RESUMO
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.
Assuntos
Giro do Cíngulo , Locus Cerúleo , Norepinefrina , Comportamento Espacial , Animais , Masculino , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/fisiologia , Norepinefrina/metabolismo , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/fisiologia , Comportamento Espacial/fisiologia , Comportamento Espacial/efeitos dos fármacos , Ratos , Muscimol/farmacologia , Aprendizagem em Labirinto/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neurônios Adrenérgicos/efeitos dos fármacos , Neurônios Adrenérgicos/fisiologiaRESUMO
The prepositus hypoglossi nucleus (PHN) and the interstitial nucleus of Cajal (INC) are involved in the control of horizontal and vertical gaze, respectively. A previous study showed that PHN neurons exhibit depolarized or hyperpolarized responses to noradrenaline (NA). However, the adrenoceptor types that participate in NA-induced responses and the effects of NA on INC neurons have not yet been investigated. Furthermore, the relationship between NA-induced responses and neuron types defined by neurotransmitter phenotypes has not been determined. In this study, we investigated NA-induced current responses in PHN and INC neurons and the relationships between these responses and neuron types using whole cell recordings in wild-type and transgenic rat brainstem slices. Local application of NA to the cell soma induced slow inward (SI) and slow outward (SO) currents that were mainly mediated by α1 and α2 adrenoceptors, respectively. These current responses were observed in both PHN and INC neurons, although the proportion of INC neurons that responded to NA was low. Analyses of the distributions of the current responses revealed that in the PHN, all fluorescently identified inhibitory neurons exhibited SI currents, whereas glutamatergic and cholinergic neurons exhibited both SI and SO currents. In the INC, glutamatergic and inhibitory neurons preferentially exhibited SI and SO currents, respectively. When the PHN and INC neurons were characterized by their firing pattern, we found that the proportions of the currents depended on their firing pattern. These results suggest that various modes of noradrenergic modulation in horizontal and vertical neural integrators are dependent on neuron type.NEW & NOTEWORTHY Noradrenergic modulation of oculomotor neural integrators involved in gaze control has not been elucidated. Here, we report that noradrenaline (NA)-induced slow inward (SI) and outward (SO) currents are mediated mainly by α1 and α2 adrenoceptors in neurons that participate in horizontal and vertical gaze control. The NA-induced current responses differed depending on the neurotransmitter phenotype and firing pattern. These results suggest various modes of noradrenergic modulation in horizontal and vertical integrator neurons.
Assuntos
Norepinefrina , Animais , Norepinefrina/farmacologia , Ratos , Masculino , Ratos Transgênicos , Neurônios/fisiologia , Neurônios/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 1/fisiologia , Neurônios Adrenérgicos/fisiologia , Neurônios Adrenérgicos/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos alfa 2/fisiologia , Técnicas de Patch-Clamp , Tronco Encefálico/fisiologia , Tronco Encefálico/citologia , Tronco Encefálico/efeitos dos fármacos , Neurônios Colinérgicos/fisiologia , Neurônios Colinérgicos/efeitos dos fármacosRESUMO
Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1 receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose-response manner, the firing activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT1 receptors in the LC-NE neurons. In conclusion, MT1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments.
Assuntos
Locus Cerúleo , Ratos Sprague-Dawley , Receptor MT1 de Melatonina , Sono REM , Animais , Masculino , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Locus Cerúleo/fisiologia , Ratos , Receptor MT1 de Melatonina/agonistas , Receptor MT1 de Melatonina/metabolismo , Sono REM/fisiologia , Sono REM/efeitos dos fármacos , Norepinefrina/metabolismo , Neurônios Adrenérgicos/efeitos dos fármacos , Neurônios Adrenérgicos/metabolismo , Neurônios Adrenérgicos/fisiologia , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/fisiologiaRESUMO
The supraspinal descending pain modulatory system (DPMS) shapes pain perception via monoaminergic modulation of sensory information in the spinal cord. However, the role and synaptic mechanisms of descending noradrenergic signaling remain unclear. Here, we establish that noradrenergic neurons of the locus coeruleus (LC) are essential for supraspinal opioid antinociception. While much previous work has emphasized the role of descending serotonergic pathways, we find that opioid antinociception is primarily driven by excitatory output from the ventrolateral periaqueductal gray (vlPAG) to the LC. Furthermore, we identify a previously unknown opioid-sensitive inhibitory input from the rostroventromedial medulla (RVM), the suppression of which disinhibits LC neurons to drive spinal noradrenergic antinociception. We describe pain-related activity throughout this circuit and report the presence of prominent bifurcating outputs from the vlPAG to the LC and the RVM. Our findings substantially revise current models of the DPMS and establish a supraspinal antinociceptive pathway that may contribute to multiple forms of descending pain modulation.
Assuntos
Analgésicos Opioides , Locus Cerúleo , Bulbo , Dor , Substância Cinzenta Periaquedutal , Locus Cerúleo/metabolismo , Locus Cerúleo/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Animais , Bulbo/metabolismo , Bulbo/efeitos dos fármacos , Dor/tratamento farmacológico , Dor/metabolismo , Analgésicos Opioides/farmacologia , Masculino , Neurônios Adrenérgicos/metabolismo , Neurônios Adrenérgicos/efeitos dos fármacos , Camundongos , Vias Neurais/efeitos dos fármacosRESUMO
Photoaffinity ligands are best known as tools used to identify the specific binding sites of drugs to their molecular targets. However, photoaffinity ligands have the potential to further define critical neuroanatomic targets of drug action. In the brains of WT male mice, we demonstrate the feasibility of using photoaffinity ligands in vivo to prolong anesthesia via targeted yet spatially restricted photoadduction of azi-m-propofol (aziPm), a photoreactive analog of the general anesthetic propofol. Systemic administration of aziPm with bilateral near-ultraviolet photoadduction in the rostral pons, at the border of the parabrachial nucleus and locus coeruleus, produced a 20-fold increase in the duration of sedative and hypnotic effects compared with control mice without UV illumination. Photoadduction that missed the parabrachial-coerulean complex also failed to extend the sedative or hypnotic actions of aziPm and was indistinguishable from nonadducted controls. Paralleling the prolonged behavioral and EEG consequences of on target in vivo photoadduction, we conducted electrophysiologic recordings in rostral pontine brain slices. Using neurons within the locus coeruleus to further highlight the cellular consequences of irreversible aziPm binding, we demonstrate transient slowing of spontaneous action potentials with a brief bath application of aziPm that becomes irreversible on photoadduction. Together, these findings suggest that photochemistry-based strategies are a viable new approach for probing CNS physiology and pathophysiology.SIGNIFICANCE STATEMENT Photoaffinity ligands are drugs capable of light-induced irreversible binding, which have unexploited potential to identify the neuroanatomic sites of drug action. We systemically administer a centrally acting anesthetic photoaffinity ligand in mice, conduct localized photoillumination within the brain to covalently adduct the drug at its in vivo sites of action, and successfully enrich irreversible drug binding within a restricted 250 µm radius. When photoadduction encompassed the pontine parabrachial-coerulean complex, anesthetic sedation and hypnosis was prolonged 20-fold, thus illustrating the power of in vivo photochemistry to help unravel neuronal mechanisms of drug action.
Assuntos
Anestésicos Intravenosos , Encéfalo , Hipnose , Hipnóticos e Sedativos , Ligantes , Marcadores de Fotoafinidade , Propofol , Animais , Masculino , Camundongos , Neurônios Adrenérgicos/efeitos dos fármacos , Anestesia Intravenosa , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Eletrocorticografia , Eletroencefalografia , Hipnose/métodos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/efeitos da radiação , Locus Cerúleo/citologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Locus Cerúleo/efeitos da radiação , Camundongos Endogâmicos C57BL , Núcleos Parabraquiais/efeitos dos fármacos , Núcleos Parabraquiais/metabolismo , Núcleos Parabraquiais/efeitos da radiação , Marcadores de Fotoafinidade/química , Marcadores de Fotoafinidade/efeitos da radiação , Propofol/administração & dosagem , Propofol/análogos & derivados , Propofol/farmacologia , Propofol/efeitos da radiação , Fatores de Tempo , Raios Ultravioleta , Anestésicos Intravenosos/administração & dosagem , Anestésicos Intravenosos/química , Anestésicos Intravenosos/farmacologia , Anestésicos Intravenosos/efeitos da radiaçãoRESUMO
Although guanethidine (GUA) was used in the past as a drug to suppress hyperactivity of the sympathetic nerve fibers, there are no available data concerning the possible action of this substance on the sensory component of the peripheral nervous system supplying the urinary bladder. Thus, the present study was aimed at disclosing the influence of intravesically instilled GUA on the distribution, relative frequency, and chemical coding of dorsal root ganglion neurons associated with the porcine urinary bladder. The investigated sensory neurons were visualized with a retrograde tracing method using Fast Blue (FB), while their chemical profile was disclosed with single-labeling immunohistochemistry using antibodies against substance P (SP), calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase activating polypeptide (PACAP), galanin (GAL), neuronal nitric oxide synthase (nNOS), somatostatin (SOM), and calbindin (CB). After GUA treatment, a slight decrease in the number of FB+ neurons containing SP was observed when compared with untreated animals (34.6 ± 6.5% vs. 45.6 ± 1.3%), while the number of retrogradely traced cells immunolabeled for GAL, nNOS, and CB distinctly increased (12.3 ± 1.0% vs. 7.4 ± 0.6%, 11.9 ± 0.6% vs. 5.4 ± 0.5% and 8.6 ± 0.5% vs. 2.7 ± 0.4%, respectively). However, administration of GUA did not change the number of FB+ neurons containing CGRP, PACAP, or SOM. The present study provides evidence that GUA significantly modifies the sensory innervation of the porcine urinary bladder wall and thus may be considered a potential tool for studying the plasticity of this subdivision of the bladder innervation.
Assuntos
Gânglios Espinais/metabolismo , Guanetidina/farmacologia , Bexiga Urinária/inervação , Antagonistas Adrenérgicos/farmacologia , Neurônios Adrenérgicos/efeitos dos fármacos , Neurônios Adrenérgicos/metabolismo , Animais , Calbindinas/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Feminino , Galanina/metabolismo , Gânglios Espinais/efeitos dos fármacos , Guanetidina/metabolismo , Neurotoxinas/farmacologia , Óxido Nítrico Sintase/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Células Receptoras Sensoriais/metabolismo , Somatostatina/metabolismo , Substância P/metabolismo , Suínos , Bexiga Urinária/efeitos dos fármacosRESUMO
Noradrenaline (NE) is a catecholamine acting as both a neurotransmitter and a hormone, with relevant effects in modulating feeding behavior and satiety. Several studies have assessed the relationship between the noradrenergic system and Eating Disorders (EDs). This systematic review aims to report the existing literature on the role of the noradrenergic system in the development and treatment of EDs. A total of 35 studies were included. Preclinical studies demonstrated an involvement of the noradrenergic pathways in binge-like behaviors. Genetic studies on polymorphisms in genes coding for NE transporters and regulating enzymes have shown conflicting evidence. Clinical studies have reported non-unanimous evidence for the existence of absolute alterations in plasma NE values in patients with Anorexia Nervosa (AN) and Bulimia Nervosa (BN). Pharmacological studies have documented the efficacy of noradrenaline-modulating therapies in the treatment of BN and Binge Eating Disorder (BED). Insufficient evidence was found concerning the noradrenergic-mediated genetics of BED and BN, and psychopharmacological treatments targeting the noradrenergic system in AN. According to these data, further studies are required to expand the existing knowledge on the noradrenergic system as a potential target for treatments of EDs.
Assuntos
Encéfalo/metabolismo , Transtornos da Alimentação e da Ingestão de Alimentos/tratamento farmacológico , Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Norepinefrina/metabolismo , Neurônios Adrenérgicos/efeitos dos fármacos , Neurônios Adrenérgicos/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Comportamento Alimentar/fisiologia , Transtornos da Alimentação e da Ingestão de Alimentos/diagnóstico por imagem , Humanos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismoRESUMO
The pontine A5 noradrenergic group contributes to the maturation of the respiratory system before birth in rats. These neurons are connected to the neural network responsible for respiratory rhythmogenesis. In the present study, we investigated the participation of A5 noradrenergic neurons in neonates (P7-8 and P14-15) in the control of ventilation during hypoxia and hypercapnia in in vivo experiments using conjugated saporin anti-dopamine beta-hydroxylase (DßH-SAP) to specifically ablate noradrenergic neurons. Thus, DßH-SAP (420 ng/µL) or saporin (SAP, control) was injected into the A5 region of neonatal male Wistar rats. Hypoxia reduced respiratory variability in control animals; however, A5 lesion prevented this effect in P7-8 rats. Our data suggest that noradrenergic neurons of the A5 region in neonate rats do not participate in the control of ventilation under baseline and hypercapnic conditions, but exert an inhibitory modulation on breathing variability under hypoxic challenge in early life (P7-8).
Assuntos
Neurônios Adrenérgicos/metabolismo , Tronco Encefálico/citologia , Hipercapnia/fisiopatologia , Hipóxia/fisiopatologia , Respiração , Neurônios Adrenérgicos/efeitos dos fármacos , Neurônios Adrenérgicos/fisiologia , Animais , Animais Recém-Nascidos , Tronco Encefálico/crescimento & desenvolvimento , Tronco Encefálico/fisiopatologia , Dopamina beta-Hidroxilase/farmacologia , Masculino , Ratos , Ratos Wistar , Saporinas/farmacologiaRESUMO
BACKGROUND: Clinical studies have shown that the rapid antidepressant effect of the glutamate N-methyl-D-aspartate receptor antagonist ketamine generally disappears within 1 week but can be maintained by repeated administration. Preclinical studies showed that a single ketamine injection immediately increases the firing and burst activity of norepinephrine (NE) neurons, but not that of serotonin (5-HT) neurons. It also enhances the population activity of dopamine (DA) neurons. In the present study, we investigated whether such alterations of monoamine neuronal firing are still present 1 day after a single injection, and whether they can be maintained by repeated injections. METHODS: Rats received a single ketamine injection or 6 over 2 weeks and the firing activity of dorsal raphe nucleus 5-HT, locus coeruleus NE, and ventral tegmental area DA neurons was assessed. RESULTS: One day following a single injection of ketamine, there was no change in the firing activity of 5-HT, NE, or DA neurons. One day after repeated ketamine administration, however, there was a robust increase of the firing activity of NE neurons and an enhancement of burst and population activities of DA neurons, but still no change in firing parameters of 5-HT neurons. The increased activity of NE neurons was no longer present 3 days after the last injection, whereas that of DA neurons was still present. DA neurons were firing normally 7 days after repeated injections. CONCLUSION: These results imply that the enhanced activity of NE and DA neurons may play a significant role in the maintenance of the antidepressant action of ketamine.
Assuntos
Neurônios Adrenérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Tegmento Mesencefálico/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ketamina/administração & dosagem , Locus Cerúleo/efeitos dos fármacos , Masculino , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Neurônios Serotoninérgicos/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
RATIONALE: The flashing lights and sounds of modern casinos are alluring and may contribute to the addictive nature of gambling. Such cues can have a profound impact on the noradrenaline (NA) system, which could therefore be a viable therapeutic target for gambling disorder (GD). While there is substantial evidence to support the involvement of NA in the impulsive symptoms of GD, its function in mediating the "pro-addictive" impact of cues is less understood. OBJECTIVE: We wished to investigate the role of NA in our rodent assay of decision making and impulsivity, the cued rat gambling task (crGT). Given that sex differences are prominent in addiction disorders, and increasingly reported in the monoaminergic regulation of behaviour, we also prioritised evaluating noradrenergic drugs in both sexes. METHODS: Female and male rats were trained to stability on the crGT and then given intraperitoneal injections of the noradrenaline reuptake inhibitor atomoxetine, the α2A receptor agonist guanfacine, the beta receptor antagonist propranolol, and the α2 receptor antagonist yohimbine. RESULTS: Atomoxetine dose-dependently improved decision-making score. Guanfacine selectively enhanced decision making in risk-preferring males and optimal performing females. Propranolol and yohimbine did not influence decision making. Atomoxetine and guanfacine reduced premature responses, while yohimbine bi-phasically affected this index of motor impulsivity. CONCLUSIONS: These results support the hypothesis that NA is an important neuromodulator of the cue-induced deficits in decision making observed in laboratory-based gambling paradigms, and suggest that NAergic drugs like atomoxetine and guanfacine may be useful in treating GD.
Assuntos
Inibidores da Captação Adrenérgica/uso terapêutico , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Sinais (Psicologia) , Jogo de Azar/psicologia , Comportamento Impulsivo/efeitos dos fármacos , Assunção de Riscos , Neurônios Adrenérgicos/efeitos dos fármacos , Neurônios Adrenérgicos/fisiologia , Inibidores da Captação Adrenérgica/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Cloridrato de Atomoxetina/farmacologia , Cloridrato de Atomoxetina/uso terapêutico , Tomada de Decisões/efeitos dos fármacos , Tomada de Decisões/fisiologia , Relação Dose-Resposta a Droga , Feminino , Jogo de Azar/tratamento farmacológico , Guanfacina/farmacologia , Guanfacina/uso terapêutico , Comportamento Impulsivo/fisiologia , Masculino , Norepinefrina/farmacologia , Norepinefrina/uso terapêutico , Ratos , Ratos Long-Evans , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologiaRESUMO
Animals subjected to early life maternal separation exhibit increased sensitivity to chemical, thermal, and mechanical stimuli during adulthood. However, the mechanism by which maternal separation can alter pain sensitivity in adulthood has not yet been investigated. Thus, we aimed to evaluate the activity of serotonergic and noradrenergic neurons and the effect of serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors in male and female Wistar rats subjected to maternal separation. This study consisted of two experiments: 1) to confirm whether maternal separation increased pain sensitivity (n = 8 per group) and to evaluate the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus in animals subjected to maternal separation in comparison to controls (n = 6 per group); and 2) to evaluate the effect of fluoxetine (a selective 5-HT reuptake inhibitor) and desipramine (a NA reuptake inhibitor) on sensitivity to chemical stimulation using formalin in animals subjected to maternal separation (n = 8 per group). Our findings indicated that maternal separation increases an animal's sensitivity to painful chemical stimulation and reduces the activity of 5-HT and NA neurons. In addition, acute pretreatment with a 5-HT or NA reuptake inhibitor prevented the increased response to painful stimulation induced by maternal separation. In conclusion, maternal separation increases pain sensitivity by reducing the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus. This study contributes to possible treatments for pain in individuals exposed to early life stress.
Assuntos
Fluoxetina/farmacologia , Privação Materna , Dor/fisiopatologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Adrenérgicos/efeitos dos fármacos , Animais , Núcleo Dorsal da Rafe/efeitos dos fármacos , Locus Cerúleo/efeitos dos fármacos , Dor/tratamento farmacológico , Ratos WistarRESUMO
Activation of the adrenergic system in response to hypoglycemia is important for proper recovery from low glucose levels. However, it has been suggested that repeated adrenergic stimulation may also contribute to counterregulatory failure, but the underlying mechanisms are not known. The aim of this study was to establish whether repeated activation of noradrenergic receptors in the ventromedial hypothalamus (VMH) contributes to blunting of the counterregulatory response by enhancing local lactate production. The VMH of nondiabetic rats were infused with either artificial extracellular fluid, norepinephrine (NE), or salbutamol for 3 hours/day for 3 consecutive days before they underwent a hypoglycemic clamp with microdialysis to monitor changes in VMH lactate levels. Repeated exposure to NE or salbutamol suppressed both the glucagon and epinephrine responses to hypoglycemia compared to controls. Furthermore, antecedent NE and salbutamol treatments raised extracellular lactate levels in the VMH. To determine whether the elevated lactate levels were responsible for impairing the hormone response, we pharmacologically inhibited neuronal lactate transport in a subgroup of NE-treated rats during the clamp. Blocking neuronal lactate utilization improved the counterregulatory hormone responses in NE-treated animals, suggesting that repeated activation of VMH ß2-adrenergic receptors increases local lactate levels which in turn, suppresses the counterregulatory hormone response to hypoglycemia.
Assuntos
Neurônios Adrenérgicos/efeitos dos fármacos , Epinefrina/farmacologia , Hipoglicemia/metabolismo , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Agonistas Adrenérgicos/farmacologia , Neurônios Adrenérgicos/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Regulação para Baixo/efeitos dos fármacos , Técnica Clamp de Glucose , Hipoglicemia/patologia , Ácido Láctico/metabolismo , Masculino , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos/metabolismo , Recidiva , Núcleo Hipotalâmico Ventromedial/metabolismoRESUMO
Trauma patients treated with ketamine during emergency care present aggravated early post- traumatic stress reaction which is highly predictive of post-traumatic stress disorder (PTSD) development and severity. The use of ketamine in the acute trauma phase may directly or indirectly interfere with neural processes of memory consolidation of the traumatic event, thus leading to the formation of maladaptive memories, a hallmark symptom of PTSD. We have recently shown that ketamine anesthesia, immediately after a traumatic event, enhances memory consolidation and leads to long-lasting alterations of social behavior in rats. Based on the evidence that ketamine induces a robust central and peripheral adrenergic/noradrenergic potentiation and that activation of this system is essential for the formation of memory for stressful events, we explored the possibility that the strong sympathomimetic action of ketamine might underlie its memory enhancing effects. We found that rats given immediate, but not delayed, post-training ketamine anesthesia (125 mg/kg) presented enhanced 48-h memory retention in an inhibitory avoidance task and that these effects were blocked by adrenal medullectomy, lesions of the locus coeruleus, systemic or intra-basolateral amygdala ß-adrenergic receptor antagonism. Thus, the memory enhancing effects of ketamine anesthesia are time-dependent and mediated by a combined peripheral-central sympathomimetic action. We elucidated a mechanism by which ketamine exacerbates acute post-traumatic reaction, possibly leading to development of PTSD symptomatology later in life. These findings will help guide for a better management of sedation/anesthesia in emergency care to promote the prophylaxis and reduce the risk of developing trauma-related disorders in trauma victims.
Assuntos
Neurônios Adrenérgicos/efeitos dos fármacos , Anestésicos Dissociativos/administração & dosagem , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Medo/efeitos dos fármacos , Ketamina/administração & dosagem , Consolidação da Memória/efeitos dos fármacos , Neurônios Adrenérgicos/metabolismo , Animais , Nível de Alerta/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Ratos , Transtornos de Estresse Pós-Traumáticos/metabolismoRESUMO
Vincristine is a vinca alkaloid anti-mitotic drug with a broad spectrum of effects on solid and hematologic cancers. The major dose-limiting factor of this anti-cancer regimen is painful peripheral neuropathy. However, no gold-standard analgesic option has been used clinically. In this study, we investigated the effects and mechanism of bee venom acupuncture (BVA) to alleviate peripheral neuropathic pain induced by repeated intraperitoneal infusions of vincristine (1 mg/kg/day, days 1-5 and 8-12) in rats. Subcutaneous injection with bee venom (BV, 1.0 mg/kg) at the ST36 acupoint ameliorated cold and mechanical hypersensitivity (i.e., aberrant withdrawal responses in acetone drop and von Frey hair tests, respectively). In vivo extracellular recording demonstrated that BVA inhibited cutaneous cold (acetone) and mechanical (brush, press, and pinch) stimuli-elicited abnormal hyperexcitation of the spinal wide dynamic range (WDR) neurons in vincristine-treated rats. In addition, the microinjection of lidocaine into the ipsilateral locus coeruleus or the antagonism of the spinal α2-adrenergic receptors clearly reversed the effects of BVA on cold and mechanical hypersensitivity, indicating a vital role of the descending noradrenergic modulation in analgesia. These findings suggest that BVA could be a potential therapeutic option for vincristine-induced peripheral neuropathy.
Assuntos
Pontos de Acupuntura , Neurônios Adrenérgicos/efeitos dos fármacos , Venenos de Abelha/administração & dosagem , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Vincristina/toxicidade , Terapia por Acupuntura/métodos , Neurônios Adrenérgicos/metabolismo , Animais , Antineoplásicos Fitogênicos/toxicidade , Masculino , Microinjeções/métodos , Doenças do Sistema Nervoso Periférico/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
RATIONALE: In rodents, exposure to novel environments elicits initial anxiety-like behavior (neophobia) followed by intense exploration (neophilia) that gradually subsides as the environment becomes familiar. Thus, innate novelty-induced behaviors are useful indices of anxiety and motivation in animal models of psychiatric disease. Noradrenergic neurons are activated by novelty and implicated in exploratory and anxiety-like responses, but the role of norepinephrine (NE) in neophobia has not been clearly delineated. OBJECTIVE: We sought to define the role of central NE transmission in neophilic and neophobic behaviors. METHODS: We assessed dopamine ß-hydroxylase knockout (Dbh -/-) mice lacking NE and their NE-competent (Dbh +/-) littermate controls in neophilic (novelty-induced locomotion; NIL) and neophobic (novelty-suppressed feeding; NSF) behavioral tests with subsequent quantification of brain-wide c-fos induction. We complimented the gene knockout approach with pharmacological interventions. RESULTS: Dbh -/- mice exhibited blunted locomotor responses in the NIL task and completely lacked neophobia in the NSF test. Neophobia was rescued in Dbh -/- mice by acute pharmacological restoration of central NE with the synthetic precursor L-3,4-dihydroxyphenylserine (DOPS), and attenuated in control mice by the inhibitory α2-adrenergic autoreceptor agonist guanfacine. Following either NSF or NIL, Dbh -/- mice demonstrated reduced c-fos in the anterior cingulate cortex, medial septum, ventral hippocampus, bed nucleus of the stria terminalis, and basolateral amygdala. CONCLUSION: These findings indicate that central NE signaling is required for the expression of both neophilic and neophobic behaviors. Further, we describe a putative noradrenergic novelty network as a potential therapeutic target for treating anxiety and substance abuse disorders.
Assuntos
Neurônios Adrenérgicos/metabolismo , Comportamento Exploratório/fisiologia , Locomoção/fisiologia , Rede Nervosa/metabolismo , Norepinefrina/deficiência , Prosencéfalo/metabolismo , Agonistas Adrenérgicos/farmacologia , Neurônios Adrenérgicos/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Dopamina beta-Hidroxilase/genética , Dopamina beta-Hidroxilase/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Feminino , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Rede Nervosa/efeitos dos fármacos , Norepinefrina/metabolismo , Prosencéfalo/efeitos dos fármacosRESUMO
BACKGROUND: Cariprazine, the novel dopamine (DA) D3-preferring D3/D2 and serotonin (5-HT)1A receptor partial agonist, has activity as an adjunctive therapy in major depressive disorder (MDD). AIMS: This study aims to investigate the effects of chronic cariprazine administration in combination with the selective serotonin reuptake inhibitor escitalopram on the activity of monoaminergic systems. METHODS: Rats received cariprazine alone and in adjunct to escitalopram for 2 and 14 days and the firing activity of dorsal raphe nucleus 5-HT, locus coeruleus norepinephrine (NE) and ventral tegmental area DA neurons was assessed. 5-HT and NE neurotransmission in hippocampus pyramidal neurons was evaluated by assessing tonic activation of their 5-HT1A, and α1- and α2-adrenergic receptors, using their selective antagonists. RESULTS: Two and 14-day cariprazine regimens increased the firing rate of NE, but not 5-HT and DA neurons. Addition of cariprazine to escitalopram reversed the inhibitory effect of escitalopram on NE but not 5-HT and DA neurons. In the hippocampus, there was an increase in neurotransmission at 5-HT1A receptors in cariprazine-treated rats, but no change in overall NE transmission by either regimen. CONCLUSION: Cariprazine increased NE neuronal firing and reversed the escitalopram-induced inhibition of these neurons. Despite a lack of effect on 5-HT neuronal firing activity, there was an increase in tonic activation of hippocampus 5-HT1A receptors by cariprazine alone but not with the combination. These effects provide a possible rationale for the clinical efficacy of cariprazine as an adjunctive strategy in patients with MDD.
Assuntos
Antipsicóticos/farmacologia , Citalopram/farmacologia , Piperazinas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Neurônios Adrenérgicos/efeitos dos fármacos , Neurônios Adrenérgicos/metabolismo , Animais , Antipsicóticos/administração & dosagem , Citalopram/administração & dosagem , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/metabolismo , Quimioterapia Combinada , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locus Cerúleo/efeitos dos fármacos , Masculino , Norepinefrina/metabolismo , Piperazinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Transmissão Sináptica/efeitos dos fármacos , Fatores de TempoRESUMO
Hindbrain estrogen receptors (ER) impose sex-dimorphic control of counter-regulatory hormone and hypothalamic glucoregulatory transmitter and glycogen metabolic responses to hypoglycemia. A2 noradrenergic neurons are estradiol- and metabolic-sensitive. Estradiol controls dopamine-beta-hydroxylase (DBH) protein habituation to recurrent insulin-induced hypoglycemia (RIIH) in females. Current research investigated the premise that sex-dimorphic patterns of A2 ER variant acclimation to RIIH correlate with differential A2 DBH and 5'-AMP-activated protein kinase (AMPK) adaptation to RIIH. A2 neurons were laser-catapult-microdissected from male and female rats after one or four insulin injections for Western blot analysis. A2 pAMPK and DBH levels were increased in males, but suppressed in females after single insulin dosing. ER-alpha (ERα) and -beta (ERß) protein profiles were unaffected or decreased by acute hypoglycemia in each sex, whereas G protein-linked ER-1 (GPER) reactivity varied by sex. Antecedent hypoglycemia diminished basal A2 ERα/GPER and elevated ERß content in each sex, yet reduced pAMPK and DBH levels in female rats only. Reintroduced hypoglycemia suppressed A2 ERß levels in each sex, but altered DBH (↓), ERα (↓), and GPER (↑) levels in males only. Data document sex differences in A2 DBH adaptation to RIIH, e.g. a shift from positive-to-negative response in males versus loss of negative reactivity in females, as well as attenuated AMPK activation in both sexes. Between hypoglycemic episodes, A2 neurons in each sex likely exhibit diminished sensitivity to ERα/GPER signaling, but heightened receptivity to ERß input. RIIH-induced changes in ERα and GPER expression in male but not female may contribute to DBH suppression (males) versus no change (females) relative to adapted baseline expression.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Neurônios Adrenérgicos/metabolismo , Dopamina beta-Hidroxilase/metabolismo , Hipoglicemia/metabolismo , Insulina/farmacologia , Receptores de Estrogênio/metabolismo , Neurônios Adrenérgicos/efeitos dos fármacos , Animais , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Fatores SexuaisRESUMO
The brain neuromodulatory systems heavily influence behavioral and cognitive processes. Previous work has shown that norepinephrine (NE), a classic neuromodulator mainly derived from the locus coeruleus (LC), enhances neuronal responses to sensory stimuli. However, the role of the LC-NE system in modulating perceptual task performance is not well understood. In addition, systemic perturbation of NE signaling has often been proposed to specifically target the LC in functional studies, yet the assumption that localized (specific) and systemic (nonspecific) perturbations of LC-NE have the same behavioral impact remains largely untested. In this study, we trained mice to perform a head-fixed, quantitative tactile detection task, and administered an α2 adrenergic receptor agonist or antagonist to pharmacologically down- or up-regulate LC-NE activity, respectively. We addressed the outstanding question of how bidirectional perturbations of LC-NE activity affect tactile detection, and tested whether localized and systemic drug treatments exert the same behavioral effects. We found that both localized and systemic suppression of LC-NE impaired tactile detection by reducing motivation. Surprisingly, while locally activating LC-NE enabled mice to perform in a near-optimal regime, systemic activation impaired behavior by promoting impulsivity. Our results demonstrate that localized silencing and activation of LC-NE differentially affect tactile detection, and that localized and systemic NE activation induce distinct behavioral changes.
Assuntos
Neurônios Adrenérgicos/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Locus Cerúleo/metabolismo , Norepinefrina/metabolismo , Tato/fisiologia , Neurônios Adrenérgicos/efeitos dos fármacos , Animais , Clonidina/administração & dosagem , Feminino , Locus Cerúleo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tato/efeitos dos fármacos , Ioimbina/administração & dosagemRESUMO
Noradrenergic neurons in the locus coeruleus referred to as locus coeruleus neurons, provide the major supply of norepinephrine to the forebrain and play important roles in behavior through regulation of wakefulness and arousal. In a previous study using brain slice preparations, we reported that locus coeruleus neurons are subject to tonic inhibition mediated by γ-aminobutyric acid B receptors (GABABRs) and that the extent of tonic inhibition varies with ambient GABA levels. Since ambient GABA in the locus coeruleus was reported to fluctuate during the sleep-wakefulness cycle, here we tested whether GABABR-mediated tonic inhibition of locus coeruleus neurons could be a mechanism underlying changes in brain arousal. We first demonstrated that GABABR-mediated tonic inhibition of locus coeruleus neurons also exists in vivo by showing that local infusion of CGP35348, a GABABR antagonist, into the locus coeruleus increased the firing rate of locus coeruleus neurons in anesthetized rats. We then showed that this manipulation accelerated the behavioral emergence of rats from deep anesthesia induced by isoflurane. Together, these observations show that GABABR-mediated tonic inhibition of locus coeruleus neurons occurs in vivo and support the idea that this effect may be important in regulating the functional state of the brain.