginosa , Serotonina , Fatores de Transcrição , Animais , Caenorhabditis elegans/microbiologia , Caenorhabditis elegans/imunologia , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Pseudomonas aeruginosa/fisiologia , Pseudomonas aeruginosa/patogenicidade , Serotonina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Neurônios/metabolismo , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/metabolismo , Infecções por Pseudomonas/microbiologia , Imunidade Inata , Transdução de Sinais , Apatia/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
BACKGROUND: This study aimed to observe the clinical effects of "He Tiao Du Ren An Shen Acupuncture" (HTDRAS Acupuncture) for treating restless leg syndrome (RLS). METHODS: We randomly divided 66 RLS patients into 2 groups: the observation group received "He Tiao Du Ren An Shen Acupuncture" and the control group received conventional acupuncture. All participants were treated once a day, 6 days a week, with 1 day off, for a total of 1 month. Clinical effectiveness of the 2 groups was compared, neurotransmitter levels, the International Restless Leg Syndrome Scale and the Hamilton Anxiety Scale were assessed in both groups. RESULTS: The curative effect in the observation group was better than that in the control group (Pâ <â .05). After treatment, the expression of 5-hydroxytryptamine in the observation group was higher than in the control group (Pâ <â .05). The International Restless Leg Syndrome Scale and Hamilton Anxiety Scale scores in observation group were lower than those in control group (Pâ <â .05). CONCLUSION: "He Tiao Du Ren An Shen Acupuncture" for RLS is significantly effective and safe. It can effectively improve the levels of 5-hydroxytryptamine in RLS patients, alleviate clinical symptoms and reduce anxiety. This treatment has a high clinical application value and is worthy of clinical promotion.
Assuntos
Terapia por Acupuntura , Síndrome das Pernas Inquietas , Humanos , Síndrome das Pernas Inquietas/terapia , Síndrome das Pernas Inquietas/psicologia , Masculino , Feminino , Terapia por Acupuntura/métodos , Pessoa de Meia-Idade , Serotonina/metabolismo , Adulto , Resultado do Tratamento , Ansiedade/terapia , IdosoRESUMO
The use of phosphodiesterase inhibitors in the treatment of Parkinson's disease is currently widely discussed. The study aimed to investigate the impact of acute and chronic treatment with the phosphodiesterase 5 inhibitor, sildenafil, at low and moderate doses of 2 mg/kg and 6 mg/kg, and L-DOPA (12.5 mg/kg), alone or in combination, on asymmetric behavior and dopamine (DA) and serotonin metabolism in the striatum and substantia nigra of unilaterally 6-OHDA-lesioned rats. Acute administration of sildenafil at both tested doses jointly with L-DOPA significantly increased the number of contralateral rotations during a 2 h measurement compared to L-DOPA alone. The effect of a lower dose of sildenafil combined with L-DOPA was much greater in the second hour of measurement. However, the acute combined administration of a higher dose of sildenafil with L-DOPA resulted in an immediate and much stronger increase in the number of contralateral rotations compared to L-DOPA alone, already visible in the first hour of measurement. Interestingly, the chronic combined administration of 2 mg/kg of sildenafil and L-DOPA significantly reduced the number of contralateral rotations, especially during the first hour of measurement, compared to the long-term treatment with L-DOPA alone. Such an effect was not observed after the long-term combined treatment of a higher dose of sildenafil and L-DOPA compared to L-DOPA alone. The concentration of DA in the ipsilateral striatum and substantia nigra after the last combined chronic dose of sildenafil (2 or 6 mg/kg) and L-DOPA (12.5 mg/kg) was significantly higher than after L-DOPA alone. In spite of much stronger increases in the DA concentration in the ipsilateral striatum and substantia nigra, the number of contralateral rotations was reduced in the group of rats treated with the combination of 2 mg/kg sildenafil and L-DOPA compared to the group receiving L-DOPA alone. Moreover, the combined treatment with a low dose of sildenafil and L-DOPA had an opposite effect on DA catabolism, as assessed by DOPAC/DA and HVA/DA indexes, and these indexes were reduced in the ipsilateral striatum but increased in the contralateral striatum and substantia nigra compared to the treatment with L-DOPA alone. The results of the present study show that the addition of a low dose of a PDE5 inhibitor to the standard L-DOPA therapy differently modulates rotational behavior, the tissue DA concentration and its catabolism in the striatum and substantia nigra.
Assuntos
Corpo Estriado , Levodopa , Oxidopamina , Inibidores da Fosfodiesterase 5 , Citrato de Sildenafila , Substância Negra , Animais , Citrato de Sildenafila/farmacologia , Levodopa/farmacologia , Substância Negra/metabolismo , Substância Negra/efeitos dos fármacos , Ratos , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Masculino , Inibidores da Fosfodiesterase 5/farmacologia , Dopamina/metabolismo , Comportamento Animal/efeitos dos fármacos , Quimioterapia Combinada , Serotonina/metabolismo , Modelos Animais de Doenças , Monoaminas Biogênicas/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismoRESUMO
BACKRGROUND: Akkermansia muciniphila, a next-generation probiotic, is known as a cornerstone regulating the gut-organ axis in various diseases, but the underlying mechanism remains poorly understood. Here, we revealed the neuronal and antifibrotic effects of A. muciniphila on the gut-liver-brain axis in liver injury. RESULTS: To investigate neurologic dysfunction and characteristic gut microbiotas, we performed a cirrhosis cohort (154 patients with or without hepatic encephalopathy) and a community cognition cohort (80 participants in one region for three years) and validated the existence of cognitive impairment in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced hepatic injury mouse model. The effects of the candidate strain on cognition were evaluated in animal models of liver injury. The expression of brain-derived neurotrophic factor (BDNF) and serotonin receptors was accessed in patients with fibrosis (100 patients) according to the fibrosis grade and hepatic venous pressure gradient. The proportion of A. muciniphila decreased in populations with hepatic encephalopathy and cognitive dysfunction. Tissue staining techniques confirmed gut-liver-brain damage in liver injury, with drastic expression of BDNF and serotonin in the gut and brain. The administration of A. muciniphila significantly reduced tissue damage and improved cognitive dysfunction and the expression of BDNF and serotonin. Isolated vagus nerve staining showed a recovery of serotonin expression without affecting the dopamine pathway. Conversely, in liver tissue, the inhibition of injury through the suppression of serotonin receptor (5-hydroxytryptamine 2A and 2B) expression was confirmed. The severity of liver injury was correlated with the abundance of serotonin, BDNF, and A. muciniphila. CONCLUSIONS: A. muciniphila, a next-generation probiotic, is a therapeutic candidate for alleviating the symptoms of liver fibrosis and cognitive impairment.
Assuntos
Akkermansia , Fator Neurotrófico Derivado do Encéfalo , Disfunção Cognitiva , Microbioma Gastrointestinal , Cirrose Hepática , Fígado , Probióticos , Serotonina , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Serotonina/metabolismo , Camundongos , Disfunção Cognitiva/metabolismo , Masculino , Probióticos/uso terapêutico , Feminino , Fígado/metabolismo , Cirrose Hepática/metabolismo , Pessoa de Meia-Idade , Eixo Encéfalo-Intestino/fisiologia , Encefalopatia Hepática/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , IdosoRESUMO
Pairs of adult male crickets, Gryllus bimaculatus, fight and immediately determine winner and loser statuses. The winner male repeatedly produces an aggressive (rival) song by rubbing his forewings together. In this study, I removed the plectrum, a sound-producing structure in the forewing, from male crickets and measured their brain serotonin (5-hydroxytryptamine: 5-HT) levels immediately after a 10-min aggressive interaction. Pairs of plectrum-removed males fought and established clear winner-loser relationships, like the case of intact males. The plectrum-removed winner males frequently rubbed their forewings together, but were unable to produce song. Aggressive interaction reduced significantly brain 5-HT levels in the plectrum-removed males, regardless of their winner and loser statuses. Furthermore, the reduction of brain 5-HT was detected primarily in the central body, a group of neuropils spanning the midline of the brain. In contrast, in pairs of intact males, aggressive interaction reduced brain 5-HT levels in the loser males, but not in the winner males. Plectrum removal alone did not affect the brain's 5-HT levels. These results suggest that aggressive song emitted by the winner male cricket prevents the reduction of 5-HT levels in his own brain, especially in the central body.
Assuntos
Agressão , Encéfalo , Gryllidae , Serotonina , Animais , Masculino , Gryllidae/fisiologia , Gryllidae/metabolismo , Serotonina/metabolismo , Encéfalo/metabolismo , Vocalização AnimalRESUMO
Recent evidence indicates that neuronal activity within the claustrum (CLA) may be central to cellular and behavioral responses to psychedelic hallucinogens. The CLA prominently innervates many cortical targets and displays exceptionally high levels of serotonin (5-HT) binding. However, the influence of serotonin receptors, prime targets of psychedelic drug action, on CLA activity remains unexplored. We characterize the CLA expression of all known 5-HT subtypes and contrast the effects of 5-HT and the psychedelic hallucinogen, 2,5-dimethoxy-4-iodoamphetamine (DOI), on excitability of cortical-projecting CLA neurons. We find that the CLA is particularly enriched with 5-HT2C receptors, expressed predominantly on glutamatergic neurons. Electrophysiological recordings from CLA neurons that project to the anterior cingulate cortex (ACC) indicate that application of 5-HT inhibits glutamate receptor-mediated excitatory postsynaptic currents (EPSCs). In contrast, application of DOI stimulates EPSCs. We find that the opposite effects of 5-HT and DOI on synaptic signaling can both be reversed by inhibition of the 5-HT2C, but not 5-HT2A, receptors. We identify specific 5-HT receptor subtypes as serotonergic regulators of the CLA excitability and argue against the canonical role of 5-HT2A in glutamatergic synapse response to psychedelics within the CLA-ACC circuit.
Assuntos
Anfetaminas , Claustrum , Potenciais Pós-Sinápticos Excitadores , Alucinógenos , Receptores de Serotonina , Serotonina , Animais , Serotonina/farmacologia , Serotonina/metabolismo , Alucinógenos/farmacologia , Anfetaminas/farmacologia , Claustrum/efeitos dos fármacos , Claustrum/fisiologia , Receptores de Serotonina/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Serotonin is distinct among synaptic neurotransmitters because it is amphipathic and released from synaptic vesicles at concentrations superior to its water solubility limit (270 mM in synaptic vesicles for a solubility limit of 110 mM). Hence, serotonin is mostly aggregated in the synaptic cleft, due to extensive aromatic stacking. This important characteristic has received scant attention, as most representations of the serotonergic synapse take as warranted that serotonin molecules are present as monomers after synaptic vesicle exocytosis. Using a combination of in silico and physicochemical approaches and a new experimental device mimicking synaptic conditions, we show that serotonin aggregates are efficiently dissolved by gangliosides (especially GM1) present in postsynaptic membranes. This initial interaction, driven by electrostatic forces, attracts serotonin from insoluble aggregates and resolves micelles into monomers. Serotonin also interacts with cholesterol via a set of CH-π and van der Waals interactions. Thus, gangliosides and cholesterol act together as a functional serotonin-collecting funnel on brain cell membranes. Based on this unique mode of interaction with postsynaptic membranes, we propose a new model of serotonergic transmission that takes into account the post-exocytosis solubilizing effect of gangliosides and cholesterol on serotonin aggregates.
Assuntos
Colesterol , Gangliosídeos , Serotonina , Serotonina/metabolismo , Colesterol/metabolismo , Colesterol/química , Gangliosídeos/metabolismo , Gangliosídeos/química , Lipídeos de Membrana/metabolismo , Lipídeos de Membrana/química , Bicamadas Lipídicas/metabolismo , Bicamadas Lipídicas/química , Membrana Celular/metabolismo , Animais , Vesículas Sinápticas/metabolismoRESUMO
Increasing research suggests a connection between gut microbiota and depressive disorders. Targeted changes to the intestinal flora may contribute to alleviating anxiety and depression. This study aimed to identify probiotics that could attenuate stress-induced abnormal behavior and explore potential mechanisms. The administration of LR.KY16 significantly reduced stress-induced abnormal behaviors and physiological dysfunction. The mechanism may be via regulating the structure of the intestinal microbiota in mice, increasing the abundance of Akkermansia muciniphila, prompting enterochromaffin cells to secrete 5-HTP in the gut, which enters the brain through the bloodstream and promotes the synthesis of 5-HT in the brain, and then activates brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) through the 5-HT1A receptor. In addition, LR.KY16 also increased the expression of claudin-7, occludin, and zonula occludens-1 (ZO-1) in the colon, inhibited microglial M1 polarization, and inhibited systemic inflammation.
Assuntos
Depressão , Microbioma Gastrointestinal , Lacticaseibacillus rhamnosus , Camundongos Endogâmicos C57BL , Probióticos , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Camundongos , Probióticos/administração & dosagem , Probióticos/farmacologia , Masculino , Depressão/metabolismo , Depressão/tratamento farmacológico , Depressão/microbiologia , Lacticaseibacillus rhamnosus/metabolismo , Humanos , Serotonina/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Akkermansia , Intestinos/microbiologia , Mucosa Intestinal/metabolismoRESUMO
PURPOSE: Little is known about the relationship between apelin and serotonin in emotion regulation. This study aimed to examine children's emotional regulation skills and salivary apelin and serotonin levels. METHODS: This is a cross-sectional study performed in Türkiye. The research was completed with the participation of 146 children, 8-10 years old, from the general population. Emotion Regulation Skills Scale for Children (CERS) was used to assess children's levels of emotion regulation skills. Apelin and serotonin levels were examined by ELISA technique in saliva samples obtained from children. RESULTS: A statistically significant correlation was found between the mean total score of the CERS and the mean apelin and serotonin levels (p Ë .01). We found that females had higher emotion regulation skills compared to males, older higher than younger ones (p Ë .01). The regression analysis results show that age and gender together explain 50.5% of the variance in CERS scores, while apelin and serotonin together explain 35.8% of the variance. When all four variables (age, gender, apelin, and serotonin) are included in the model, they explain 51.3% of the variance in CERS scores. CONCLUSION: Older age and female gender explained most of emotion regulations skills.Key pointsIt was determined that the average salivary apelin and serotonin levels increased with increased age, and with increased age ERS also increased.More research is needed as this is the first time that the relationship between emotion regulation skills and serotonin and apelin levels has been examined.
Assuntos
Apelina , Regulação Emocional , Saliva , Serotonina , Humanos , Feminino , Masculino , Serotonina/metabolismo , Estudos Transversais , Criança , Apelina/metabolismo , Saliva/química , Saliva/metabolismo , Regulação Emocional/fisiologia , Fatores Sexuais , Fatores EtáriosRESUMO
BACKGROUND: The present study aimed to investigate the impact of the light-emitting diode (LED) green light alone or in combination with melatonin on pecking-related hormone regulation during incubation under normal and under hormonal stress conditions in breeder eggs. This study was divided into 2 experiments: In the first experiment effect of LED green light incubation on pecking-related hormones under normal conditions, on Hy-line brown (low pecking phenotype) and Roman pink (high pecking phenotype) eggs were tested. The 296 eggs of each strain were divided into two groups: LED green light incubation and dark incubation (control), each containing four replicates (37 eggs/replicate). The second experiment was conducted to evaluate the effect of LED green light incubation alone or in combination with melatonin under hormonal stress conditions on Roman pink eggs. A total of 704 Roman pink eggs were taken and divided into four groups, each consisting of 176 eggs. Each group was further divided into 2 subgroups, LED green light-regulated incubation and dark incubation with 88 eggs per subgroup, having 4 replicates of 22 eggs each. The groups were as follows: corticosterone solution injection (CI), corticosterone + melatonin mixed solution injection (CMI), Phosphate buffer solution injection (PI), and no injection (UI). RESULTS: Results of the first experiment revealed a higher level of serotonin hormone and lower corticosterone hormone in Hy-Line brown embryos compared to Roman pink embryos during dark incubation. The LED green light incubation significantly (P < 0.05) increased the level of 5-HT while decreasing the CORT level in Roman pink embryos indicating its regulatory effect on pecking-related hormones. Results of the second experiment showed that LED green light incubation significantly (P < 0.05) alleviated the CORT-induced hyperactivity of plasma 5-HT in Roman pink embryos. Furthermore, Melatonin (MLT) injection and LED green light together significantly (P < 0.05) reduced the hormonal stress caused by corticosterone injection in the eggs. CONCLUSIONS: Overall, the LED green light regulatory incubation demonstrated a regulatory effect on hormones that influence pecking habits. Additionally, when coupled with MLT injection, it synergistically mitigated hormonal stress in the embryos. So, LED green light incubation emerged as a novel method to reduce the damaging pecking habits of poultry birds.
Assuntos
Criação de Animais Domésticos , Galinhas , Corticosterona , Luz , Melatonina , Animais , Melatonina/farmacologia , Melatonina/administração & dosagem , Galinhas/fisiologia , Criação de Animais Domésticos/métodos , Embrião de Galinha , Serotonina/metabolismo , Estresse Fisiológico , Comportamento Animal , Luz VerdeRESUMO
INTRODUCTION: Nausea and vomiting are distressing symptoms experienced by cancer patients undergoing treatment, impacting their physical well-being and quality of life. Serotonin, a neurotransmitter known for its role in regulating mood and gastrointestinal function, has been implicated in chemotherapy-induced nausea and vomiting (CINV). This study aimed to investigate serotonin level differences between CINV and non-CINV groups among cancer patients undergoing chemotherapy. METHODS: An analytical observational investigation utilizing a cross-sectional design was conducted at Dr. Kariadi General Hospital from 2021-2022. Non-random consecutive sampling was employed to select participants meeting inclusion criteria, including age between 18 and 65 years, undergoing chemotherapy, non-smoking, and no recent antibiotic use. Platelet-poor plasma samples were analyzed for serotonin levels using a radioimmunoassay kit (Microplate reader ELx800). RESULTS: This study included 61 subjects compared serotonin levels in two groups to investigate their potential association with chemotherapy-induced nausea and vomiting (CINV). The non-CINV group (n=31) had a median serotonin level of 70 (IQR: 20) ng/mL, while the CINV group (n=30) had a significantly higher median of 170 ng/mL (IQR: 50) ng/mL. Age was associated with a 1.2 ng/mL increase in serotonin per year (95% CI: 0.5-1.9, p = 0.002), adjusted for sex. Being male correlated with a 40 ng/mL increase (95% CI: 10-70, p = 0.010), adjusted for age. CONCLUSION: This study underscores the importance of understanding serotonin's role in CINV and highlights the need for tailored treatment approaches based on chemotherapy emetogenicity.
Assuntos
Antineoplásicos , Náusea , Neoplasias , Serotonina , Vômito , Humanos , Estudos Transversais , Náusea/induzido quimicamente , Masculino , Vômito/induzido quimicamente , Feminino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Serotonina/sangue , Serotonina/metabolismo , Antineoplásicos/efeitos adversos , Adulto , Idoso , Prognóstico , Seguimentos , Qualidade de Vida , Adolescente , Adulto JovemRESUMO
Obstructive Sleep Apnea (OSA) is a disorder characterized by repeated upper airway collapse during sleep, leading to apneas and/or hypopneas, with associated symptoms like intermittent hypoxia and sleep fragmentation. One of the agents contributing to OSA occurrence and development seems to be serotonin (5-HT). Currently, the research focuses on establishing and interlinking OSA pathogenesis and the severity of the disease on the molecular neurotransmitter omnipresent in the human body-serotonin, its pathway, products, receptors, drugs affecting the levels of serotonin, or genetic predisposition. The 5-HT system is associated with numerous physiological processes such as digestion, circulation, sleep, respiration, and muscle tone-all of which are considered factors promoting and influencing the course of OSA because of correlations with comorbid conditions. Comorbidities include obesity, physiological and behavioral disorders as well as cardiovascular diseases. Additionally, both serotonin imbalance and OSA are connected with psychiatric comorbidities, such as depression, anxiety, or cognitive dysfunction. Pharmacological agents that target 5-HT receptors have shown varying degrees of efficacy in reducing the Apnea-Hypopnea Index and improving OSA symptoms. The potential role of the 5-HT signaling pathway in modulating OSA provides a promising avenue for new therapeutic interventions that could accompany the primary treatment of OSA-continuous positive airway pressure. Thus, this review aims to elucidate the complex role of 5-HT and its regulatory mechanisms in OSA pathophysiology, evaluating its potential as a therapeutic target. We also summarize the relationship between 5-HT signaling and various physiological functions, as well as its correlations with comorbid conditions.
Assuntos
Serotonina , Transdução de Sinais , Apneia Obstrutiva do Sono , Humanos , Apneia Obstrutiva do Sono/metabolismo , Apneia Obstrutiva do Sono/terapia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/fisiopatologia , Serotonina/metabolismo , Animais , Receptores de Serotonina/metabolismoRESUMO
5-Hydroxytryptamine (5-HT) is an inhibitory neurotransmitter widely distributed in mammalian tissues, exerting its effects through binding to various receptors. It plays a crucial role in the proliferation of granulosa cells (GCs) and the development of follicles in female animals, however, its effect on porcine follicle development is not clear. The aim of this study is to investigate the expression of 5-HT and its receptors in various parts of the pig ovary, as well as the effect of 5-HT on porcine follicular development by using ELISA, quantitative real-time PCR (qPCR) and EdU assays. Firstly, we examined the levels of 5-HT and its receptors in porcine ovaries, follicles, and GCs. The findings revealed that the expression of different 5-HT receptors varied among follicles of different sizes. To investigate the relationship between 5-HT and its receptors, we exposed the GCs to 5-HT and found a decrease in 5-HT receptor expression compared to the control group. Subsequently, the treatment of GCs with 0.5 µM, 5 µM, and 50 µM 5-HT showed an increase in the expression of cell cycle-related genes, and EdU results indicated cell proliferation after the 0.5 µM 5-HT treatment. Additionally, the expression of genes involved in E2 synthesis was examined after the treatment of granulosa cells with 0.5 µM 5-HT. The results showed that CYP19A1 and HSP17ß1 expression was decreased. These results suggest that 5-HT might affect the development of porcine follicle by promoting the proliferation of GCs and inhibiting the synthesis of estrogen. This provides a new finding for exploring the effect of 5-HT on follicular development, and lays a foundation for further research on the mechanism of 5-HT in follicles.