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1.
Ecotoxicol Environ Saf ; 203: 111014, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888589

RESUMO

Tributyltin (TBT), a widely and persistently distributed organontin, has been well documented to disrupt reproduction and behaviors in animals due to its anti-aromatase activity. TBT has been also reported to enhance anxiety in several fish species, whereas the mechanism underlying remains largely unknown. To investigate the disruption of TBT on fish anxiety and the mechanisms possibly involved, adult male zebrafish (Danio rerio) were treated with TBT (100 and 500 ng/L) for 28 days and anxiety behavior was further investigated using a novel tank dive test. Result showed that TBT treatment significantly enhanced the total time of the fish spent in the lower half, delayed the onset time to the higher half of the tank and increased the total duration of freezing of the fish, indicating an enhanced anxiety in TBT-treated fish. Accordingly, TBT sharply elevated the cortisol levels in plasma in a concentration-dependent manner, suggesting that the elevated cortisol level might be involved in the enhanced anxiety. Although the expression of crha was significantly increased and crhbp was significantly decreased in the brain of TBT-treated fish which is consistent to the elevated cortisol level, the expressions of actha and acthb were sharply down-regulated. In contrast, the expressions of genes responsible for the synthesis and action of serotonin (5-HT) (pet1, thp2 and htr1aa), dopamine (DA) (th1, slc6a3, drd2a and drd2b) and gamma-aminobutyric acid (GABA) (gad2 and gabrg2) were all significantly inhibited. The down-regulation of these pivotal genes acting in 5-HT, DA and GABA neurotransmitter systems in response to TBT corresponded well with the TBT-enhanced anxiety in fish. It was thus strongly suggested that these neurotransmitters might be also involved in TBT-enhanced anxiety in adult male zebrafish. The present study extended our understanding of the neurotoxicity of TBT on the anxiety control and behavioral modulation in fish.


Assuntos
Ansiedade/induzido quimicamente , Hidrocortisona/metabolismo , Neurotransmissores/metabolismo , Compostos de Trialquitina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Dopamina/metabolismo , Masculino , Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra/metabolismo , Ácido gama-Aminobutírico/metabolismo
2.
PLoS Genet ; 16(8): e1009003, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866139

RESUMO

Sensory systems rely on neuromodulators, such as serotonin, to provide flexibility for information processing as stimuli vary, such as light intensity throughout the day. Serotonergic neurons broadly innervate the optic ganglia of Drosophila melanogaster, a widely used model for studying vision. It remains unclear whether serotonin modulates the physiology of interneurons in the optic ganglia. To address this question, we first mapped the expression patterns of serotonin receptors in the visual system, focusing on a subset of cells with processes in the first optic ganglion, the lamina. Serotonin receptor expression was found in several types of columnar cells in the lamina including 5-HT2B in lamina monopolar cell L2, required for spatiotemporal luminance contrast, and both 5-HT1A and 5-HT1B in T1 cells, whose function is unknown. Subcellular mapping with GFP-tagged 5-HT2B and 5-HT1A constructs indicated that these receptors localize to layer M2 of the medulla, proximal to serotonergic boutons, suggesting that the medulla neuropil is the primary site of serotonergic regulation for these neurons. Exogenous serotonin increased basal intracellular calcium in L2 terminals in layer M2 and modestly decreased the duration of visually induced calcium transients in L2 neurons following repeated dark flashes, but otherwise did not alter the calcium transients. Flies without functional 5-HT2B failed to show an increase in basal calcium in response to serotonin. 5-HT2B mutants also failed to show a change in amplitude in their response to repeated light flashes but other calcium transient parameters were relatively unaffected. While we did not detect serotonin receptor expression in L1 neurons, they, like L2, underwent serotonin-induced changes in basal calcium, presumably via interactions with other cells. These data demonstrate that serotonin modulates the physiology of interneurons involved in early visual processing in Drosophila.


Assuntos
Receptor 5-HT1B de Serotonina/genética , Receptores 5-HT1 de Serotonina/genética , Receptores 5-HT2 de Serotonina/genética , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Animais , Ritmo Circadiano/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Regulação da Expressão Gênica/genética , Interneurônios/metabolismo , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Neurotransmissores/genética , Receptores de Serotonina/genética , Serotonina/genética , Percepção Visual/genética
3.
Nat Commun ; 11(1): 4218, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839452

RESUMO

Exposure to social stress and dysregulated serotonergic neurotransmission have both been implicated in the etiology of psychiatric disorders. However, the serotonergic circuit involved in stress vulnerability is still unknown. Here, we explored whether a serotonergic input from the dorsal raphe (DR) to ventral tegmental area (VTA) influences vulnerability to social stress. We identified a distinct, anatomically and functionally defined serotonergic subpopulation in the DR that projects to the VTA (5-HTDR→VTA neurons). Moreover, we found that susceptibility to social stress decreased the firing activity of 5-HTDR→VTA neurons. Importantly, the bidirectional manipulation of 5-HTDR→VTA neurons could modulate susceptibility to social stress. Our findings reveal that the activity of 5-HTDR→VTA neurons may be an essential factor in determining individual levels of susceptibility to social stress and suggest that targeting specific serotonergic circuits may aid the development of therapies for the treatment of stress-related disorders.


Assuntos
Núcleo Dorsal da Rafe/fisiologia , Vias Neurais/fisiologia , Neurônios Serotoninérgicos/fisiologia , Estresse Psicológico/fisiopatologia , Transmissão Sináptica/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Núcleo Dorsal da Rafe/citologia , Núcleo Dorsal da Rafe/metabolismo , Ácido Glutâmico/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Neurônios Serotoninérgicos/citologia , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/metabolismo
4.
Yakugaku Zasshi ; 140(8): 979-983, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741871

RESUMO

Monoamine neurotransmitters are released by specialized neurons that regulate behavioral and cognitive functions. Although localization of monoaminergic neurons in the brain is well known, the distribution, concentration, and kinetics of monoamines remain unclear. We used mass spectrometry imaging (MSI) for simultaneous and quantitative imaging of endogenous monoamines to generate a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels. We observed several nuclei rich in both 5-HT and a catecholamine (DA or NE). Additionally, we analyzed de novo monoamine synthesis or fluctuations in those nuclei. We propose that MSI is a useful tool to gain deeper understanding of associations among the localization, levels, and turnover of monoamines in different brain areas and their role in inducing behavioral changes.


Assuntos
Monoaminas Biogênicas/análise , Monoaminas Biogênicas/metabolismo , Mapeamento Encefálico/métodos , Encéfalo/metabolismo , Espectrometria de Massas/métodos , Imagem Molecular/métodos , Neurotransmissores/metabolismo , Animais , Dopamina/análise , Dopamina/metabolismo , Camundongos , Neurônios/metabolismo , Neurotransmissores/fisiologia , Norepinefrina/análise , Norepinefrina/metabolismo , Serotonina/análise , Serotonina/metabolismo
5.
Aquat Toxicol ; 226: 105564, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32683169

RESUMO

Millions of pharmaceuticals are prescribed each year. Wastewater treatment plants fail to remove all pharmaceuticals from discharge leading to detectable concentrations entering aquatic ecosystems where the compounds can encounter nontarget organisms. Selective serotonin reuptake inhibitor (SSRI) class of antidepressants interact with transporters in the brain and peripheral nervous system to change serotonin levels in the synapse. Sublethal exposure to SSRIs can impact fish feeding behaviors, which can have impacts on ecological fitness. We exposed hybrid striped bass (Morone saxatilis x Morone chrysops) to low, medium, and high concentrations of sertraline (4.5 ± 0.84 µg/L, 35.4 ± 2.18 µg/L, and 96.8 ± 6.4 µg/L) over six days with six additional recovery days. Concentrations were chosen to compare results with a mixture study previously completed in our lab. Every three days we tracked how long each bass took to consume four fathead minnows (Pimephales promelas) and conducted destructive sampling to obtain brain and plasma samples. Brain and plasma samples were analyzed for sertraline levels and we calculated whole brain serotonin levels. During the exposure period, bass showed an increased time to capture prey, but time to capture prey returned to control levels during the six-day recovery period. Sertraline was detected in brain and plasma during the duration of the experiment, though not always in a dose-dependent fashion. While we demonstrated a relationship between time to capture prey and decrease whole brain serotonin levels, the decrease in time to capture prey during the recovery period suggests the serotonin levels in the brain are not solely responsible for the outward behavioral expression observed.


Assuntos
Bass/fisiologia , Química Encefálica/efeitos dos fármacos , Comportamento Predatório/efeitos dos fármacos , Inibidores de Captação de Serotonina/toxicidade , Sertralina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Bass/sangue , Bass/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ecossistema , Comportamento Alimentar/efeitos dos fármacos , Serotonina/metabolismo
6.
PLoS One ; 15(6): e0233979, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32492052

RESUMO

BACKGROUND: Exposure to maternal stress during pregnancy can have adverse effects on the fetus, which has potential long-term effects on offspring´s development and health. We investigated the kinetics and metabolism of the hormones and amino acids: cortisol, cortisone, tryptophan and serotonin in the term placenta in an ex vivo human placental perfusion model. The placentas used in the experiments were donated from families participating in the Maternal Stress and Placental Function project with a known maternal stress background. METHOD: Cortisol, cortisone, tryptophan and serotonin were added simultaneously to the maternal side in the 6 hour ex vivo term human recirculating placental perfusion model, in four experimental set-ups: without inhibitors, with carbenoxolone -that inhibits cortisol metabolism into cortisone, with fluoxetine that inhibits the serotonin transporter, and with PCPA that inhibits metabolism of tryptophan into serotonin. The concentration of cortisol and cortisone, and tryptophan and serotonin were quantified using UPLC and HPLC-MS respectively. RESULTS: Cortisol was rapidly metabolized into cortisone in the placenta, to a somewhat lesser degree when adding the inhibitor carbenoxolone, resulting in higher fetal exposure to cortisol. Serotonin was also rapidly metabolized in the placenta. When adding fluoxetine a peak of fetal serotonin levels was seen in the first hour of the perfusion. No effect was seen of the maternal stress levels on placental transport kinetics in this study. CONCLUSION: Inhibiting the metabolism of cortisol in the placenta increased fetal exposure to cortisol as expected. Unexpectedly we saw an increased fetal exposure to serotonin when inhibiting the serotonin transporter, which may be related to the increased serotonin concentration on the maternal side of the placenta. No effect on placental kinetics were evident on maternal stress levels during the pregnancy as the majority of participating mothers had normal stress levels.


Assuntos
Feto/metabolismo , Troca Materno-Fetal , Placenta/metabolismo , Estresse Psicológico/metabolismo , Adulto , Cortisona/metabolismo , Feminino , Humanos , Hidrocortisona/metabolismo , Perfusão , Gravidez , Serotonina/metabolismo , Triptofano/metabolismo
7.
Psychiatry Res ; 291: 113198, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32535509

RESUMO

An option currently being explored for the treatment of COVID-19 is the use of interferons (INFs), either alone or in combination with other antiviral agents. INFs are known to shift the metabolism of tryptophan (TRP) away from its role as a precursor of serotonin. For some patients, reduction in TRP levels may either expose an underlying vulnerability to depression or trigger a de novo episode of depression. This Commentary discusses the pathway involved and recommends in-hospital augmentation with foods or supplements that increase TRP levels for COVID-19 patients treated with INFs. Selective serotonin reuptake inhibitors may also be tried if the depressive symptomatology is not short-lived.


Assuntos
Betacoronavirus , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/psicologia , Depressão/metabolismo , Interferons/metabolismo , Pneumonia Viral/metabolismo , Pneumonia Viral/psicologia , Depressão/psicologia , Humanos , Pandemias , Serotonina/metabolismo , Triptofano/metabolismo
8.
Life Sci ; 255: 117867, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32479954

RESUMO

Obesity continues to be a growing health concern around the world, and elevated levels of free fatty acids as a result of high-fat intake might play a role in neuroendocrine alterations leading to obesity. However, it is unclear how fatty acids affect neuroendocrine functions and energy metabolism. Since hypothalamic monoamines play a crucial role in regulating neuroendocrine functions relating to energy balance, we investigated the direct effects of oleic acid on hypothalamic monoamines and hypothesized that oleic acid would activate peroxisome proliferator-activated receptor alpha (PPAR-α), a nuclear transcription factor involved with fatty acid metabolism, to affect monoamines. We also hypothesized that this response would be subdued in diet-induced obesity (DIO). To test these hypotheses, hypothalami from Sprague Dawley and DIO rats were incubated with 0 (Control), 0.00132 mM, 0.132 mM, 1.32 mM oleic acid, 50 µM MK 886 (a selective PPAR- α antagonist), or oleic acid + MK 886 in Krebs Ringers Henseleit (KRH) solution. HPLC-EC was used to measure monoamine levels in perfusates. Oleic acid produced a significant increase in norepinephrine, dopamine, and serotonin levels in a dose-dependent manner, and incubation with MK886 blocked these effects. The effect of oleic acid on hypothalamic monoamines was attenuated in DIO rats. These findings suggest that PPARα probably plays an essential role in fatty acid sensing in the hypothalamus, by affecting monoamine efflux and DIO rats are resistant to the effects of oleic acid.


Assuntos
Hipotálamo/efeitos dos fármacos , Obesidade/fisiopatologia , Ácido Oleico/farmacologia , PPAR alfa/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Ácidos Graxos não Esterificados/metabolismo , Hipotálamo/metabolismo , Indóis/farmacologia , Masculino , Norepinefrina/metabolismo , Ácido Oleico/administração & dosagem , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo
9.
Proc Biol Sci ; 287(1928): 20200713, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32517612

RESUMO

Serotonin is a biogenic monoamine conserved across phyla that is implicated in diverse physiological and behavioural functions. On examining the expression of the rate-limiting enzymes in serotonin synthesis, tryptophan hydroxylases (TPHs), in the teleost medaka (Oryzias latipes), we found that males have much higher levels of tph1 expression as compared with females. This robust sexual dimorphism was found to probably result from the direct stimulation of tph1 transcription by androgen/androgen receptor binding to canonical bipartite androgen-responsive elements in its proximal promoter region. Our results further revealed that tph1 expression occurs exclusively in pro-opiomelanocortin (pomc)-expressing cells and that the resulting serotonin and its derivative melatonin inhibit the expression of the pituitary hormone genes, fshb, sl and tshb. This suggests that serotonin and/or melatonin synthesized in pomc-expressing cells act in a paracrine manner to suppress pituitary hormone levels. Consistent with these findings and the male-biased expression of tph1, the expression levels of fshb, sl and tshb were all higher in females than in males. Taken together, the male bias in tph1 expression and consequent serotonin/melatonin production presumably contribute to sex differences in the expression of pituitary hormones and ultimately in the physiological functions mediated by them.


Assuntos
Oryzias/fisiologia , Hormônios Hipofisários/metabolismo , Caracteres Sexuais , Animais , Feminino , Masculino , Melatonina/metabolismo , Oryzias/metabolismo , Serotonina/metabolismo , Triptofano Hidroxilase/metabolismo
10.
Psychopharmacology (Berl) ; 237(7): 1909-1915, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32529266

RESUMO

RATIONALE: Depression is a major mental disorder affecting millions of people worldwide. Serotonin and norepinephrine reuptake inhibitors (SNRIs) are one of the antidepressant drugs prescribed for depression treatment. OBJECTIVE AND METHOD: There are many contradiction studies about the adverse effect and genotoxicity of SNRIs. So here, based on the guidelines proposed at the PRISMA statement, we performed a quantitative systematic review by searching international electronic databases (PubMed, Scopus, Embase, and Web of Science) for published documents on SSNRIs and their genotoxicity effects. RESULTS: The database searches retrieved 336 records, 18 of which met the inclusion criteria. Evaluation of the selected articles showed that a total of 9 articles were appropriate for final review. Most of these studies (78%) reported positive results for the genotoxicity of SNRIs CONCLUSION: Finally, we can conclude that these drugs have the potential to damage DNA.


Assuntos
Antidepressivos/efeitos adversos , Dano ao DNA/efeitos dos fármacos , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , Inibidores da Recaptação de Serotonina e Norepinefrina/efeitos adversos , Antidepressivos/farmacologia , Dano ao DNA/fisiologia , Transtorno Depressivo/metabolismo , Humanos , Norepinefrina/antagonistas & inibidores , Norepinefrina/genética , Norepinefrina/metabolismo , Serotonina/genética , Serotonina/metabolismo , Inibidores de Captação de Serotonina/efeitos adversos , Inibidores de Captação de Serotonina/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia
11.
Artigo em Inglês | MEDLINE | ID: mdl-32384728

RESUMO

Environmental studies, metabolic research, and state of the art research in neurobiology point towards the reduced amount of natural day and sunlight exposure of the developing child, as a consequence of increasingly long hours spent indoors online, as the single unifying source of a whole set of health risks identified worldwide, as is made clear in this review of currently available literature. Over exposure to digital environments, from abuse to addiction, now concerns even the youngest (ages 0 to 2) and triggers, as argued on the basis of clear examples herein, a chain of interdependent negative and potentially long-term metabolic changes. This leads to a deregulation of the serotonin and dopamine neurotransmitter pathways in the developing brain, currently associated with online activity abuse and/or internet addiction, and akin to that found in severe substance abuse syndromes. A general functional working model is proposed under the light of evidence brought to the forefront in this review.


Assuntos
Comportamento Aditivo , Transtornos Relacionados ao Uso de Substâncias , Encéfalo , Saúde da Criança , Dopamina/metabolismo , Humanos , Lactente , Recém-Nascido , Serotonina/metabolismo
12.
J Headache Pain ; 21(1): 35, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32316909

RESUMO

BACKGROUND: The neurochemical background of the evolution of headache disorders, still remains partially undiscovered. Accordingly, our aim was to further explore the neurochemical profile of Complete Freund's adjuvant (CFA)-induced orofacial pain, involving finding the shift point regarding small molecule neurotransmitter concentrations changes vs. that of the previously characterized headache-related neuropeptides. The investigated neurotransmitters consisted of glutamate, γ-aminobutyric acid, noradrenalin and serotonin. Furthermore, in light of its influence on glutamatergic neurotransmission, we measured the level of kynurenic acid (KYNA) and its precursors in the kynurenine (KYN) pathway (KP) of tryptophan metabolism. METHODS: The effect of CFA was evaluated in male Sprague Dawley rats. Animals were injected with CFA (1 mg/ml, 50 µl/animal) into the right whisker pad. We applied high-performance liquid chromatography to determine the concentrations of the above-mentioned compounds from the trigeminal nucleus caudalis (TNC) and somatosensory cortex (ssCX) of rats. Furthermore, we measured some of these metabolites from the cerebrospinal fluid and plasma as well. Afterwards, we carried out permutation t-tests as post hoc analysis for pairwise comparison. RESULTS: Our results demonstrated that 24 h after CFA treatment, the level of glutamate, KYNA and that of its precursor, KYN was still elevated in the TNC, all diminishing by 48 h. In the ssCX, significant concentration increases of KYNA and serotonin were found. CONCLUSION: This is the first study assessing neurotransmitter changes in the TNC and ssCX following CFA treatment, confirming the dominant role of glutamate in early pain processing and a compensatory elevation of KYNA with anti-glutamatergic properties. Furthermore, the current findings draw attention to the limited time interval where medications can target the glutamatergic pathways.


Assuntos
Dor Facial/metabolismo , Ácido Glutâmico/metabolismo , Ácido Cinurênico/metabolismo , Norepinefrina/metabolismo , Serotonina/metabolismo , Triptofano/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Dor Facial/induzido quimicamente , Adjuvante de Freund , Masculino , Ratos , Ratos Sprague-Dawley , Núcleo Inferior Caudal do Nervo Trigêmeo/metabolismo , Vibrissas/efeitos dos fármacos
13.
Chemosphere ; 254: 126715, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32334245

RESUMO

Perinatal exposure to bisphenol A (BPA) contributes to neurological disorders in offspring, but the underlying mechanisms are still poorly understood. The abnormal release of neuroactive metabolites in the tryptophan (TRP) and dopamine (DA) pathways is considered to be closely associated with some disorders. Thus, in this study, TRP and DA pathways in adult female mouse offspring were investigated when the pregnant mice were given either vehicle or BPA (2, 10, or 100 µg/kg/d) from day 6 of gestation until weaning. Then, the serum and brain samples of offspring were collected at 3, 6 and 9 months, and 12 neuroactive metabolites in the TRP and DA pathways were detected. The results showed that, in the TRP pathway, TRP levels decreased, whereas kynurenine (KYN) levels and TRP turnover increased in the brain. In the serum, TRP, KYN and 5-hydroxytryptamine (5-HT) levels decreased significantly. For the DA pathway, DA and DA metabolites, including 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA), reduced significantly in the brain and serum. DA turnover decreased dramatically in the brain but enhanced in the serum. The disturbance of these two metabolic pathways might be one of the potential mechanisms of BPA-induced neuropsychiatric disorders.


Assuntos
Compostos Benzidrílicos/toxicidade , Dopamina/metabolismo , Poluentes Ambientais/toxicidade , Neurotransmissores/metabolismo , Fenóis/toxicidade , Triptofano/metabolismo , Ácido 3,4-Di-Hidroxifenilacético , Animais , Encéfalo/metabolismo , Dopamina/análogos & derivados , Feminino , Masculino , Redes e Vias Metabólicas , Camundongos , Gravidez , Serotonina/metabolismo
14.
PLoS One ; 15(4): e0228357, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32275662

RESUMO

Increasingly, studies are revealing that endocrine disrupting chemicals (EDCs) can alter animal behavior. Early life exposure to EDCs may permanently alter phenotypes through to adulthood. In addition, the effects of EDCs may not be isolated to a single generation - offspring may indirectly be impacted, via non-genetic processes. Here, we analyzed the effects of paternal atrazine exposure on behavioral traits (distance moved, exploration, bottom-dwelling time, latency to enter the top zone, and interaction with a mirror) and whole-brain mRNA of genes involved in the serotonergic system regulation (slc6a4a, slc6a4b, htr1Aa, htr1B, htr2B) of zebrafish (Danio rerio). F0 male zebraFIsh were exposed to atrazine at 0.3, 3 or 30 part per billion (ppb) during early juvenile development, the behavior of F1 progeny was tested at adulthood, and the effect of 0.3 ppb atrazine treatment on mRNA transcription was quantified. Paternal exposure to atrazine significantly reduced interactions with a mirror (a proxy for aggression) and altered the latency to enter the top zone of a tank in unexposed F1 offspring. Bottom-dwelling time (a proxy for anxiety) also appeared to be somewhat affected, and activity (distance moved) was reduced in the context of aggression. slc6a4a and htr1Aa mRNA transcript levels were found to correlate positively with anxiety levels in controls, but we found that this relationship was disrupted in the 0.3 ppb atrazine treatment group. Overall, paternal atrazine exposure resulted in alterations across a variety of behavioral traits and showed signs of serotonergic system dysregulation, demonstrating intergenerational effects. Further research is needed to explore transgenerational effects on behavior and possible mechanisms underpinning behavioral effects.


Assuntos
Comportamento Animal/efeitos dos fármacos , Herbicidas/toxicidade , Exposição Paterna , Serotonina/metabolismo , Peixe-Zebra/fisiologia , Animais , Atrazina/toxicidade , Cruzamentos Genéticos , Comportamento Exploratório/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
15.
Nat Commun ; 11(1): 1673, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245974

RESUMO

Environmental and epigenetic factors often play an important role in polygenic disorders. However, how such factors affect disease-specific tissues at the molecular level remains to be understood. Here, we address this in pulmonary arterial hypertension (PAH). We obtain pulmonary arterial endothelial cells (PAECs) from lungs of patients and controls (n = 19), and perform chromatin, transcriptomic and interaction profiling. Overall, we observe extensive remodeling at active enhancers in PAH PAECs and identify hundreds of differentially active TFs, yet find very little transcriptomic changes in steady-state. We devise a disease-specific enhancer-gene regulatory network and predict that primed enhancers in PAH PAECs are activated by the differentially active TFs, resulting in an aberrant response to endothelial signals, which could lead to disturbed angiogenesis and endothelial-to-mesenchymal-transition. We validate these predictions for a selection of target genes in PAECs stimulated with TGF-ß, VEGF or serotonin. Our study highlights the role of chromatin state and enhancers in disease-relevant cell types of PAH.


Assuntos
Elementos Facilitadores Genéticos , Redes Reguladoras de Genes , Hipertensão Arterial Pulmonar/genética , Artéria Pulmonar/patologia , Remodelação Vascular/genética , Adulto , Biópsia , Estudos de Casos e Controles , Células Cultivadas , Cromatina/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/citologia , Epigênese Genética , Transição Epitelial-Mesenquimal/genética , Feminino , Código das Histonas/genética , Histonas/genética , Humanos , Lactente , Pulmão/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Hipertensão Arterial Pulmonar/patologia , Artéria Pulmonar/citologia , RNA-Seq , Serotonina/metabolismo , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto Jovem
16.
J Anim Sci ; 98(5)2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32315027

RESUMO

Exercise improves the health of dogs; however, the extreme exertion experienced by sled dogs may lead to variable metabolic and fecal characteristics. Nutritional interventions, such as dietary tryptophan (Trp), may reduce the prevalence of these exercise-induced disturbances. Sporting diets tend to have high crude protein concentrations in contrast to adult maintenance diets and this results in less Trp relative to other amino acids (AA). Therefore, sporting dogs represent an ideal cohort to assess the effects of supplemental Trp. The objective was to evaluate the effects of supplemental dietary Trp and an incremental training regimen on AA and serotonin status, fecal scores and metabolites, and body composition in client-owned Siberian huskies. Sixteen dogs (nine females and seven males) were used, with a mean age of 4.8 ± 2.5 yr and body weight (BW) of 24.3 ± 4.3 kg. Dogs were blocked for sex, age, and BW and randomly allocated into two groups with eight fed a dry extruded control diet (Ctl) and eight fed Ctl supplemented with Trp to reach a Trp:large-neutral AA (LNAA) ratio of 0.075:1 (treatment, Trt). The exercise regimen was designed to increase in distance each week, but weather played a role in setting the daily distance. Each week BW was recorded and food allotments were adjusted to maintain initial BW. Pre and post-exercise blood samples were taken every 3 wk, dogs then received a meal followed by 1, 2, and 4 h post meal blood collections (serum AA, serotonin). Stool collection and scoring occurred each week and body composition was measured on weeks -1 and 11. Serotonin, AA, fecal metabolite, and body composition data were analyzed using PROC MIXED of SAS with dog as a random effect and week and Trt as fixed effects. Stool score data were analyzed using PROC FREQ to compare stool score and Trt, and PROC CORR was used to analyze associations between fecal score, temperature, humidity, and run distance. Dogs on Trt had greater fasted Trp compared with baseline, greater post-meal Trp and serotonin compared with baseline, greater post-meal Trp compared with fasted, and greater post-meal Trp and serotonin compared with Ctl (P < 0.05). Fecal data indicated that Trp improved stool scores (P < 0.05) yet had no effect on fecal metabolites. An overall increase in lean and decrease in fat mass was found (P < 0.05), but Trt had no effect on body composition. Optimization of the dietary Trp:LNAA ratio may help to improve GI health without compromising performance in actively training sled dogs.


Assuntos
Aminoácidos/metabolismo , Composição Corporal/efeitos dos fármacos , Suplementos Nutricionais/análise , Cães/fisiologia , Serotonina/metabolismo , Triptofano/administração & dosagem , Ração Animal/análise , Animais , Peso Corporal/efeitos dos fármacos , Dieta/veterinária , Fezes/química , Feminino , Masculino , Condicionamento Físico Animal , Distribuição Aleatória
17.
Radiat Res ; 193(5): 407-424, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134362

RESUMO

Radiotherapy, surgery and the chemotherapeutic agent temozolomide (TMZ) are frontline treatments for glioblastoma multiforme (GBM). However beneficial, GBM treatments nevertheless cause anxiety or depression in nearly 50% of patients. To further understand the basis of these neurological complications, we investigated the effects of combined radiotherapy and TMZ chemotherapy (combined treatment) on neurological impairments using a mouse model. Five weeks after combined treatment, mice displayed anxiety-like behaviors, and at 15 weeks both anxiety- and depression-like behaviors were observed. Relevant to the known roles of the serotonin axis in mood disorders, we found that 5HT1A serotonin receptor levels were decreased by ∼50% in the hippocampus at both early and late time points, and a 37% decrease in serotonin levels was observed at 15 weeks postirradiation. Furthermore, chronic treatment with the selective serotonin reuptake inhibitor fluoxetine was sufficient for reversing combined treatment-induced depression-like behaviors. Combined treatment also elicited a transient early increase in activated microglia in the hippocampus, suggesting therapy-induced neuroinflammation that subsided by 15 weeks. Together, the results of this study suggest that interventions targeting the serotonin axis may help ameliorate certain neurological side effects associated with the clinical management of GBM to improve the overall quality of life for cancer patients.


Assuntos
Neurologia , Radioterapia/efeitos adversos , Temozolomida/efeitos adversos , Animais , Ansiedade/diagnóstico , Ansiedade/etiologia , Ansiedade/metabolismo , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/efeitos da radiação , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/patologia , Região CA1 Hipocampal/efeitos da radiação , Terapia Combinada/efeitos adversos , Depressão/induzido quimicamente , Depressão/etiologia , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/efeitos da radiação , Receptor 5-HT1A de Serotonina/metabolismo , Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Temozolomida/uso terapêutico
18.
BMC Complement Med Ther ; 20(1): 70, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143600

RESUMO

BACKGROUND: Post-traumatic stress disorder (PTSD) is an extreme mood disorder that occurs after experiencing extreme stress, and patients with this disorder are known to accompany with symptoms of depression, anxiety, and memory impairments. Silibinin (SIL) is a natural polyphenolic flavonoid and is the main active ingredient of silymarin, which is primarily extracted from the milk thistle. Although some studies have assessed the properties of this flavonoid, the potential of SIL as a treatment for PTSD patients and its mechanisms of action have yet to be fully elucidated. METHODS: After exposure to a model of single prolonged stress (SPS), the open field test (OFT) and forced swimming test (FST), were used to investigate the effects of SIL on anxiety- and depression-like symptoms in male rats. The rats received of SIL (25, 50, and 100 mg/kg) for 14 days following exposure to SPS. RESULTS: Administration of SIL significantly improved anxiety-like behaviors in the OFT, depression-like behaviors in the FST, and freezing behavior in fear conditioning test. SIL also increased levels of serotonin in the hippocampus (Hipp) and amygdala, and enhanced expression of tryptophan hydroxylase-1 mRNA in the Hipp. The administration of SIL also inhibited SPS-induced decreases dopamine levels and increases norepinephrine levels in the Hipp. CONCLUSIONS: Taken together, the present findings suggest that SIL can be a useful therapeutic ingredient for the treatment of trauma stress-associated symptoms, including PTSD-induced anxiety and depression caused by PTSD.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Silimarina/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Animais , Transtornos de Ansiedade/prevenção & controle , Transtorno Depressivo/prevenção & controle , Masculino , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo
19.
Nat Commun ; 11(1): 1491, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198394

RESUMO

The serotonin transporter (SERT) terminates serotonin signaling by rapid presynaptic reuptake. SERT activity is modulated by antidepressants, e.g., S-citalopram and imipramine, to alleviate symptoms of depression and anxiety. SERT crystal structures reveal two S-citalopram binding pockets in the central binding (S1) site and the extracellular vestibule (S2 site). In this study, our combined in vitro and in silico analysis indicates that the bound S-citalopram or imipramine in S1 is allosterically coupled to the ligand binding to S2 through altering protein conformations. Remarkably, SERT inhibitor Lu AF60097, the first high-affinity S2-ligand reported and characterized here, allosterically couples the ligand binding to S1 through a similar mechanism. The SERT inhibition by Lu AF60097 is demonstrated by the potentiated imipramine binding and increased hippocampal serotonin level in rats. Together, we reveal a S1-S2 coupling mechanism that will facilitate rational design of high-affinity SERT allosteric inhibitors.


Assuntos
Sítio Alostérico/efeitos dos fármacos , Citalopram/farmacologia , Imipramina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico/genética , Animais , Antidepressivos/farmacologia , Citalopram/química , Desenvolvimento de Medicamentos , Engenharia Genética , Imipramina/química , Ligantes , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Conformação Proteica , Ratos , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
20.
Psychopharmacology (Berl) ; 237(6): 1745-1756, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32123974

RESUMO

RATIONALE: Problematic patterns of gambling are characterised by loss of control and persistent gambling often to recover losses. However, little is known about the mechanisms that mediate initial choices to begin gambling and then continue to gamble in the face of losing outcomes. OBJECTIVES: These experiments first assessed gambling and loss-chasing performance under different win/lose probabilities in C57Bl/6 mice, and then investigated the effects of antagonism of 5-HT2CR with SB242084, 5-HT1AR agonism with 8-OH-DPAT and modafinil, a putative cognitive enhancer. RESULTS: As seen in humans and other species, mice demonstrated the expected patterns of behaviour as the odds for winning were altered increasing gambling and loss-chasing when winning was more likely. SB242084 decreased the likelihood to initially gamble, but had no effects on subsequent gambling choices in the face of repeated losses. In contrast, 8-OH-DPAT had no effects on choosing to gamble in the first place, but once started 8-OH-DPAT increased gambling choices in a dose-sensitive manner. Modafinil effects were different to the serotonergic drugs in both decreasing the propensity to initiate gambling and chase losses. CONCLUSIONS: We present evidence for dissociable effects of systemic drug administration on different aspects of gambling behaviour. These data extend and reinforce the importance of serotonergic mechanisms in mediating discrete components of gambling behaviour. They further demonstrate the ability of modafinil to reduce gambling behaviour. Our work using a novel mouse paradigm may be of utility in modelling the complex psychological and neurobiological underpinnings of gambling problems, including the analysis of genetic and environmental factors.


Assuntos
Jogo de Azar/prevenção & controle , Jogo de Azar/psicologia , Modafinila/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Reforço Psicológico , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Cognição/efeitos dos fármacos , Cognição/fisiologia , Humanos , Masculino , Camundongos , Modafinila/uso terapêutico , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico
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