RESUMO
Neuromodulators act on multiple timescales to affect neuronal activity and behavior. They function as synaptic fine-tuners and master coordinators of neuronal activity across distant brain regions and body organs. While much research on neuromodulation has focused on roles in promoting features of wakefulness and transitions between sleep and wake states, the precise dynamics and functions of neuromodulatory signaling during sleep have received less attention. This review discusses research presented at our minisymposium at the 2024 Society for Neuroscience meeting, highlighting how norepinephrine, dopamine, and acetylcholine orchestrate brain oscillatory activity, control sleep architecture and microarchitecture, regulate responsiveness to sensory stimuli, and facilitate memory consolidation. The potential of each neuromodulator to influence neuronal activity is shaped by the state of the synaptic milieu, which in turn is influenced by the organismal or systemic state. Investigating the effects of neuromodulator release across different sleep substates and synaptic environments offers unique opportunities to deepen our understanding of neuromodulation and explore the distinct computational opportunities that arise during sleep. Moreover, since alterations in neuromodulatory signaling and sleep are implicated in various neuropsychiatric disorders and because existing pharmacological treatments affect neuromodulatory signaling, gaining a deeper understanding of the less-studied aspects of neuromodulators during sleep is of high importance.
Assuntos
Neurotransmissores , Sono , Humanos , Animais , Sono/fisiologia , Neurotransmissores/fisiologia , Encéfalo/fisiologia , Norepinefrina/fisiologia , Norepinefrina/metabolismo , Acetilcolina/metabolismo , Acetilcolina/fisiologia , Dopamina/metabolismo , Dopamina/fisiologia , Vigília/fisiologiaRESUMO
The objective of this investigation was to assess the impact of elevated catecholamine concentrations, induced through cold-water hand immersion, on the oxygen consumption (VÌO2) kinetics during intense exercise, and to contrast this effect with that of the priming effect. Ten active participants underwent three 8-minute constant work rate exercises (CWR) at ∆25%, with one CWR preceded by hand cooling (2 min at 0 °C, HC) and two consecutive CWR to induced priming effect on the second bout (SB). Pulmonary gas exchange and blood samples were analyzed to measure levels of epinephrine (E) and norepinephrine (NE). Results demonstrated a significant increase in the primary phase amplitude of VÌO2 kinetics in response to both hand HC (33.9 mL.min-1.kg-1; CI [32.2;35.7], p < 0.001) and SB (34.6 mL.min-1.kg-1; CI [33.0;36.3], p < 0.001) relative to the control (32.7 mL.min-1.kg-1; CI [31.5;35.1]). Additionally, the amplitude of the VÌO2 slow component was reduced for both HC (3.2 mL.min-1.kg-1; CI [2.2;4.1], p = 0.018) and SB (2.9 mL.min-1.kg-1; CI [1.8;4.2], p = 0.009) in comparison to control (3.9 mL.min-1.kg-1; CI [2.9;4.2]). These findings suggest that the increase in E and NE induced by hand cooling prior to exercise modifies VÌO2 kinetics in a manner akin to the priming effect. This research underscores the potential role of catecholamines in facilitating the priming effect and its subsequent impact on VÌO2 kinetics. However, further studies are necessary to clearly establish this link.
Assuntos
Epinefrina , Exercício Físico , Mãos , Norepinefrina , Consumo de Oxigênio , Humanos , Masculino , Adulto , Cinética , Norepinefrina/sangue , Norepinefrina/metabolismo , Epinefrina/sangue , Epinefrina/metabolismo , Mãos/fisiologia , Adulto Jovem , Exercício Físico/fisiologia , Temperatura Baixa , Feminino , Oxigênio/metabolismo , Troca Gasosa Pulmonar/fisiologiaRESUMO
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.
Assuntos
Tecido Adiposo Marrom , Complexo CD3 , Macrófagos , Termogênese , Animais , Tecido Adiposo Marrom/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Complexo CD3/metabolismo , Norepinefrina/farmacologia , Norepinefrina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Receptores Adrenérgicos beta 3/metabolismoRESUMO
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.
Assuntos
Encéfalo , Estudos Cross-Over , Fadiga Mental , Metilfenidato , Transmissão Sináptica , Humanos , Fadiga Mental/fisiopatologia , Adulto , Adolescente , Adulto Jovem , Encéfalo/fisiologia , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Metilfenidato/farmacologia , Masculino , Feminino , Reboxetina , Cognição/fisiologia , Norepinefrina/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Atenção/fisiologia , Atenção/efeitos dos fármacos , Eletroencefalografia , Dopamina/metabolismoRESUMO
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.
Assuntos
Cafeína , Hipertermia , Risperidona , Serotonina , Animais , Cafeína/farmacologia , Risperidona/farmacologia , Masculino , Hipertermia/induzido quimicamente , Serotonina/metabolismo , Ratos Sprague-Dawley , Dopamina/metabolismo , Ratos , Hipercinese/induzido quimicamente , Hipercinese/prevenção & controle , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/toxicidade , Norepinefrina/metabolismoRESUMO
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.
Assuntos
Microscopia Crioeletrônica , Modelos Moleculares , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Humanos , Sítios de Ligação , Especificidade por Substrato , Ligação Proteica , Norepinefrina/metabolismoRESUMO
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.
Assuntos
Tecido Adiposo Marrom , Adiposidade , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Obesidade , Ocitocina , Sistema Nervoso Simpático , Animais , Ocitocina/farmacologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/inervação , Masculino , Camundongos , Obesidade/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Adiposidade/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Redução de Peso/efeitos dos fármacos , Camundongos Obesos , Metabolismo Energético/efeitos dos fármacos , Norepinefrina/metabolismoRESUMO
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.
Assuntos
Bloqueio Cardíaco , Hipoglicemia , Norepinefrina , Ratos Sprague-Dawley , Animais , Norepinefrina/metabolismo , Norepinefrina/líquido cefalorraquidiano , Masculino , Hipoglicemia/metabolismo , Ratos , Bloqueio Cardíaco/fisiopatologia , Reserpina/farmacologiaRESUMO
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.
Assuntos
Fluoruracila , Grelina , Caracteres Sexuais , Aumento de Peso , Animais , Feminino , Aumento de Peso/efeitos dos fármacos , Masculino , Antimetabólitos Antineoplásicos , Ingestão de Alimentos/efeitos dos fármacos , Camundongos , Estradiol/sangue , Norepinefrina/metabolismo , Camundongos Endogâmicos C57BLRESUMO
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.
Assuntos
Percepção Auditiva , Discriminação Psicológica , Locus Cerúleo , Optogenética , Animais , Locus Cerúleo/fisiologia , Camundongos , Masculino , Percepção Auditiva/fisiologia , Discriminação Psicológica/fisiologia , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Estimulação Acústica/métodos , Ritmo Gama/fisiologia , Neurônios/fisiologia , Córtex Cerebral/fisiologiaRESUMO
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.
Assuntos
Modelos Animais de Doenças , Locus Cerúleo , Síndrome de Prader-Willi , Animais , Locus Cerúleo/fisiopatologia , Camundongos , Síndrome de Prader-Willi/fisiopatologia , Feminino , Masculino , Proteínas do Tecido Nervoso/genética , Norepinefrina/metabolismo , Ansiedade/fisiopatologia , Ansiedade/etiologia , Camundongos Endogâmicos C57BL , Aprendizagem em Labirinto/fisiologia , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Interação Social , Proteínas NuclearesRESUMO
Pain perception is the consequence of a complex interplay between activation and inhibition. Noradrenergic pain modulation inhibits nociceptive transmission and pain perception. The main source of norepinephrine (NE) in the central nervous system is the Locus Coeruleus (LC), a small but complex cluster of cells in the pons. The aim of this study is to review the literature on the LC-NE inhibitory system, its influence on chronic pain pathways and its frequent comorbidities. The literature research showed that pain perception is the consequence of nociceptive and environmental processing and is modulated by the LC-NE system. If perpetuated in time, nociceptive inputs can generate neuroplastic changes in the central nervous system that reduce the inhibitory effects of the LC-NE complex and facilitate the development of chronic pain and frequent comorbidities, such as anxiety, depression or sleeping disturbances. The exact mechanisms involved in the LC functional shift remain unknown, but there is some evidence that they occur through plastic changes in the medial and lateral pathways and their brain projections. Additionally, there are other influencing factors, like developmental issues, neuroinflammatory glial changes, NE receptor affinity and changes in LC neuronal firing rates.
Assuntos
Dor Crônica , Locus Cerúleo , Norepinefrina , Locus Cerúleo/metabolismo , Humanos , Dor Crônica/fisiopatologia , Dor Crônica/metabolismo , Animais , Norepinefrina/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Neurônios/fisiologia , Percepção da Dor/fisiologiaRESUMO
BACKGROUND: In humans with pheochromocytomas (PCCs), targeted metabolomics is used to determine the catecholamine phenotype or to uncover underlying pathogenic variants in tricarboxylic acid (TCA) cycle genes such as succinate dehydrogenase subunits (SDHx). HYPOTHESIS/OBJECTIVES: To analyze catecholamine contents and TCA cycle metabolites of PCCs and normal adrenals (NAs). ANIMALS: Ten healthy dogs, 21 dogs with PCC. METHODS: Prospective observational study. Dogs diagnosed with PCC based on histopathological and immunohistochemical confirmation were included. Tissue catecholamine contents and TCA metabolites in PCCs and NAs were measured by liquid chromatography with mass spectrometry or electrochemical detection. RESULTS: Compared to NAs, PCCs had significantly higher tissue proportion of norepinephrine (88% [median: range, 38%-98%] vs 14% [11%-26%]; P < .001), and significantly lower tissue proportion of epinephrine (12% [1%-62%] vs 86% [74%-89%]; P < .001). Pheochromocytomas exhibited significantly lower fumarate (0.4-fold; P < .001), and malate (0.5-fold; P = .008) contents than NAs. Citrate was significantly higher in PCCs than in NAs (1.6-fold; P = .015). One dog in the PCC group had an aberrant succinate : fumarate ratio that was 25-fold higher than in the other PCCs, suggesting an SDHx mutation. CONCLUSIONS AND CLINICAL IMPORTANCE: This study reveals a distinct catecholamine content and TCA cycle metabolite profile in PCCs. Metabolite profiling might be used to uncover underlying pathogenic variants in TCA cycle genes in dogs.
Assuntos
Neoplasias das Glândulas Suprarrenais , Catecolaminas , Ciclo do Ácido Cítrico , Doenças do Cão , Feocromocitoma , Animais , Cães , Feocromocitoma/veterinária , Feocromocitoma/metabolismo , Feocromocitoma/genética , Neoplasias das Glândulas Suprarrenais/veterinária , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/genética , Doenças do Cão/metabolismo , Doenças do Cão/genética , Masculino , Feminino , Catecolaminas/metabolismo , Estudos Prospectivos , Metabolômica , Fenótipo , Malatos/metabolismo , Norepinefrina/metabolismo , Fumaratos/metabolismo , Epinefrina/metabolismoRESUMO
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.
Assuntos
Sítio Alostérico , Simulação de Dinâmica Molecular , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/química , Humanos , Ligantes , Norepinefrina/metabolismo , Norepinefrina/química , Ligação Proteica , Conformação Proteica , TermodinâmicaRESUMO
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.
Assuntos
Amidas , Ansiedade , Depressão , Etanolaminas , Morfina , Ácidos Palmíticos , Síndrome de Abstinência a Substâncias , Animais , Síndrome de Abstinência a Substâncias/psicologia , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Etanolaminas/farmacologia , Ácidos Palmíticos/farmacologia , Camundongos , Masculino , Morfina/farmacologia , Depressão/metabolismo , Depressão/tratamento farmacológico , Depressão/psicologia , Depressão/etiologia , Amidas/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Ansiedade/metabolismo , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Emoções/efeitos dos fármacos , Serotonina/metabolismo , Dependência de Morfina/metabolismo , Dependência de Morfina/psicologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Norepinefrina/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacosRESUMO
Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.
Assuntos
Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Secreção de Insulina , Camundongos Endogâmicos C57BL , Bulbo Olfatório , Núcleo Hipotalâmico Paraventricular , Animais , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Masculino , Bulbo Olfatório/metabolismo , Bulbo Olfatório/efeitos dos fármacos , Secreção de Insulina/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Camundongos , Núcleo Hipotalâmico Paraventricular/metabolismo , Insulina/metabolismo , Obesidade/metabolismo , Sistema Nervoso Simpático/metabolismo , Neurônios/metabolismo , Transdução de Sinais , Norepinefrina/metabolismo , Glucose/metabolismoRESUMO
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.
Assuntos
Cobre , Corpo Estriado , Dopamina , Líquido Extracelular , Ácido Homovanílico , Animais , Dopamina/metabolismo , Cobre/metabolismo , Ácido Homovanílico/metabolismo , Ratos , Masculino , Líquido Extracelular/metabolismo , Corpo Estriado/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Ratos Wistar , Serotonina/metabolismo , Norepinefrina/metabolismoRESUMO
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.
Assuntos
Astrócitos , Percepção da Dor , Humanos , Percepção da Dor/fisiologia , Encéfalo , Animais , Neurociências , Norepinefrina/metabolismo , Dor/fisiopatologia , Neurônios/fisiologiaRESUMO
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.
Assuntos
Microglia , Microglia/fisiologia , Microglia/metabolismo , Humanos , Animais , Estresse Fisiológico/fisiologia , Estresse Psicológico/fisiopatologia , Epinefrina/metabolismo , Epinefrina/fisiologia , Norepinefrina/metabolismo , Norepinefrina/fisiologia , Glucocorticoides/metabolismo , Encéfalo/fisiologia , Encéfalo/metabolismo , Fagocitose/fisiologiaRESUMO
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.