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1.
Science ; 373(6560): 1197-1198, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516803

RESUMO

[Figure: see text].


Assuntos
Comportamento Aditivo , Serotonina
2.
Artigo em Russo | MEDLINE | ID: mdl-34481450

RESUMO

Antidepressants are one of the most important classes of psychotropic drugs and they are widely used in clinical practice, mainly in psychiatry and neurology. The main indications for the use of antidepressants are depression and anxiety disorders. First-line antidepressants are selective serotonin reuptake inhibitors, as well as serotonin-norepinephrine reuptake inhibitors which due to their dual pharmacological action have an additional effect on pain syndromes that determines their use in the treatment of neuropathic pain and fibromyalgia. A special place among the serotonin-norepinephrine reuptake inhibitors has duloxetine, which is characterized by proven efficacy in the treatment of depression, anxiety disorders, as well as isolated and comorbid pain. The optimal balance of efficacy and tolerability determines the possibility of safe use of duloxetine in patients with severe neurological disorders.


Assuntos
Neurologia , Psiquiatria , Humanos , Norepinefrina , Serotonina , Inibidores de Captação de Serotonina/uso terapêutico
3.
Cell Adh Migr ; 15(1): 261-271, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34494935

RESUMO

Serotonin is well known as a neurotransmitter. Its roles in neuronal processes such as learning, memory or cognition are well established, and also in disorders such as depression, schizophrenia, bipolar disorder, and dementia. However, its effects on adhesion and cytoskeletal remodelling which are strongly affected by 5-HT receptors, are not as well studied with some exceptions for e.g. platelet aggregation. Neuronal function is strongly dependent on cell-cell contacts and adhesion-related processes. Therefore the role played by serotonin in psychiatric illness, as well as in the positive and negative effects of neuropsychiatric drugs through cell-related adhesion can be of great significance. In this review, we explore the role of serotonin in some of these aspects based on recent findings.


Assuntos
Adesão Celular/fisiologia , Movimento Celular/fisiologia , Citoesqueleto/fisiologia , Neurotransmissores/fisiologia , Serotonina/fisiologia , Animais , Humanos , Transtornos Mentais/metabolismo
5.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445375

RESUMO

Fast and sustained antidepressant effects of ketamine identified the mammalian target of rapamycin (mTOR) signaling pathway as the main modulator of its antidepressive effects. Thus, mTOR signaling has become integral for the preclinical evaluation of novel compounds to treat depression. However, causality between mTOR and depression has yet to be determined. To address this, we knocked down mTOR expression in mice using an acute intracerebral infusion of small interfering RNAs (siRNA) in the infralimbic (IL) or prelimbic (PrL) cortices of the medial prefrontal cortex (mPFC), and evaluated depressive- and anxious-like behaviors. mTOR knockdown in IL, but not PrL, cortex produced a robust depressive-like phenotype in mice, as assessed in the forced swimming test (FST) and the tail suspension test (TST). This phenotype was associated with significant reductions of mTOR mRNA and protein levels 48 h post-infusion. In parallel, decreased brain-derived neurotrophic factor (BDNF) expression was found bilaterally in both IL and PrL cortices along with a dysregulation of serotonin (5-HT) and glutamate (Glu) release in the dorsal raphe nucleus (DRN). Overall, our results demonstrate causality between mTOR expression in the IL cortex and depressive-like behaviors, but not in anxiety.


Assuntos
Depressão/psicologia , Córtex Pré-Frontal/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/genética , Depressão/metabolismo , Modelos Animais de Doenças , Núcleo Dorsal da Rafe/metabolismo , Técnicas de Silenciamento de Genes , Ácido Glutâmico/metabolismo , Elevação dos Membros Posteriores , Masculino , Camundongos , Serotonina/metabolismo , Natação
6.
Arch Oral Biol ; 130: 105245, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34438320

RESUMO

OBJECTIVE: To examine whether maternal chewing affects prenatal stress-induced behavioral alternations associated with the changes in apoptosis-related proteins and serotonin pathway of the mouse offspring. DESIGN: Pregnant mice were assigned to control, stress, and stress/chewing groups. Stress mice were placed in restraint tubes, from gestational day 12 until parturition. Stress/chewing mice were given a wooden stick for chewing during stress period. Morris water maze and hole-board tests were applied for behavioral alterations in one-month-old male pups. Hippocampal mRNA expression of B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X protein (Bax) was analyzed by quantitative real-time PCR. Serotonin and tryptophan hydroxylase expression level in the dorsal raphe nucleus was investigated immunohistochemically. RESULTS: Prenatal stress impaired the spatial learning, induced anxiety-like behavior, increased the ratio of hippocampal Bax/Bcl-2 expression, and decreased the expression of serotonin and tryptophan hydroxylase in dorsal raphe nucleus of the offspring. Maternal chewing ameliorated prenatal stress-induced cognitive impairment, anxiety-like behavior, and attenuated the increased ratio of hippocampal Bax/Bcl-2 expression, and the downregulated serotonin signaling in dorsal raphe nucleus of the offspring. CONCLUSIONS: Our results indicate that maternal chewing could improve prenatal stress-related anxiety-like behavior and cognitive impairment in mouse offspring, at least in part by affecting hippocampal apoptotic response and central serotonin pathway.


Assuntos
Disfunção Cognitiva , Efeitos Tardios da Exposição Pré-Natal , Animais , Ansiedade , Cognição , Feminino , Hipocampo , Masculino , Mastigação , Camundongos , Gravidez , Serotonina , Estresse Psicológico/complicações
7.
J Pak Med Assoc ; 71(8): 1963-1966, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34418010

RESUMO

OBJECTIVE: To determine the level of serotonin in patients of vasovagal syncope and postural tachycardia syndrome after head-up tilt test. METHODS: The cross-sectional analytical study was conducted at the Islamic International Medical College and the Department of Electrophysiology, Armed Forces Institute of Cardiology, Rawalpindi, from April 2017 to March 2018. Group A comprised cases of vasovagal syncope, group B had patients of postural tachycardia syndrome, and group C had healthy controls. Cases were chosen on the basis of history, episodes of syncope and findings of head-up tilt test. After the test, blood samples were taken for hormonal analysis of serotonin using enzyme-linked immunosorbent assay. Data was analysed using SPSS 21. RESULTS: Of the 80 subjects, 35(43.8%) were in group A, 35(43.8%) in group B and 10(12.4%) in group C. Mean serotonin value in group A was 918.39±380.16nM, in group B it was 1188.70±449.55nM., while in control group C the mean value was 771.40±376.14nM (p<0.05). CONCLUSIONS: Serotonin was found to have a significant role in syncope pathophysiology.


Assuntos
Síndrome da Taquicardia Postural Ortostática , Síncope Vasovagal , Estudos Transversais , Humanos , Serotonina , Teste da Mesa Inclinada
8.
Biomed Khim ; 67(4): 323-330, 2021 Jul.
Artigo em Russo | MEDLINE | ID: mdl-34414890

RESUMO

We investigated the levels of biogenic monoamines and their metabolites in the rat hypothalamus, midbrain and cerebellum in acute complex intoxication with morphine and alcohol. The distinctive features of neurotransmitter disorders in various parts of the rat brain under a single exposure to ethanol and morphine, as well as the differences between acute morphine-alcohol and alcohol-morphine intoxication were established. Complex intoxication with alcohol and morphine resulted in signs of dopamine consumption only in the hypothalamus, regardless of the order of alcohol and morphine administration. Under conditions of alcohol-morphine intoxication an increase in the level of metabolites of the serotonergic system was noted in the investigated parts of the brain. In the midbrain and cerebellum the manifestation of combined action of ethanol and morphine is mainly determined by the effect of the last of the administered substances. There are features of changes in the indices of the dopaminergic and serotonergic systems in these experimental conditions, confirmed by the processes of dopamine catabolism and a decrease in the norepinephrine and serotonin concentration in the hypothalamus, which are not observed under individual action of ethanol and morphine.


Assuntos
Morfina , Neurotransmissores , Animais , Encéfalo , Etanol/toxicidade , Ratos , Serotonina
9.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360573

RESUMO

Serotonin (5-HT) plays an extensive role during pregnancy in regulating both the placental physiology and embryonic/fetal development. The uptake of 5-HT into cells is central to the control of local concentrations of 5-HT near its molecular targets. Here, we investigated the mechanisms of 5-HT uptake into human primary placental cells and cord blood platelets, all isolated immediately after birth. Trophoblasts and cord blood platelets showed 5-HT uptake with similar Michaelis constant (Km) values (~0.6 µM), typical of the high-affinity serotonin transporter (SERT). The uptake of 5-HT into trophoblasts was efficiently inhibited by various SERT-targeting drugs. In contrast, the uptake of 5-HT into feto-placental endothelial cells was not inhibited by a SERT blocker and showed a Km value (~782 µM) in the low-affinity range. Consistent with this, SERT mRNAs were abundant in term trophoblasts but sparse in feto-placental endothelial cells, whereas the opposite was found for the low-affinity plasma membrane monoamine transporter (PMAT) mRNAs. Organic cation transporter (OCT) 1, 2, and 3 mRNAs were absent or sparse in both cell types. In summary, the results demonstrate, for the first time, the presence of functional 5-HT uptake systems in feto-placental endothelial cells and fetal platelets, cells that are in direct contact with fetal blood plasma. The data also highlight the sensitivity to various psychotropic drugs of 5-HT transport into trophoblasts facing the maternal blood. The multiple, high-, and low-affinity systems present for the cellular uptake of 5-HT underscore the importance of 5-HT homeostasis at the maternal-fetal interface.


Assuntos
Feto/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Troca Materno-Fetal , Placenta/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/agonistas , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/farmacologia , Feminino , Feto/efeitos dos fármacos , Humanos , Placenta/efeitos dos fármacos , Gravidez , Trofoblastos/efeitos dos fármacos , Trofoblastos/metabolismo
10.
Int J Mol Sci ; 22(15)2021 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-34360695

RESUMO

Serotonin, also known as 5-hydroxytryptamine (5-HT), is a metabolite of tryptophan and is reported to modulate the development and neurogenesis of the enteric nervous system, gut motility, secretion, inflammation, sensation, and epithelial development. Approximately 95% of 5-HT in the body is synthesized and secreted by enterochromaffin (EC) cells, the most common type of neuroendocrine cells in the gastrointestinal (GI) tract, through sensing signals from the intestinal lumen and the circulatory system. Gut microbiota, nutrients, and hormones are the main factors that play a vital role in regulating 5-HT secretion by EC cells. Apart from being an important neurotransmitter and a paracrine signaling molecule in the gut, gut-derived 5-HT was also shown to exert other biological functions (in autism and depression) far beyond the gut. Moreover, studies conducted on the regulation of 5-HT in the immune system demonstrated that 5-HT exerts anti-inflammatory and proinflammatory effects on the gut by binding to different receptors under intestinal inflammatory conditions. Understanding the regulatory mechanisms through which 5-HT participates in cell metabolism and physiology can provide potential therapeutic strategies for treating intestinal diseases. Herein, we review recent evidence to recapitulate the mechanisms of synthesis, secretion, regulation, and biofunction of 5-HT to improve the nutrition and health of humans.


Assuntos
Mucosa Intestinal/metabolismo , Serotonina/metabolismo , Células Enterocromafins/metabolismo , Microbioma Gastrointestinal , Humanos , Intestinos
11.
J Sex Med ; 18(9): 1491-1499, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34384732

RESUMO

BACKGROUND: Premature ejaculation (PE) is one of the most common ejaculatory disorders. Recent studies have suggested a close relationship between the serotonin (5-hydroxytryptamine [5-HT]) system and brain-derived neurotrophic factor (BDNF), raising the question of whether BDNF plays a role in ejaculation regulation. To our knowledge, no previous studies have explored BDNF level of the central nervous system in ejaculatory disorders. At the same time, the interaction of central BDNF and 5-HT systems has not been undertaken in ejaculation regulation field. AIM: The aim of this study was to investigate the interaction between BDNF and 5-HT levels in raphe nuclei which contains the serotonergic neurons in a rat animal model with different ejaculatory behavior. METHODS: Eighteen male rats were selected and classified as "sluggish," "normal," and "rapid" ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. BDNF and 5-HT levels were determined by enzyme-linked immunosorbent assay (ELISA). Real-Time Quantitative PCR and Western blot analyses were used to measure the mRNA level of Tryptophan Hydroxylase-2 (TPH2) gene and the expression of TPH2 protein (the rate-limiting enzyme in central 5-HT synthesis) in raphe nuclei, respectively. OUTCOMES: Male rat sexual behavior, the levels of BDNF and 5-HT in raphe nuclei of rats with different ejaculatory behavior, the mRNA level of gene encoding TPH2 and the expression of TPH2 protein in raphe nuclei. RESULTS: The primary finding of our study was that BDNF concentration was significantly decreased in raphe nuclei of rapid ejaculators. There was a strong positive correlation between the levels of BDNF and 5-HT (r = 0.944, P < .001). Further results showed that decreased TPH2 gene expression accompanied by TPH2 protein was shown in rapid ejaculators with lower BDNF level. CLINICAL IMPLICATIONS: With refinement of current knowledge, BDNF may eventually serve as a promising biomarker in patients with PE. STRENGTHS & LIMITATIONS: There are no previous studies examining the interaction of the brain BDNF and 5-HT in ejaculation regulation field. The main limitation is the limited sample size. CONCLUSION: BDNF may act via increasing the synthesis of central 5-HT in the process of ejaculation regulation. Our results suggest lack of endogenous BDNF induces the downregulation of TPH2 gene expression and the decrease of 5-HT synthesis in raphe nuclei of rapid ejaculator rats. Huang Y, Peng D, Geng H, et al. Endogenous Deficiency of Brain-Derived Neurotrophic Factor Induces the Downregulation of Tryptophan Hydroxylase-2 Expression in Raphe Nuclei of Rapid Ejaculator Rats. J Sex Med 2021;18:1491-1499.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Ejaculação Precoce/genética , Triptofano Hidroxilase , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Regulação para Baixo , Humanos , Masculino , Núcleos da Rafe/metabolismo , Ratos , Serotonina , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
12.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360959

RESUMO

BACKGROUND: Rates of major depressive disorder (MDD) increase with living at altitude. In our model, rats housed at moderate altitude (in hypobaric hypoxia) exhibit increased depression-like behavior, altered brain serotonin and a lack of antidepressant response to most selective serotonin reuptake inhibitors (SSRIs). A forebrain deficit in the bioenergetic marker creatine is noted in people living at altitude or with MDD. METHODS: Rats housed at 4500 ft were given dietary creatine monohydrate (CRMH, 4% w/w, 5 weeks) vs. un-supplemented diet, and impact on depression-like behavior, brain bioenergetics, serotonin and SSRI efficacy assessed. RESULTS: CRMH significantly improved brain creatine in a sex-based manner. At altitude, CRMH increased serotonin levels in the female prefrontal cortex and striatum but reduced male striatal and hippocampal serotonin. Dietary CRMH was antidepressant in the forced swim test and anti-anhedonic in the sucrose preference test in only females at altitude, with motor behavior unchanged. CRMH improved fluoxetine efficacy (20 mg/kg) in only males at altitude: CRMH + SSRI significantly improved male striatal creatine and serotonin vs. CRMH alone. CONCLUSIONS: Dietary CRMH exhibits sex-based efficacy in resolving altitude-related deficits in brain biomarkers, depression-like behavior and SSRI efficacy, and may be effective clinically for SSRI-resistant depression at altitude. This is the first study to link CRMH treatment to improving brain serotonin.


Assuntos
Encéfalo/efeitos dos fármacos , Creatina/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Fluoxetina/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Serotonina/metabolismo , Animais , Encéfalo/metabolismo , Creatina/administração & dosagem , Creatina/farmacologia , Suplementos Nutricionais , Sinergismo Farmacológico , Metabolismo Energético , Feminino , Fluoxetina/administração & dosagem , Fluoxetina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacologia , Fatores Sexuais
13.
Life Sci ; 283: 119872, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352261

RESUMO

The interaction of Toxoplasma gondii with the gastrointestinal tract of its host is highly regulated. Once ingested, the parasite crosses the epithelium without altering the permeability of the intestinal barrier. Nevertheless, many studies report alterations ranging from structural to functional damage in cells and tissues that make up the wall of the small and large intestine. Although the immune response to the parasite has been extensively studied, the role of serotonin (5-HT) in toxoplasmosis is poorly understood. Here we investigate the distribution of cells expressing 5-HT and its effects on cells and tissues of the jejunal wall of rats after 2, 3, or 7 days of T. gondii infection. KEY RESULTS: Our results show that transposition of the jejunal epithelium by T. gondii leads to ruptures in the basement membrane and activation of the immune system, as confirmed by the decrease in laminin immunostaining and the increase in the number of mast cells, respectively. CONCLUSIONS AND INFERENCES: We showed an increase in the number of enterochromaffin cells and mast cells expressing 5-HT in the jejunal wall. We also observed that the percentage of serotonergic mast cells increased in the total population. Thus, we can suggest that oral infection by T. gondii oocysts preferentially activates non-neuronal cells expressing 5-HT. Together, these results may explain both the changes in the extracellular matrix and the morphology of the enteric ganglia.


Assuntos
Células Enterocromafins , Jejuno , Oocistos/metabolismo , Serotonina/biossíntese , Toxoplasma/metabolismo , Toxoplasmose/metabolismo , Doença Aguda , Animais , Células Enterocromafins/metabolismo , Células Enterocromafins/parasitologia , Jejuno/metabolismo , Jejuno/parasitologia , Masculino , Ratos , Ratos Wistar
14.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445231

RESUMO

There is recognition that both stress and immune responses are important factors in a variety of neurological disorders. Moreover, there is an important role of several neurotransmitters that connect these factors to several neurological diseases, with a special focus in this paper on serotonin. Accordingly, it is known that imbalances in stressors can promote a variety of neuropsychiatric or neurodegenerative pathologies. Here, we discuss some facts that link major depressive disorder, Alzheimer's, and Parkinson's to the stress and immune responses, as well as the connection between these responses and serotonergic signaling. These are important topics of investigation which may lead to new or better treatments, improving the life quality of patients that suffer from these conditions.


Assuntos
Doença de Alzheimer/imunologia , Transtorno Depressivo Maior/imunologia , Sistema Imunitário/imunologia , Doença de Parkinson/imunologia , Serotonina/imunologia , Doença de Alzheimer/patologia , Transtorno Depressivo Maior/patologia , Humanos , Sistema Imunitário/patologia , Doença de Parkinson/patologia
15.
Nat Commun ; 12(1): 5063, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417466

RESUMO

Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [3H]imipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.


Assuntos
Antidepressivos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Cloridrato de Vilazodona/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Sítios de Ligação , Células COS , Chlorocebus aethiops , Humanos , Cinética , Simulação de Dinâmica Molecular , Proteínas Mutantes/metabolismo , Mutação/genética , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/ultraestrutura
16.
Neuropsychopharmacology ; 46(11): 2000-2010, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34239048

RESUMO

Autism spectrum disorder (ASD) is a common set of heterogeneous neurodevelopmental disorders resulting from a variety of genetic and environmental risk factors. A core feature of ASD is impairment in prosocial interactions. Current treatment options for individuals diagnosed with ASD are limited, with no current FDA-approved medications that effectively treat its core symptoms. We recently demonstrated that enhanced serotonin (5-HT) activity in the nucleus accumbens (NAc), via optogenetic activation of 5-HTergic inputs or direct infusion of a specific 5-HT1b receptor agonist, reverses social deficits in a genetic mouse model for ASD based on 16p11.2 copy number variation. Furthermore, the recreational drug MDMA, which is currently being evaluated in clinical trials, promotes sociability in mice due to its 5-HT releasing properties in the NAc. Here, we systematically evaluated the ability of MDMA and a selective 5-HT1b receptor agonist to rescue sociability deficits in multiple different mouse models for ASD. We find that MDMA administration enhances sociability in control mice and reverses sociability deficits in all four ASD mouse models examined, whereas administration of a 5-HT1b receptor agonist selectively rescued the sociability deficits in all six mouse models for ASD. These preclinical findings suggest that pharmacological enhancement of 5-HT release or direct 5-HT1b receptor activation may be therapeutically efficacious in ameliorating some of the core sociability deficits present across etiologically distinct presentations of ASD.


Assuntos
Transtorno do Espectro Autista , Animais , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/genética , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Camundongos , Serotonina , Comportamento Social
17.
Behav Neurosci ; 135(3): 359-368, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34264689

RESUMO

We previously reported that the dorsal raphe nucleus (DRN) was involved in the regulation of maternal care in lactating female mice. The DRN receives multiple innervations from a variety of the brain regions. Corticotropin-releasing factor (CRF) Type 1 and Type 2 receptors are distributed in the DRN. Both receptors have been implicated in regulating negative aspects including stress, fear, and anxiety. However, it remains unknown how CRF receptors in the DRN regulate maternal care. In the present study, we investigated how CRF receptors in the DRN is involved in regulating maternal care in lactating female mice. Injection of antalarmin or antisauvagine-30, which is an antagonist of CRF Type 1 or Type 2 receptor, respectively, into the DRN increased the latency to retrieving pups into the nest and to crouching over pups, and decreased the duration of crouching over pups, indicating that blockage of CRF receptor signaling in the DRN decreased maternal care. Each treatment did not affect anxiety-related behaviors, which were assayed using the hole-board test. These results suggest that CRF receptor signaling in the DRN positively regulates maternal care in lactating female mice. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Hormônio Liberador da Corticotropina , Receptores de Hormônio Liberador da Corticotropina , Animais , Hormônio Liberador da Corticotropina/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Feminino , Lactação , Camundongos , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Serotonina
18.
Brain Behav ; 11(8): e2308, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34327873

RESUMO

OBJECTIVES: Although many antidepressants are available, they are not always used appropriately. For appropriate use of antidepressants, the old concept of a linear dose-response relationship, in which the dose is linearly increased to achieve a sufficient antidepressant effect, should be reconsidered. Furthermore, there is ongoing debate on the safe and appropriate use of antidepressants in patients with bipolar depression. Antidepressants may be used under certain conditions in patients with bipolar depression. These neglected-but not negligible-aspects of antidepressants have been discussed herein. METHODS: A narrative qualitative review RESULTS: Dose-response relationships of antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are not linear. They may be bell-shaped, with efficacy initially increasing with an increase in dose but decreasing when the dose is increased beyond a certain point. Despite using international diagnostic criteria, uncertainty remains on whether operationally diagnosed depression is latent bipolar I depression, latent bipolar II depression, or true depression. Furthermore, operationally diagnosed bipolar II depression may be latent bipolar I depression, true bipolar II depression, or depression with false hypomanic episodes. Manic/hypomanic switches are most likely to occur in patients receiving tricyclic antidepressants, followed by those receiving serotonin and noradrenaline reuptake inhibitors and SSRIs, in that order. Also, these switches are most likely to occur in patients with bipolar I depression, followed by those with bipolar II depression and true depression, in that order. CONCLUSIONS: Considering the diagnostic subtype of bipolar depression and antidepressant properties may help to determine the optimal treatment strategy.


Assuntos
Transtorno Bipolar , Antidepressivos/efeitos adversos , Antidepressivos Tricíclicos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Depressão/tratamento farmacológico , Humanos , Serotonina , Inibidores de Captação de Serotonina/efeitos adversos
19.
Molecules ; 26(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201675

RESUMO

The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α2-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α2-adrenoceptors and 5-HT7 receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α2A/5-HT7 receptor antagonist and displayed moderate-to-high selectivity over α1-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/química , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/síntese química , Antagonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Antidepressivos/uso terapêutico , Escala de Avaliação Comportamental , Depressão/fisiopatologia , Células HEK293 , Humanos , Ligantes , Masculino , Camundongos , Mirtazapina/farmacologia , Mirtazapina/uso terapêutico , Norepinefrina/metabolismo , Piperidinas/química , Ratos , Receptores de Serotonina/genética , Serotonina/metabolismo , Natação
20.
Molecules ; 26(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208700

RESUMO

Cardamonin, a naturally occurring chalcone isolated from Alpinia species has shown to possess strong anti-inflammatory and anti-nociceptive activities. Previous studies have demonstrated that cardamonin exerts antihyperalgesic and antiallodynic properties in chronic constriction injury (CCI)-induced neuropathic pain animal model. However, the mechanisms underlying cardamonin's effect have yet to be fully understood. The present study aims to investigate the involvement of the serotonergic system in cardamonin induced antihyperalgesic and antiallodynic effects in CCI-induced neuropathic pain mice model. The neuropathic pain symptoms in the CCI mice model were assessed using Hargreaves Plantar test and von-Frey filament test on day 14 post-surgery. Central depletion of serotonin along the descending serotonergic pathway was done using ρ-chlorophenylalanine (PCPA, 100 mg/kg, i.p.), an inhibitor of serotonin synthesis for four consecutive days before cardamonin treatment, and was found to reverse the antihyperalgesic and antiallodynic effect produced by cardamonin. Pretreatment of the mice with several 5-HT receptor subtypes antagonists: methiothepin (5-HT1/6/77 receptor antagonist, 0.1 mg/kg), WAY 100635 (5-HT1A receptor antagonist, 1 mg/kg), isamoltane (5-HT1B receptor antagonist, 2.5 mg/kg), ketanserin (5-HT2A receptor antagonist, 0.3 mg/kg), and ondansetron (5-HT3 receptor antagonist, 0.5 mg/kg) were shown to abolish the effect of cardamonin induced antihyperalgesic and antiallodynic effects. Further evaluation of the 5-HT1A receptor subtype protein expressions reveals that cardamonin significantly upregulated its expression in the brainstem and spinal cord. Our results suggest that the serotonergic pathway is essential for cardamonin to exert its antineuropathic effect in CCI mice through the involvement of the 5-HT1A receptor subtype in the central nervous system.


Assuntos
Chalconas/farmacologia , Neuralgia/tratamento farmacológico , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Analgésicos/farmacologia , Animais , Chalconas/metabolismo , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Receptor 5-HT1A de Serotonina/metabolismo , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Medula Espinal/efeitos dos fármacos
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