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BACKGROUND: Exploring clinical trial data using alternative methods may enhance original study's findings and provide new insights. The SOAP II trial has been published more than 10 years ago; but there is still some speculation that some patients may benefit from dopamine administration for shock management. We aimed to reanalyse the trial under different approaches and evaluate for heterogeneity in treatment effect (HTE). METHODS: All patients enrolled in SOAP II were eligible for reanalysis. We used a variety of methods including the win-ratio (WR), a Bayesian reanalysis stratified according to shock type, and both a risk-based and effect-based explorations for HTE. The methods were applied to different endpoints, including a hierarchy of death, new use of renal-replacement therapy (RRT), and new-onset arrhythmia; 28-day mortality; a composite endpoint (mortality, new use of RRT, and new-onset arrhythmia), and days alive and free of ICU at 28-days (DAFICU28). RESULTS: A total of 1679 patients were included (average age was 64.9 years, 57% male, 62% with septic and 17% with cardiogenic shock). All analysis favoured norepinephrine over dopamine. Under the WR approach, dopamine had fewer wins compared to norepinephrine (WR 0.79; 95% confidence intervals [CI] 0.68-0.92; p = 0.003), evident in both cardiogenic and septic shock subgroups. The Bayesian reanalysis for type of shock showed, for dopamine, a probability of harm of 0.95 for mortality, > 0.99 probability of harm for composite endpoint, and 0.91 probability of harm for DAFICU28. The fewer DAFICU28 with dopamine was more apparent in those with cardiogenic shock (0.92). Under the risk-based HTE, there was a high probability that dopamine resulted fewer DAFICU28 in the highest quartile of predicted mortality risk. The effect-based HTE assessment model did not recommended dopamine over norepinephrine for any combination of possible modifiers including age, type of shock, presence of cardiomyopathy, and SOFA score. Receiving dopamine when the effect-based model recommended norepinephrine was associated with an absolute increase in composite endpoint of 6%. CONCLUSION: The harm associated with the use of dopamine for the management of shock appears to be present in both septic and cardiogenic shock patients. There was no suggestion of any subgroup in which dopamine was found to be favourable over norepinephrine.
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Teorema de Bayes , Dopamina , Norepinefrina , Humanos , Dopamina/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Norepinefrina/uso terapéutico , Anciano , Choque/tratamiento farmacológicoRESUMEN
Macrophages play a multifaceted role in maintaining tissue homeostasis, fighting infections, and regulating cold-induced thermogenesis. The brown adipose tissue (BAT) is crucial for maintaining body temperature during cold exposure. Cold stress triggers the sympathetic nervous system to release norepinephrine (NE), which activates BAT via ß3-adrenergic receptors, initiating lipolysis and glycolysis. BAT-infiltrating macrophages can either hinder or enhance thermogenesis by controlling the interplay between BAT cells and sympathetic nerves. In this study we report on a unique population of CD3+F4/80+ dual lineage co-expressing (DE) cells within the interscapular BAT (iBAT), that increased following chronic adrenergic stimulation. In forward scatter/side scatter plots, they formed a cluster distinct from lymphocytes, appearing larger and more complex. These CD3+F4/80+ DE cells demonstrated the lack of T cell markers CD62L and TCRß and expressed higher levels of Ly6C, F4/80, and CD11b markers compared to T cells and CD3- macrophages. Furthermore, analysis revealed two subpopulations within the CD3+F4/80+ DE population based on MHCII expression, with the proportion of MHCII-low subset increasing with adrenergic stimulation. This novel DE population within iBAT, unequivocally identified by the its unique surface marker profile, warrants further investigation into the intricate mechanisms governing adaptive thermogenesis regulation.
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Tejido Adiposo Pardo , Complejo CD3 , Macrófagos , Termogénesis , Animales , Tejido Adiposo Pardo/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Complejo CD3/metabolismo , Norepinefrina/farmacología , Norepinefrina/metabolismo , Masculino , Ratones Endogámicos C57BL , Receptores Adrenérgicos beta 3/metabolismoRESUMEN
INTRODUCTION: Mental fatigue (MF) significantly affects both cognitive and physical performance. However, the precise mechanisms, particularly concerning neurotransmission, require further investigation. An implication of the role of dopamine (DA) and noradrenaline (NA) is stated, but empirical evidence for this theory still needs to be provided. To address this gap, we aim to investigate the role of brain neurotransmission in elucidating if, and how prolonged cognitive activity induces MF and its subsequent impact on cognitive performance. METHODS: This study (registration number: G095422N) will adopt a randomized cross-over design with sixteen healthy participants aged 18-35 years. The sessions include a familiarization, two experimental (DA: 20mg Methylphenidate; NA: 8mg Reboxetine) conditions, and one placebo (lactose tablet: 10mg) condition. A 60-minute individualized Stroop task will be used to investigate whether, and how the onset of MF changes under the influence of reuptake inhibitors. Attention and response inhibition will be assessed before and after the MF-inducing task using a Go/NoGo task. The integration of physiological (electroencephalography, heart rate), behavioral (attention, response inhibition), and subjective indicators (scales and questionnaires) will be used to detect the underlying mechanisms holistically. Data analysis will involve linear mixed models with significance at p<0.05. DISCUSSION: The integration of diverse techniques and analyses offers a comprehensive perspective on the onset and impact of MF, introducing a novel approach. Future research plans involve extending this protocol to explore the connection between brain neurotransmission and physical fatigue. This protocol will further advance our understanding of the complex interplay between the brain and fatigue.
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Encéfalo , Estudios Cruzados , Fatiga Mental , Metilfenidato , Transmisión Sináptica , Humanos , Fatiga Mental/fisiopatología , Adulto , Adolescente , Adulto Joven , Encéfalo/fisiología , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Metilfenidato/farmacología , Masculino , Femenino , Reboxetina , Cognición/fisiología , Norepinefrina/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Atención/fisiología , Atención/efectos de los fármacos , Electroencefalografía , Dopamina/metabolismoRESUMEN
Caffeine, a methylxanthine alkaloid, works as a nonselective adenosine receptor antagonist. It is the most widely used psychostimulant drug worldwide. However, caffeine overdose can lead to acute intoxication, posing a clinical problem. Hyperthermia and hyperactivity are associated issues with acute caffeine intoxication; however, no definitive treatment exists. This study aimed to assess the ability of risperidone to attenuate caffeine-induced hyperthermia and hyperactivity while elucidating the unknown mechanisms of caffeine intoxication. The rats received intraperitoneal injections of saline, risperidone (0.25 mg/kg, 0.5 mg/kg), WAY-100635, ketanserin, haloperidol, sulpiride, or SCH 23390, 5 min after the administration of caffeine (25 mg/kg). Subcutaneous temperature and activity counts were measured using nano tag ® for up to 90 min. In vivo microdialysis was used to determine the effect of risperidone on caffeine-induced elevation of dopamine (DA), serotonin (5-HT), and noradrenaline (NA) concentrations in the anterior hypothalamus. Rats were injected with caffeine (25 mg/kg), followed by saline or risperidone (0.5 mg/kg) 5 min later. The levels of DA, 5-HT, and noradrenaline were measured every 15 min for up to 90 min after caffeine administration. Risperidone and 5-HT2A receptor antagonist ketanserin attenuated caffeine-induced hyperthermia and hyperactivity. Haloperidol and dopamine D1 antagonist SCH-23390 exacerbated hyperthermia without any effect on the hyperactivity. In the microdialysis study, risperidone treatment further attenuated caffeine-induced 5-HT elevation, but not DA and NA. Our results indicate that risperidone attenuates caffeine-induced hyperthermia and hyperactivity by blocking 5-HT2A receptor activity and may be potentially useful for treating caffeine intoxication.
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Cafeína , Hipertermia , Risperidona , Serotonina , Animales , Cafeína/farmacología , Risperidona/farmacología , Masculino , Hipertermia/inducido químicamente , Serotonina/metabolismo , Ratas Sprague-Dawley , Dopamina/metabolismo , Ratas , Hipercinesia/inducido químicamente , Hipercinesia/prevención & control , Estimulantes del Sistema Nervioso Central/farmacología , Estimulantes del Sistema Nervioso Central/toxicidad , Norepinefrina/metabolismoRESUMEN
BACKGROUND: Invasive cardiopulmonary exercise testing (iCPET) combines traditional cardiopulmonary exercise testing with invasive hemodynamic measurements to assess exercise intolerance, which can be caused by preload insufficiency (PI), characterized by low ventricular filling pressures and reduced cardiac output during exertion. We hypothesize that plasma catecholamine levels at rest and during exercise correlate with hemodynamic parameters in PI. METHODS: We included adult patients who underwent iCPET for exercise intolerance and had plasma catecholamines measured at rest and peak exercise. RESULTS: Among 84 patients, PI was identified in 57 (67.8 %). Compared to patients without PI, those with PI were younger [median (IQR) 37 (28, 46) vs 47 (39,55) years, p = 0.005] and had lower workload at peak exercise [81 (66, 96) vs 95 (83.5, 110.50) Watts, p = 0.006]. Patients with PI had higher heart rates at rest and peak exercise [87 (78, 97) vs 79 (74, 87) bpm, p = 0.04; and 167 (154, 183) vs 156 (136, 168) bpm, p = 0.01, respectively]. In all patients, epinephrine and norepinephrine at peak exercise directly correlated with peak workload (r:0.41, p < 0.001 and r:0.47, p < 0.001, respectively). Resting epinephrine was higher in patients with PI [136 (60, 210) vs 77 (41, 110) pg/mL, p = 0.02]. There was no significant difference in the change in catecholamines from rest to peak exercise between patients with or without PI. CONCLUSION: PI patients exhibited elevated heart rate and epinephrine at rest, indicating increased sympathetic activity. We did not find strong associations between catecholamines and cardiac filling pressures, suggesting that catecholamine levels are predominantly influenced by peak workload.
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Catecolaminas , Prueba de Esfuerzo , Tolerancia al Ejercicio , Humanos , Prueba de Esfuerzo/métodos , Persona de Mediana Edad , Masculino , Tolerancia al Ejercicio/fisiología , Femenino , Catecolaminas/sangre , Adulto , Norepinefrina/sangre , Hemodinámica/fisiología , Frecuencia Cardíaca/fisiología , Epinefrina/sangre , Ejercicio Físico/fisiología , Gasto Cardíaco/fisiologíaRESUMEN
Astrocytes play an active role in the function of the brain integrating neuronal activity and regulating back neuronal dynamic. They have recently emerged as active contributors of brain's emergent properties such as perceptions. Here, we analyzed the role of astrocytes in pain perception from the lens of systems neuroscience, and we do this by analyzing how astrocytes encode nociceptive information within brain processing areas and how they are key regulators of the internal state that determines pain perception. Specifically, we discuss the dynamic interactions between astrocytes and neuromodulators, such as noradrenaline, highlighting their role in shaping the level of activation of the neuronal ensemble, thereby influencing the experience of pain. Also, we will discuss the possible implications of an "Astro-NeuroMatrix" in the integration of pain across sensory, affective, and cognitive dimensions of pain perception.
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Astrocitos , Percepción del Dolor , Humanos , Percepción del Dolor/fisiología , Encéfalo , Animales , Neurociencias , Norepinefrina/metabolismo , Dolor/fisiopatología , Neuronas/fisiologíaRESUMEN
The activation of stressors can disrupt the body's homeostasis, leading to the release of stress hormones such as epinephrine, noradrenaline, and glucocorticoids. Moreover, emerging evidence highlights the profound impact of stress on microglia, which are specialized macrophages residing in the brain's parenchyma. Following stress, microglia exhibit notable morphological activation and increased phagocytic activity. Microglia express various receptors that enable them to respond to stress hormones originating from both central and peripheral sources, thereby exerting pro-inflammatory or anti-inflammatory effects. In this article, we review the advancements in studying the structural and functional changes of microglia induced by exposure to stressors. Additionally, we explore the role of stress hormones in mediating the effects of these stressors on microglia.
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Microglía , Microglía/fisiología , Microglía/metabolismo , Humanos , Animales , Estrés Fisiológico/fisiología , Estrés Psicológico/fisiopatología , Epinefrina/metabolismo , Epinefrina/fisiología , Norepinefrina/metabolismo , Norepinefrina/fisiología , Glucocorticoides/metabolismo , Encéfalo/fisiología , Encéfalo/metabolismo , Fagocitosis/fisiologíaRESUMEN
Hypoglycemia is common in people with type 1 diabetes. Sometimes, severe hypoglycemia can be fatal. The underlying mechanisms by which severe hypoglycemia can lead to death are unclear. The sympathetic nervous system is thought to be proarrhythmic. We hypothesized that norepinephrine is the main mediator of severe hypoglycemia-induced fatal cardiac arrhythmias. To test this hypothesis, adult, non-diabetic Sprague-Dawley rats were subjected to hyperinsulinemic-severe hypoglycemic clamps (3 h, 10-15 mg/dL) during two different experiments: (1) intracerebroventricular (ICV) norepinephrine (n = 26) or artificial cerebrospinal fluid (aCSF) (n = 20) infusion or (2) blockade of norepinephrine release by intraperitoneal reserpine (n = 20) or control (n = 29). In experiment 1, brain norepinephrine infusion during severe hypoglycemia led to a 2.5-fold increase in third-degree heart block and a 24% incidence of ST elevation compared to no ST elevation in aCSF controls. In experiment 2, reserpine successfully reduced plasma and cardiac norepinephrine levels. During severe hypoglycemia, reserpine completely prevented second and third-degree heart block and T wave increases, a marker of myocardial infarction, compared to controls. In conclusion, norepinephrine increases while reserpine, used to reduce norepinephrine nerve terminal release, reduces heart block and markers of myocardial infarction during severe hypoglycemia.
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Bloqueo Cardíaco , Hipoglucemia , Norepinefrina , Ratas Sprague-Dawley , Animales , Norepinefrina/metabolismo , Norepinefrina/líquido cefalorraquídeo , Masculino , Hipoglucemia/metabolismo , Ratas , Bloqueo Cardíaco/fisiopatología , Reserpina/farmacologíaRESUMEN
Copper is a trace element whose electronic configuration provides it with essential structural and catalytic functions. However, in excess, both its high protein affinity and redox-catalyzing properties can lead to hazardous consequences. In addition to promoting oxidative stress, copper is gaining interest for its effects on neurotransmission through modulation of GABAergic and glutamatergic receptors and interaction with the dopamine reuptake transporter. The aim of the present study was to investigate the effects of copper overexposure on the levels of dopamine, noradrenaline, and serotonin, or their main metabolites in rat's striatum extracellular fluid. Copper was injected intraperitoneally using our previously developed model, which ensured striatal overconcentration (2 mg CuCl2/kg for 30 days). Subsequently, extracellular fluid was collected by microdialysis on days 0, 15, and 30. Dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and noradrenaline (NA) levels were then determined by HPLC coupled with electrochemical detection. We observed a significant increase in the basal levels of DA and HVA after 15 days of treatment (310% and 351%), which was maintained after 30 days (358% and 402%), with no significant changes in the concentrations of 5-HIAA, DOPAC, and NA. Copper overload led to a marked increase in synaptic DA concentration, which could contribute to the psychoneurological alterations and the increased oxidative toxicity observed in Wilson's disease and other copper dysregulation states.
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Cobre , Cuerpo Estriado , Dopamina , Líquido Extracelular , Ácido Homovanílico , Animales , Dopamina/metabolismo , Cobre/metabolismo , Ácido Homovanílico/metabolismo , Ratas , Masculino , Líquido Extracelular/metabolismo , Cuerpo Estriado/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Ratas Wistar , Serotonina/metabolismo , Norepinefrina/metabolismoRESUMEN
OBJECTIVE: Mean arterial pressure (MAP) plays a significant role in regulating tissue perfusion and urine output (UO). The optimal MAP target in critically ill patients remains a subject of debate. We aimed to explore the relationship between MAP and UO. DESIGN: A retrospective observational study. SETTING: A general ICU in a tertiary medical center. PATIENTS: All critically ill patients admitted to the ICU for more than 10 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: MAP values and hourly UO were collected in 5,207 patients. MAP levels were categorized into 10 groups of 5 mm Hg (from MAP < 60 mm Hg to MAP > 100 mg Hg), and 656,423 coupled hourly mean MAP and UO measurements were analyzed. Additionally, we compared the UO of individual patients in each MAP group with or without norepinephrine (NE) support or diuretics, as well as in patients with acute kidney injury (AKI).Hourly UO rose incrementally between MAP values of 65-100 mm Hg. Among 2,226 patients treated with NE infusion, mean UO was significantly lower in the MAP less than 60 mm Hg group (53.4 mL/hr; 95% CI, 49.3-57.5) compared with all other groups (p < 0.001), but no differences were found between groups of 75 less than or equal to MAP. Among 2500 patients with AKI, there was a linear increase in average UO from the MAP less than 60 mm Hg group (57.1 mL/hr; 95% CI, 54.2-60.0) to the group with MAP greater than or equal to 100 mm Hg (89.4 mL/hr; 95% CI, 85.7-93.1). When MAP was greater than or equal to 65 mm Hg, we observed a statistically significant trend of increased UO in periods without NE infusion. CONCLUSIONS: Our analysis revealed a linear correlation between MAP and UO within the range of 65-100 mm Hg, also observed in the subgroup of patients treated with NE or diuretics and in those with AKI. These findings highlight the importance of tissue perfusion to the maintenance of diuresis and achieving adequate fluid balance in critically ill patients.
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Presión Arterial , Enfermedad Crítica , Unidades de Cuidados Intensivos , Humanos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Presión Arterial/efectos de los fármacos , Presión Arterial/fisiología , Anciano , Lesión Renal Aguda/fisiopatología , Lesión Renal Aguda/orina , Lesión Renal Aguda/diagnóstico , Norepinefrina/orina , Micción/efectos de los fármacos , Micción/fisiologíaRESUMEN
Prader-Willi syndrome (PWS) is a multisystemic disorder. Notably, many characteristic symptoms of PWS are correlated with locus coeruleus norepinephrine system (LC-NE) dysfunction, including impairment in arousal, learning, pain modulation, and stress-induced negative affective states. Although electrophysiological experiments in necdin-deficient mice, an established PWS animal model, have revealed decreased spontaneous neuronal firing activity in the LC and impaired excitability, the behavioral phenotypes related to LC-NE dysfunction remain unexplored. In this study, heterozygous necdin-deficient mice (B6.Cg-Ndntm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygous (+m/-p) animals. Compared to WT mice, Ndn + m/-p mice demonstrated impaired visual-spatial memory in the Y-maze test, reduced social interaction, impaired sexual recognition, and shorter falling latency on the Rotarod. Using the open field test (OFT) and elevated plus maze (EPM), we observed similar locomotion activity of Ndn + m/-p and WT mice, but Ndn + m/-p mice were less anxious. After acute restraint, Ndn + m/-p mice exhibited significant impairment in stress-induced anxiety. Additionally, the plasma norepinephrine surge following exposure to acute restraint stress was also impaired. Pretreatment with atomoxetine, a norepinephrine reuptake inhibitor aimed to enhance LC function, restored Ndn + m/-p mice to exhibit a normal response to acute restraint stress. Furthermore, by employing chemogenetic approaches to facilitate LC neuronal firing, post-stress anxious responses were also partially rescued in Ndn + m/-p mice. These data strongly suggest that LC dysfunction is implicated in the pathogenesis of stress-related neuropsychiatric symptoms in PWS. Manipulation of LC activity may hold therapeutic potential for patients with PWS.
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Modelos Animales de Enfermedad , Locus Coeruleus , Síndrome de Prader-Willi , Animales , Locus Coeruleus/fisiopatología , Ratones , Síndrome de Prader-Willi/fisiopatología , Femenino , Masculino , Proteínas del Tejido Nervioso/genética , Norepinefrina/metabolismo , Ansiedad/fisiopatología , Ansiedad/etiología , Ratones Endogámicos C57BL , Aprendizaje por Laberinto/fisiología , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicología , Interacción Social , Proteínas NuclearesRESUMEN
Although the locus ceruleus (LC) is recognized as a crucial modulator for attention and perception by releasing norepinephrine into various cortical regions, the impact of LC-noradrenergic (LC-NE) modulation on auditory discrimination behavior remains elusive. In this study, we firstly recorded local field potential and single-unit activity in multiple cortical regions associated with auditory-motor processing, including the auditory cortex, posterior parietal cortex, secondary motor cortex, anterior cingulate cortex, prefrontal cortex, and orbitofrontal cortex (OFC), in response to optogenetic activation (40â Hz and 0.5â s) of the LC-NE neurons in awake mice (male). We found that phasic LC stimulation induced a persistent high gamma oscillation (50-80â Hz) in the OFC. Phasic activation of LC-NE neurons also resulted in a corresponding increase in norepinephrine levels in the OFC, accompanied by a pupillary dilation response. Furthermore, when mice were performing a go/no-go auditory discrimination task, we optogeneticaly activated the neural projections from LC to OFC and revealed a shortened latency in behavioral responses to sound stimuli and an increased false alarm rate. These impulsive behavioral responses may be associated with the gamma neural activity in the OFC. These findings have broadened our understanding of the neural mechanisms involved in the role of LC in auditory-motor processing.
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Percepción Auditiva , Discriminación en Psicología , Locus Coeruleus , Optogenética , Animales , Locus Coeruleus/fisiología , Ratones , Masculino , Percepción Auditiva/fisiología , Discriminación en Psicología/fisiología , Ratones Endogámicos C57BL , Norepinefrina/metabolismo , Estimulación Acústica/métodos , Ritmo Gamma/fisiología , Neuronas/fisiología , Corteza Cerebral/fisiologíaRESUMEN
The norepinephrine transporter (NET) plays a pivotal role in recycling norepinephrine (NE) from the synaptic cleft. However, the structures referring to the conformational heterogeneity of NET during the transport cycle remain poorly understood. Here, three structural models of NE bound to the orthosteric site of NET in outward-open (OOholo), outward-occluded (OCholo), and inward-open (IOholo) conformations were first obtained using the multistate structures of serotonin transporter as templates and further characterized through Gaussian-accelerated molecular dynamics and free energy reweighting. Analysis of the structures revealed eight potential allosteric sites on the functional-specific states of NET. One of the pharmacologically relevant pockets located at the extracellular vestibule was further verified by simulating the binding behaviors of a clinical trial drug χ-MrIA that is allosterically regulating NET. These structural and energetic insights into NET advanced our understanding of NE reuptake and paved the way for discovering novel molecules targeting the allosteric sites.
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Sitio Alostérico , Simulación de Dinámica Molecular , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/química , Humanos , Ligandos , Norepinefrina/metabolismo , Norepinefrina/química , Unión Proteica , Conformación Proteica , TermodinámicaRESUMEN
Norepinephrine transporter (NET; encoded by SLC6A2) reuptakes the majority of the released noradrenaline back to the presynaptic terminals, thereby affecting the synaptic noradrenaline level1. Genetic mutations and dysregulation of NET are associated with a spectrum of neurological conditions in humans, making NET an important therapeutic target1. However, the structure and mechanism of NET remain unclear. Here we provide cryogenic electron microscopy structures of the human NET (hNET) in three functional states-the apo state, and in states bound to the substrate meta-iodobenzylguanidine (MIBG) or the orthosteric inhibitor radafaxine. These structures were captured in an inward-facing conformation, with a tightly sealed extracellular gate and an open intracellular gate. The substrate MIBG binds at the centre of hNET. Radafaxine also occupies the substrate-binding site and might block the structural transition of hNET for inhibition. These structures provide insights into the mechanism of substrate recognition and orthosteric inhibition of hNET.
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Microscopía por Crioelectrón , Modelos Moleculares , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/química , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Humanos , Sitios de Unión , Especificidad por Sustrato , Unión Proteica , Norepinefrina/metabolismoRESUMEN
Depression and anxiety are prominent symptoms of withdrawal syndrome, often caused by the abuse of addictive drugs like morphine. N-palmitoylethanolamide (PEA), a biologically active lipid, is utilized as an anti-inflammatory and analgesic medication. Recent studies have highlighted PEA's role in mitigating cognitive decline and easing depression resulting from chronic pain. However, it remains unknown whether PEA can influence negative emotions triggered by morphine withdrawal. This study seeks to explore the impact of PEA on such emotions and investigate the underlying mechanisms. Mice subjected to morphine treatment underwent a 10-day withdrawal period, followed by assessments of the effect of PEA on anxiety- and depression-like behaviors using various tests. Enzyme-linked immunosorbent assay was conducted to measure levels of monoamine neurotransmitters in specific brain regions. The findings indicate that PEA mitigated anxiety and depression symptoms and reduced 5-hydroxytryptamine, noradrenaline, and dopamine levels in the hippocampus and prefrontal cortex. In summary, PEA demonstrates a significant positive effect on negative emotions associated with morphine withdrawal, accompanied with the reduction in levels of monoamine neurotransmitters in key brain regions. These insights could be valuable for managing negative emotions arising from morphine withdrawal.
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Amidas , Ansiedad , Depresión , Etanolaminas , Morfina , Ácidos Palmíticos , Síndrome de Abstinencia a Sustancias , Animales , Síndrome de Abstinencia a Sustancias/psicología , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Etanolaminas/farmacología , Ácidos Palmíticos/farmacología , Ratones , Masculino , Morfina/farmacología , Depresión/metabolismo , Depresión/tratamiento farmacológico , Depresión/psicología , Depresión/etiología , Amidas/farmacología , Ansiedad/tratamiento farmacológico , Ansiedad/psicología , Ansiedad/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Emociones/efectos de los fármacos , Serotonina/metabolismo , Dependencia de Morfina/metabolismo , Dependencia de Morfina/psicología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Norepinefrina/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacosRESUMEN
Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase TIBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9 ± 2.0, 77.4 ± 12.7 and 93.6 ± 4.6% (P<0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on TIBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated TIBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7 ± 2.23% and 6.6 ± 1.4% in sham and denervated mice (P<0.05), respectively, and this effect was similar between groups (P=NS). OT produced corresponding reductions in whole body fat mass (P<0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.
Asunto(s)
Tejido Adiposo Pardo , Adiposidad , Dieta Alta en Grasa , Ratones Endogámicos C57BL , Obesidad , Oxitocina , Sistema Nervioso Simpático , Animales , Oxitocina/farmacología , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/inervación , Masculino , Ratones , Obesidad/metabolismo , Sistema Nervioso Simpático/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Adiposidad/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Pérdida de Peso/efectos de los fármacos , Ratones Obesos , Metabolismo Energético/efectos de los fármacos , Norepinefrina/metabolismoRESUMEN
Detecting dopamine (DA) is critical for early diagnosis of neurological and psychiatric disorders. However, the presence of other catecholamine neurotransmitters with structural similarities to DA causes significant interference in its detection. Herein, we introduce S stripping defects via laser-induced MoS2 to functionalize MoS2 electrodes and improve their selectivity for DA electrochemical detection. The sensing results show its excellent immunity to interference from other neurotransmitters, ensuring the preservation of the DA electrochemical signal even in the mixed neurotransmitters such as acetylcholine (ACh), γ-aminobutyric acid (GABA), epinephrine (EP), norepinephrine (NP), and serotonin (5-HT). DFT calculations further reveal that the negatively charged S-stripping defects enhance DA adsorption on the surface of the functionalized MoS2 electrode, contributing to its excellent performance. Moreover, this functionalized electrodes successfully monitor DA released from living PC12 cells in the presence of other interference, highlighting its potential applicability in intercellular signaling communication.
Asunto(s)
Dopamina , Técnicas Electroquímicas , Electrodos , Rayos Láser , Neurotransmisores , Dopamina/análisis , Células PC12 , Técnicas Electroquímicas/métodos , Animales , Neurotransmisores/análisis , Ratas , Disulfuros/química , Catecolaminas/análisis , Epinefrina/análisis , Norepinefrina/análisis , Teoría Funcional de la Densidad , MolibdenoRESUMEN
Research on sex differences has increased across various fields, including cancer and its treatment domains. Reports have indicated sex differences in cancer incidence, survival rates, and the efficacy of anticancer drugs. However, such reports are limited, and in-depth assessments of the underlying mechanisms are still in progress. Although various chemotherapeutic regimens are applicable for breast cancer treatment, reports have surfaced regarding weight gain in female patients undergoing fluorouracil, epirubicin, cyclophosphamide (FEC) or cyclophosphamide, methotrexate, fluorouracil (CMF) therapy. We hypothesized the potential of 5-fluorouracil (5-FU) in weight gain and sex-related differences. To address this, we conducted experiments in mice to confirm weight gain and sex differences following 5-FU administration, and elucidate the underlying mechanisms. Our findings revealed weight gain and increased food intake in female mice following 5-FU administration. Additionally, female mice receiving 5-FU exhibited increased norepinephrine and α1- and α2-adrenergic receptor expression, reduced estradiol levels, and increased ghrelin levels. These results indicate 5-FU administration-induced sex differences in weight gain and implicate increased food intake because of increased norepinephrine and α1- and α2-adrenergic receptor expression, reduced estradiol levels, and a subsequent increase in ghrelin levels, which contribute to weight gain in female patients undergoing CMF therapy.
Asunto(s)
Fluorouracilo , Ghrelina , Caracteres Sexuales , Aumento de Peso , Animales , Femenino , Aumento de Peso/efectos de los fármacos , Masculino , Antimetabolitos Antineoplásicos , Ingestión de Alimentos/efectos de los fármacos , Ratones , Estradiol/sangre , Norepinefrina/metabolismo , Ratones Endogámicos C57BLRESUMEN
Adaptive behavior relies on efficient cognitive control. The anterior cingulate cortex (ACC) is a key node within the executive prefrontal network. The reciprocal connectivity between the locus ceruleus (LC) and ACC is thought to support behavioral reorganization triggered by the detection of an unexpected change. We transduced LC neurons with either excitatory or inhibitory chemogenetic receptors in adult male rats and trained rats on a spatial task. Subsequently, we altered LC activity and confronted rats with an unexpected change of reward locations. In a new spatial context, rats with decreased noradrenaline (NA) in the ACC entered unbaited maze arms more persistently which was indicative of perseveration. In contrast, the suppression of the global NA transmission reduced perseveration. Neither chemogenetic manipulation nor inactivation of the ACC by muscimol affected the rate of learning, possibly due to partial virus transduction of the LC neurons and/or the compensatory engagement of other prefrontal regions. Importantly, we observed behavioral deficits in rats with LC damage caused by virus injection. The latter finding highlights the importance of careful histological assessment of virus-transduced brain tissue as inadvertent damage of the targeted cell population due to virus neurotoxicity or other factors might cause unwanted side effects. Although the specific role of ACC in the flexibility of spatial behavior has not been convincingly demonstrated, our results support the beneficial role of noradrenergic transmission for an optimal function of the ACC. Overall, our findings suggest the LC exerts the projection-specific modulation of neural circuits mediating the flexibility of spatial behavior.