RESUMEN
Ovarian functions are modulated by the hypothalamus-pituitary-ovary axis and neural signals. Stress modifies the activity of the sympathetic nervous system. In adult female rats, cold stress results in higher noradrenergic and steroidogenic activity of the ovary, anovulation and the presence of ovarian cysts; however, it is unknown whether this response occurs in prepubertal rats. The purpose of this study was to analyse the effects of cold stress initiated in the prepubertal stage of female rats on ovarian function. Female rats 24 days old were exposed to three, five or eight weeks of cold stress. Autopsies were performed at the end of each stress period. The parameters analysed were the number of ova shed by ovulating animals; the number of ovulating animals; the serum concentrations of progesterone, testosterone, and oestradiol; and the ovarian concentrations of norepinephrine and 3-methoxy-4-hydroxyphenyl-glycol. Our results show that chronic cold stress applied to prepubertal rats did not modify the number of ovulating animals, the total number of ova shed, or progesterone and testosterone concentrations in any of the periods analysed. Oestradiol concentration was lower in the animals exposed to five or eight weeks of stress. The ovarian norepinephrine concentration was higher in the animals exposed to three weeks of stress and was lower at eight weeks of stress. No changes in ovarian morphology were observed. Our data suggest that the changes in noradrenergic activity resulting from chronic cold stress experienced in the prepubertal stage do not modify ovarian architecture or affect the ovulatory response in adulthood.
Asunto(s)
Respuesta al Choque por Frío , Progesterona , Ratas , Animales , Femenino , Estradiol , Norepinefrina/fisiología , TestosteronaRESUMEN
The noradrenergic system is implicated in neuropathologies contributing to major disorders of the memory, including post-traumatic stress disorder and Alzheimer's disease. Determining the impact of norepinephrine on cellular function and plasticity is thus essential for making inroads into our understanding of these brain conditions, while expanding our capacity for treating them. Norepinephrine is a neuromodulator within the mammalian central nervous system which plays important roles in cognition and associated synaptic plasticity. Specifically, norepinephrine regulates the formation of memory through the stimulation of ß-ARs, increasing the dynamic range of synaptic modifiability. The mechanisms through which NE influences neural circuit function have been extended to the level of the epigenome. This review focuses on recent insights into how the noradrenergic recruitment of epigenetic modifications, including DNA methylation and post-translational modification of histones, contribute to homo- and heterosynaptic plasticity. These advances will be placed in the context of synaptic changes associated with memory formation and linked to brain disorders and neurotherapeutic applications.
Asunto(s)
Potenciación a Largo Plazo , Norepinefrina , Animales , Epigénesis Genética , Potenciación a Largo Plazo/fisiología , Mamíferos/metabolismo , Plasticidad Neuronal/genética , Norepinefrina/fisiología , Receptores Adrenérgicos beta/metabolismo , Sinapsis/metabolismoRESUMEN
BACKGROUND: The role of autonomic nervous system in the development and maintenance of portal hypertension is not fully elucidated. It is known that the gene expression of norepinephrine in the superior mesenteric artery varies with time, and it may contribute for splanchnic vasodilation and its consequent hemodynamic repercussions. It is still not known exactly how the adrenergic expression behaves at the heart level in the initial stages of this process. AIM: To evaluate the immunohistochemical expression of the enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), involved in the synthesis of norepinephrine, in the myocardium of rats submitted to partial ligation of the portal vein. METHODS: Twenty-four Wistar rats were divided into two groups: Sham Operated and Portal Hypertension. The partial ligation was performed in the Portal Hypertension group, and after 1/6/24 h and 3/5/14 days the animals were euthanized. Immunohistochemical analysis was performed to quantify the expression of the stained enzyme using the ImageJ program. RESULTS: The Portal Hypertension group expressed percentages between 4.6-6% of the marked area, while the Sham Operated group varied between 4-5%. Although there was no statistical significance, the percentage stained in the Portal Hypertension group followed an increasing pattern in the first 6 h and a decreasing pattern after 24 h, which was not observed in the Sham Operated group. CONCLUSION: The expression of noradrenaline in rat myocardium during the first two weeks after partial ligation of the portal vein, with tyrosine hydroxylase as marker, did not show differences between groups over time.
Asunto(s)
Hipertensión Portal/etiología , Miocardio/metabolismo , Norepinefrina/biosíntesis , Animales , Catecolaminas/fisiología , Modelos Animales de Enfermedad , Masculino , Norepinefrina/fisiología , Ratas , Ratas Wistar , Tirosina 3-Monooxigenasa/biosíntesisRESUMEN
Adrenaline and noradrenaline bind to membrane receptors of the superfamily of G protein-coupled receptors (GPCR) in target cells, where they modulate physiological responses such as metabolism, vasoconstriction, vasodilation and proliferation. Alteration in their function is associated with conditions such as hypertension, benign prostatic hyperplasia and cardiac hypertrophy. In response to adrenaline, receptors form signaling complexes, which enables adrenergic action to be specific, rapid and efficient. These signaling complexes or signalosomes are composed of kinases, phosphatases, and adapter and scaffold proteins, which together modulate the receptor function. Manipulation of each protein-protein interaction of the adrenergic signaling complex emerges as a promising therapeutic strategy for the design of drugs that modulate adrenergic action and help to define its pathophysiological significance. An important biological model to perform these investigations is the heart, since it expresses all adrenergic receptors; to date, several heart signalosomes have been described. Mass spectrometry (proteomics), genetic manipulation and biochemical assays, such as two-hybrid and co-immunoprecipitation assays, are tools that are used in these studies.
La adrenalina y la noradrenalina se unen a receptores membranales de la superfamilia de receptores acoplados a proteínas G (GPCR) en las células blanco, donde modulan respuestas fisiológicas tales como el metabolismo, vasoconstricción, vasodilatación y proliferación. La alteración en su función está asociada con hipertensión, hiperplasia prostática benigna e hipertrofia cardiaca. En respuesta a la adrenalina, los receptores forman complejos de señalización, lo que permite que la acción adrenérgica sea específica, rápida y eficiente. Estos complejos de señalización o signalosomas están integrados por cinasas, fosfatasas, proteínas adaptadoras y de andamio, que en conjunto modulan la función del receptor. La manipulación de cada interacción proteína-proteína del complejo de señalización adrenérgico emerge como una estrategia terapéutica prometedora para el diseño de fármacos que modulen la acción adrenérgica y ayuden a definir su significado fisiopatológico. Un modelo biológico importante para realizar estos estudios es el corazón, ya que expresa todos los receptores adrenérgicos; en la actualidad se han descrito varios signalosomas cardiacos. La espectrometría de masas (proteómica), manipulación genética y ensayos bioquímicos como el doble híbrido o la coinmunoprecipitación son herramientas que se emplean en estos estudios.
Asunto(s)
Epinefrina/fisiología , Norepinefrina/fisiología , Receptores Adrenérgicos/fisiología , Transducción de Señal/fisiología , Humanos , Receptores Adrenérgicos/clasificación , Receptores Acoplados a Proteínas G/fisiologíaRESUMEN
ABSTRACT Background: The role of autonomic nervous system in the development and maintenance of portal hypertension is not fully elucidated. It is known that the gene expression of norepinephrine in the superior mesenteric artery varies with time, and it may contribute for splanchnic vasodilation and its consequent hemodynamic repercussions. It is still not known exactly how the adrenergic expression behaves at the heart level in the initial stages of this process. Aim: To evaluate the immunohistochemical expression of the enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), involved in the synthesis of norepinephrine, in the myocardium of rats submitted to partial ligation of the portal vein. Methods: Twenty-four Wistar rats were divided into two groups: Sham Operated and Portal Hypertension. The partial ligation was performed in the Portal Hypertension group, and after 1/6/24 h and 3/5/14 days the animals were euthanized. Immunohistochemical analysis was performed to quantify the expression of the stained enzyme using the ImageJ program. Results: The Portal Hypertension group expressed percentages between 4.6-6% of the marked area, while the Sham Operated group varied between 4-5%. Although there was no statistical significance, the percentage stained in the Portal Hypertension group followed an increasing pattern in the first 6 h and a decreasing pattern after 24 h, which was not observed in the Sham Operated group. Conclusion: The expression of noradrenaline in rat myocardium during the first two weeks after partial ligation of the portal vein, with tyrosine hydroxylase as marker, did not show differences between groups over time.
RESUMO Racional: O papel do sistema nervoso autônomo na hipertensão portal não está completamente elucidado. Sabe-se que, nessa condição, a expressão gênica da norepinefrina na artéria mesentérica superior modifica-se com o tempo, podendo ser importante contribuinte para a vasodilatação esplâncnica e suas repercussões hemodinâmicas. Apesar dos estudos sobre as repercussões cardiovasculares na hipertensão portal, ainda não se sabe como a expressão adrenérgica se comporta a nível cardíaco nas etapas iniciais desse processo. Objetivo: Avaliar a expressão imunoistoquímica da enzima tirosina hidroxilase (tirosina 3-mono-oxigenase), relacionada à síntese da norepinefrina, no miocárdio de ratos submetidos à ligadura parcial da veia porta. Métodos: Foram utilizados 24 ratos, distribuídos em dois grupos: Sham Operated e Hipertensão Portal. A ligadura parcial da veia porta foi realizada apenas no grupo Hipertensão Portal e, após 1/6/24 h e 3/5/14 dias, os animais foram eutanasiados. Foi feita a análise imunoistoquímica para quantificar a expressão da enzima corada, utilizando o programa ImageJ. Resultados: No grupo Hipertensão Portal, o miocárdio expressou percentuais entre 4,6-6% de área marcada, enquanto que no grupo Sham Operated variou entre 4-5%, sem significância estatística. Apenas no grupo Hipertensão Portal, a porcentagem corada pela enzima seguiu padrão crescente nas primeiras 6 h e decrescente após 24 h. Conclusão: A expressão da noradrenalina no miocárdio de ratos durante as primeiras duas semanas após a ligadura parcial da veia porta, tendo como marcador a enzima tirosina hidroxilase, não apresentou diferenças entre grupos ao longo do tempo.
Asunto(s)
Animales , Masculino , Ratas , Norepinefrina/biosíntesis , Hipertensión Portal/etiología , Miocardio/metabolismo , Tirosina 3-Monooxigenasa/biosíntesis , Catecolaminas/fisiología , Norepinefrina/fisiología , Ratas Wistar , Modelos Animales de EnfermedadRESUMEN
Previously we showed that activation of the Nucleus of the Solitary Tract (NTS)-Nucleus Paragigantocellularis (PGi)-Locus coeruleus (LC) pathway, which theoretically culminates with norepinephrine (NE) release in dorsal hippocampus (CA1 region) and basolateral amygdala (BLA) is necessary for the consolidation of object recognition (OR) memory. Here we show that, while the microinjection of the beta-noradrenergic receptor blocker timolol into CA1 impairs OR memory consolidation, the microinjection of norepinephrine (NE) promotes the persistence of this type of memory. Further, we show that OR consolidation is attended by an increase of norepinephrine (NE) levels and of the expression of brain derived neurotrophic factor (BDNF) in hippocampus, which are impaired by inactivation of the NTS-PGi-LC pathway by the infusion of muscimol into the NTS.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/fisiología , Consolidación de la Memoria/fisiología , Norepinefrina/fisiología , Reconocimiento en Psicología/fisiología , Antagonistas Adrenérgicos beta/administración & dosificación , Animales , Agonistas de Aminoácidos Excitadores/administración & dosificación , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Agonistas de Receptores de GABA-A/administración & dosificación , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/fisiología , Masculino , Consolidación de la Memoria/efectos de los fármacos , Muscimol/administración & dosificación , N-Metilaspartato/administración & dosificación , Norepinefrina/administración & dosificación , Ratas Wistar , Reconocimiento en Psicología/efectos de los fármacos , Núcleo Solitario/efectos de los fármacos , Núcleo Solitario/fisiología , Timolol/administración & dosificaciónRESUMEN
Ursolic acid (UA) is a natural pentacyclic triterpenoid carboxylic acid that exerts antidepressant-like effects in the tail suspension test (TST) and in the forced swimming test, and this effect was reported to be mediated by the dopaminergic system. Many studies show that currently available antidepressant agents have effects on multiple neurotransmitter systems which account for their efficacy. Therefore, this study was aimed at investigating the possible involvement of the serotonergic, noradrenergic, glutamatergic and opioid systems in the antidepressant-like effect of UA. To this end, several pharmacological agents were administered to verify their ability to influence the antidepressant-like responses elicited by UA in the TST in mice. The open-field test was used to assess the locomotor activity. The results show that the pre-treatment of mice with ρ-chlorophenylalanine (100mg/kg, i.p., 4 days) or α-methyl-ρ-tyrosine (100mg/kg, i.p.) but not with N-methyl-d-aspartate (0.1 pmol/mouse, i.c.v.) or naloxone (1mg/kg, i.p.), was able to prevent the antidepressant-like effect of UA (0.1mg/kg, p.o.). Sub-effective doses of fluoxetine (5mg/kg, p.o.) or reboxetine (2mg/kg, p.o.), but not ketamine (0.1mg/kg, i.p.) or MK-801 (0.001 mg/kg, p.o.), was capable of potentiating the effect of a sub-effective dose of UA (0.001 mg/kg, p.o.) in the TST. None of the treatments affected locomotor activity. Altogether, the results show an involvement of the serotonergic and noradrenergic systems, but not the glutamatergic or opioid systems, in the antidepressant-like effect of UA.
Asunto(s)
Antidepresivos/farmacología , Norepinefrina/fisiología , Serotonina/fisiología , Triterpenos/farmacología , Animales , Antidepresivos/administración & dosificación , Conducta Animal/efectos de los fármacos , Femenino , Inyecciones Intraventriculares , Masculino , Ratones , Triterpenos/administración & dosificación , Ácido UrsólicoRESUMEN
It has been demonstrated that a short-duration stress (acute stress) may result in immunopreparatory or immunoenhancing physiological conditions. The aim of the present study was to investigate whether exposure to prenatal restraint stress (PRS) influences the impact of acute stress on the T-cell response in the adult life. We found that female mice exposed to PRS (PS mice) did not exhibit changes in the T-cell-dependent IgG antibody production with respect to prenatally non-stressed mice (no-PS mice). However, no-PS mice exposed to acute stress showed an increase of antibody production after antigen stimulation. In contrast, PS mice exhibited a decreased response after an acute situation. Spleen catecholamines and plasma corticosterone levels were increased in acute stress in both PS and no-PS mice. Nevertheless, lymphocyte response to hormones was altered in PS mice. Particularly, inhibitory effect of corticosterone was higher on lymphocytes from PS mice. In addition, an increase in protein levels and mRNA expression of glucocorticoid receptor was found in lymphoid cells from PS mice. These results show that prenatal stress alters the immune intrinsic regulatory mechanism that in turn induces an increased vulnerability to any stressful situation able to modify immune homeostasis.
Asunto(s)
Linfocitos/fisiología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Receptores de Glucocorticoides/fisiología , Estrés Psicológico/fisiopatología , Linfocitos T/fisiología , Animales , Corticosterona/sangre , Epinefrina/análisis , Epinefrina/fisiología , Femenino , Inmunidad Celular/inmunología , Inmunidad Celular/fisiología , Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Norepinefrina/análisis , Norepinefrina/fisiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/inmunología , Restricción Física/efectos adversos , Bazo/química , Bazo/fisiopatología , Estrés Psicológico/inmunología , Regulación hacia Arriba/inmunología , Regulación hacia Arriba/fisiologíaRESUMEN
We investigate whether the extinction of inhibitory avoidance (IA) learning can be subjected to endogenous state-dependence with systemic injections of epinephrine (E), and whether endogenous norepinephrine (NE) and the nucleus tractus solitarius (NTS)âlocus coeruleusâhippocampus/amygdala (HIPP/BLA) pathway participate in this. Rats trained in IA were submitted to two sessions of extinction 24 h apart: In the first, the animals were submitted to a training session of extinction, and in the second they were tested for the retention of extinction. Saline or E were given i.p. immediately after the extinction training (post-extinction training injections) and/or 6 min before the extinction test (pre-extinction test). Post-extinction training E (50 or 100 µg/kg) induced a poor retrieval of extinction in the test session of this task unless an additional E injection (50 µg/kg) was given prior to the extinction test. This suggested state-dependence. Muscimol (0.01 µg/side) microinfused into the NTS prior to the extinction test session blocked E-induced state-dependence. Norepinephrine (NE, 1 µg/side) infused bilaterally into NTS restores the extinction impairment caused by post-extinction training i.p. E. In animals with bilateral NTS blockade induced by muscimol, NE (1 µg/side) given prior to the extinction test into the CA1 region of the dorsal hippocampus or into the basolateral amygdala restored the normal extinction levels that had been impaired by muscimol. These results suggest a role for the NTSâlocus coeruleusâHIPP/BLA pathway in the retrieval of extinction, as it has been shown to have in the consolidation of inhibitory avoidance and of object recognition learning.
Asunto(s)
Amígdala del Cerebelo/fisiología , Reacción de Prevención/fisiología , Epinefrina/fisiología , Extinción Psicológica/fisiología , Hipocampo/fisiología , Locus Coeruleus/fisiología , Norepinefrina/fisiología , Transducción de Señal/fisiología , Núcleo Solitario/fisiología , Amígdala del Cerebelo/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Epinefrina/administración & dosificación , Extinción Psicológica/efectos de los fármacos , Miedo/fisiología , Agonistas de Receptores de GABA-A/administración & dosificación , Agonistas de Receptores de GABA-A/farmacología , Hipocampo/efectos de los fármacos , Locus Coeruleus/efectos de los fármacos , Masculino , Muscimol/administración & dosificación , Muscimol/farmacología , Norepinefrina/administración & dosificación , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Núcleo Solitario/efectos de los fármacosRESUMEN
17α-Ethynyl-estradiol (EE2, a synthetic steroidal estrogen) induces antidepressant-like effects in the forced swimming test (FST) similar to those induced by 5-HT and noradrenaline reuptake inhibitors (dual antidepressants). However, the precise mechanism of action of EE2 has not been studied. In the present study, the participation of estrogen receptors (ERs) and the serotonergic and the noradrenergic presynaptic sites in the antidepressant-like action of EE2 was evaluated in the FST. The effects of the ER antagonist ICI 182,780 (10 µg/rat; i.c.v.), the serotonergic and noradrenergic terminal destruction with 5,7-dihydroxytryptamine (5,7-DHT; 200 µg/rat, i.c.v.), and N-(2-chloro-ethyl)-N-ethyl-2-bromobenzylamine (DSP4; 10mg/kg, i.p.) were studied in ovariectomized rats treated with EE2 and subjected to the FST. In addition, the participation of α2-adrenergic receptors in the antidepressant-like action of EE2 was explored using the selective α2-receptor antagonist idazoxan (0.25, 0.5 and 1.0mg/kg, i.p.). EE2 induced an antidepressant-like action characterized by a decrease in immobility behavior with a concomitant increase in swimming and climbing behaviors. The ER antagonist, 5,7-DHT, DSP4, and idazoxan blocked the effects of EE2 on the immobility behavior, whereas ICI 182,780 and 5,7-DHT affected swimming behavior. The noradrenergic compound DSP4 altered climbing behavior, while Idazoxan inhibited the increase of swimming and climbing behaviors induced by EE2. Our results suggest that the antidepressant-like action of EE2 implies a complex mechanism of action on monoaminergic systems and estrogen receptors.
Asunto(s)
Antidepresivos , Etinilestradiol/farmacología , Norepinefrina/fisiología , Serotonina/fisiología , Natación/psicología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Química Encefálica/efectos de los fármacos , Catecolaminas/metabolismo , Cromatografía Líquida de Alta Presión , Estradiol/análogos & derivados , Estradiol/farmacología , Antagonistas de Estrógenos/farmacología , Femenino , Fulvestrant , Idazoxan/farmacología , Inyecciones Intraventriculares , Actividad Motora/fisiología , Ratas , Técnicas EstereotáxicasRESUMEN
Consolidation and reconsolidation are phases of memory stabilization that diverge slightly. Noradrenaline is known to influence both processes, but the relative contribution of α1- and ß-adrenoceptors is unclear. The present study sought to investigate this matter by comparing their recruitment to consolidate and/or reconsolidate a contextual fear memory trace under enhanced noradrenergic activity induced by yohimbine. We report that this α2-adrenoceptor antagonist was able to potentiate fear memory trace consolidation or reconsolidation when administered immediately after acquisition or retrieval, respectively, resulting in increased freezing expression. In either case, generalization of this response to an unpaired context was also seen when it achieved a ceiling level in the paired context. These effects endured for over 7 d and relied on action at central rather than peripheral sites, but were prevented when a memory trace was not acquired, when memory reactivation was omitted, or when administration of yohimbine was delayed until 6 h after acquiring or retrieving the memory trace. The ß-adrenoceptor antagonist propranolol was able to prevent the above-mentioned effects of yohimbine, while pretreatment with the α1-adrenoceptor antagonist prazosin blocked only its facilitating effects on memory reconsolidation. These results highlight a differential participation of α1- and ß-adrenoceptors in fear memory processing. Moreover, it was shown that the α2-adrenoceptor agonist clonidine, as opposed to yohimbine, mitigates fear expression by weakening memory consolidation or reconsolidation.
Asunto(s)
Condicionamiento Psicológico/fisiología , Miedo/fisiología , Memoria/fisiología , Norepinefrina/fisiología , Receptores Adrenérgicos alfa 1/fisiología , Receptores Adrenérgicos beta/fisiología , Adrenérgicos/farmacología , Análisis de Varianza , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Condicionamiento Psicológico/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Miedo/efectos de los fármacos , Reacción Cataléptica de Congelación/efectos de los fármacos , Reacción Cataléptica de Congelación/fisiología , Masculino , Memoria/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
BACKGROUND: Cannabinoid agonists induce norepinephrine release in central, spinal, and peripheral sites. Previous studies suggest an interaction between the cannabinoid and adrenergic systems on antinociception. In this study, we sought to verify whether the CB1 and CB2 cannabinoid receptor agonists anandamide and N-palmitoyl-ethanolamine (PEA), respectively, are able to induce peripheral antinociception via an adrenergic mechanism. METHODS: All drugs were administered locally into the right hindpaw of male Wistar rats. The rat paw pressure test was used, with hyperalgesia induced by intraplantar injection of prostaglandin E2 (2 µg). RESULTS: Anandamide, 12.5 ng/paw, 25 ng/paw, and 50 ng/paw elicited a local peripheral antinociceptive effect that was antagonized by CB1 cannabinoid receptor antagonist AM251, 20 µg/paw, 40 µg/paw, and 80 µg/paw, but not by CB2 cannabinoid receptor antagonist AM630, 100 µg/paw. PEA, 5 µg/paw, 10 µg/paw, and 20 µg/paw, elicited a local peripheral antinociceptive effect that was antagonized by AM630, 25 µg/paw, 50 µg/paw, and 100 µg/paw, but not by AM251, 80 µg/paw. Antinociception induced by anandamide or PEA was antagonized by the nonselective α2 adrenoceptor antagonist yohimbine, 05 µg/paw, 10 µg/paw, and 20 µg/paw, and by the selective α2C adrenoceptor antagonist rauwolscine, 10 µg/paw, 15 µg/paw, and 20 µg/paw, but not by the selective antagonists for α2A, α2B, and α2D adrenoceptor subtypes, 20 µg/paw. The antinociceptive effect of the cannabinoids was also antagonized by the nonselective α1 adrenoceptor antagonist prazosin, 0.5 µg/paw, 1 µg/paw, and 2 µg/paw, and by the nonselective ß adrenoceptor antagonist propranolol, 150 ng/paw, 300 ng/paw, and 600 ng/paw. Guanethidine, which depletes peripheral sympathomimetic amines (30 mg/kg/animal, once a day for 3 days), restored approximately 70% the anandamide-induced and PEA-induced peripheral antinociception. Furthermore, acute injection of the norepinephrine reuptake inhibitor reboxetine, 30 µg/paw, intensified the antinociceptive effects of low-dose anandamide, 12.5 ng/paw, and PEA, 5 µg/paw. CONCLUSIONS: This study provides evidence that anandamide and PEA induce peripheral antinociception activating CB1 and CB2 cannabinoid receptors, respectively, stimulating an endogenous norepinephrine release that activates peripheral adrenoceptors inducing antinociception.
Asunto(s)
Analgésicos/farmacología , Agonistas de Receptores de Cannabinoides/farmacología , Norepinefrina/fisiología , Nervios Periféricos/efectos de los fármacos , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Sistema Nervioso Simpático/efectos de los fármacos , Inhibidores de Captación Adrenérgica/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Antagonistas Adrenérgicos beta/farmacología , Amidas , Animales , Ácidos Araquidónicos/antagonistas & inhibidores , Ácidos Araquidónicos/farmacología , Dinoprostona , Endocannabinoides/antagonistas & inhibidores , Endocannabinoides/farmacología , Etanolaminas/antagonistas & inhibidores , Etanolaminas/farmacología , Masculino , Morfolinas/farmacología , Dimensión del Dolor/efectos de los fármacos , Ácidos Palmíticos/antagonistas & inhibidores , Ácidos Palmíticos/farmacología , Alcamidas Poliinsaturadas/antagonistas & inhibidores , Alcamidas Poliinsaturadas/farmacología , Prazosina/farmacología , Propranolol/farmacología , Ratas , Ratas Wistar , Reboxetina , Yohimbina/farmacologíaRESUMEN
We have previously reported that stimulation of alpha-1 adrenoceptors by noradrenaline (NA) injected into the lateral septal area (LSA) of anaesthetized rats causes pressor and bradycardic responses that are mediated by acute vasopressin release into the circulation through activation of the paraventricular nucleus (PVN). Although the PVN is the final structure of this pathway, the LSA has no direct connections with the PVN, suggesting that other structures may connect these areas. To address this issue, the present study employed c-Fos immunohistochemistry to investigate changes caused by NA microinjection into the LSA in neuronal activation in brain structures related to systemic vasopressin release. NA microinjected in the LSA caused pressor and bradycardic responses, which were blocked by intraseptal administration of α-1 adrenoceptor antagonist (WB4101, 10 nmol/200 nL) or systemic V-1 receptor antagonist (dTyr(CH2)5(Me)AVP, 50 µg/kg). NA also increased c-Fos immunoreactivity in the prelimbic cortex (PL), infralimbic cortex (IL), dorsomedial periaqueductal gray (dmPAG), bed nucleus of the stria terminalis (BNST), PVN, and medial amygdala (MeA). No differences in the diagonal band of Broca, cingulate cortex, and dorsolateral periaqueductal gray (dlPAG) were found. Systemic administration of the vasopressin receptor antagonist dTyr AVP (CH2)5(Me) did not change the increase in c-Fos expression induced by intra-septal NA. This latter effect, however, was prevented by local injection of the alpha-1 adrenoceptor antagonist WB4101. These results suggest that areas such as the PL, IL, dmPAG, BNST, MeA, and PVN could be part of a circuit responsible for vasopressin release after activation of alpha-1 adrenoceptors in the LSA.
Asunto(s)
Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Norepinefrina/administración & dosificación , Norepinefrina/fisiología , Tabique del Cerebro/efectos de los fármacos , Tabique del Cerebro/fisiología , Animales , Masculino , Microinyecciones , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Ratas , Ratas WistarRESUMEN
The autonomic nerve fibres converge to the testis along two major pathways, the superior spermatic nerve (SSN) and the inferior spermatic nerve (ISN). The object of this work was to evaluate whether the addition of noradrenaline (NA) in the ganglionic compartment of two ex vivo systems: superior mesenteric ganglion (SMG)-SSN-testis, inferior mesenteric ganglion (IMG)-ISN-testis modulate androstenedione (A2), NA and nitrite release and to determine whether there are secretory differences between the right and the left testis. Each gonad with its respective ganglion was transferred into a cuvette with two compartments and incubated in a Dubnoff metabolic shaker. The testis incubation liquids were collected and analysed for NA by HPLC, A2 by RIA and nitrites by the Griess method. When NA is added to the IMG, A2 and NA release diminishes and nitrite increases in the left testis, while in the right gonad, A2 and NA increase and nitrite decreases. When NA was administered to the SMG, A2 and NA increase and nitrite diminishes in the left gonad, but they show opposite fluctuations in the right testis. These ex vivo systems appear to be excellent models for studying the sympathetic ganglionic control of the testis though A2, NA and nitrite release from the male gonad. It is evident that a better knowledge about the role of catecholamines and nitric oxide in the testis physiology may facilitate the understanding of some reproductive diseases.
Asunto(s)
Androstenodiona/metabolismo , Ganglios Simpáticos/metabolismo , Neuronas/metabolismo , Óxido Nítrico/metabolismo , Norepinefrina/metabolismo , Testículo/inervación , Abdomen , Animales , Técnicas In Vitro , Cinética , Masculino , Nitritos/análisis , Norepinefrina/fisiología , Ratas , Ratas Wistar , Transmisión SinápticaRESUMEN
CONTEXT: Polygala paniculata Linnaeus (Polygalaceae) has shown neuroprotective effects, but there is no report about its antidepressant potential. OBJECTIVE: The antidepressant-like effect of the hydroalcoholic extract from P. paniculata and some of the possible mechanisms involved in this effect were investigated in forced swimming test (FST). MATERIALS AND METHODS: Mice received extract by oral route and were submitted to FST and open-field test. Animals were forced to swim and the total immobility time was registered (6-min period). A reduction in the immobility time is considered an antidepressant-like effect. In order to investigate the involvement of the monoaminergic systems, mice were treated with pharmacological antagonists before administration of the extract. RESULTS: The acute administration of the hydroalcoholic extract from P. paniculata produced an antidepressant-like effect, since it significantly reduced the immobility time in FST (0.01-30 mg/kg) as compared to control group, without changing locomotor activity. Pretreatment of mice with yohimbine (1 mg/kg, i.p., α2-adrenoceptor antagonist), propranolol (1 mg/kg, i.p., ß-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., dopamine D1 receptor antagonist) or sulpiride (50 mg/kg, i.p., dopamine D2 receptor antagonist) prevented the antidepressant-like effect of the extract in FST (30 mg/kg). Moreover, ketanserin (5 mg/kg, i.p., preferential 5-HT(2A) receptor antagonist) enhanced the effect of the extract in FST. DISCUSSION AND CONCLUSION: The results of the present study indicate that the extract from P. paniculata has an antidepressant-like action that is likely mediated by an interaction with the serotonergic (5-HT2A receptors), noradrenergic (α2 and ß-receptor) and dopaminergic (D1 and D2 receptors) systems.
Asunto(s)
Antidepresivos/farmacología , Monoaminas Biogénicas/metabolismo , Polygala/química , Antagonistas Adrenérgicos/farmacología , Animales , Dopamina/fisiología , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Pérdida de Tono Postural/efectos de los fármacos , Ratones , Actividad Motora/efectos de los fármacos , Norepinefrina/fisiología , Extractos Vegetales/antagonistas & inhibidores , Extractos Vegetales/farmacología , Serotonina/fisiología , Antagonistas de la Serotonina/farmacología , Natación/psicologíaRESUMEN
Infant rats must learn to identify their mother’s diet-dependent odor. Once learned, maternal odor controls pups’ approach to the mother, their social behavior and nipple attachment. Here we present a review of the research from four different laboratories, which suggests that neural and behavioral responses to the natural maternal odor and neonatal learned odors are similar. Together, these data indicate that pups have a unique learning circuit relying on the olfactory bulb for neural plasticity and on the hyperfunctioning noradrenergic locus coeruleus flooding the olfactory bulb with norepinephrine to support the neural changes. Another important factor making this system unique is the inability of the amygdala to become incorporated into the infant learning circuit. Thus, infant rats appear to be primed in early life to learn odors that will evoke approach responses supporting attachment to the caregiver.
Asunto(s)
Animales , Femenino , Ratas , Amígdala del Cerebelo/fisiología , Señales (Psicología) , Aprendizaje Discriminativo/fisiología , Conducta Alimentaria/fisiología , Locus Coeruleus/fisiología , Odorantes , Bulbo Olfatorio/fisiología , Animales Recién Nacidos , Plasticidad Neuronal/fisiología , Norepinefrina/fisiologíaRESUMEN
Infant rats must learn to identify their mother's diet-dependent odor. Once learned, maternal odor controls pups' approach to the mother, their social behavior and nipple attachment. Here we present a review of the research from four different laboratories, which suggests that neural and behavioral responses to the natural maternal odor and neonatal learned odors are similar. Together, these data indicate that pups have a unique learning circuit relying on the olfactory bulb for neural plasticity and on the hyperfunctioning noradrenergic locus coeruleus flooding the olfactory bulb with norepinephrine to support the neural changes. Another important factor making this system unique is the inability of the amygdala to become incorporated into the infant learning circuit. Thus, infant rats appear to be primed in early life to learn odors that will evoke approach responses supporting attachment to the caregiver.
Asunto(s)
Amígdala del Cerebelo/fisiología , Señales (Psicología) , Aprendizaje Discriminativo/fisiología , Conducta Alimentaria/fisiología , Locus Coeruleus/fisiología , Odorantes , Bulbo Olfatorio/fisiología , Animales , Animales Recién Nacidos , Femenino , Plasticidad Neuronal/fisiología , Norepinefrina/fisiología , RatasRESUMEN
The involvement of the noradrenergic system, imidazoline, dopaminergic and adenosinergic receptors in the antidepressant-like action of tramadol in the mouse forced swimming test (FST) was evaluated in this study. The antidepressant-like effect of tramadol (40mg/kg, per oral, p.o.) in the FST was blocked with yohimbine (1mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), alpha-methyl-para-tyrosine methyl ester (AMPT, 100mg/kg, i.p., an inhibitor of tyrosine hydroxylase), efaroxan (1mg/kg, i.p., an imidazoline I(1)/alpha(2)-adrenoceptor antagonist), idazoxan (0.06mg/kg, i.p., an imidazoline I(2)/alpha(2)-adrenoceptor antagonist), antazoline (5mg/kg, i.p., a ligand with high affinity for the I(2) receptor), haloperidol (0.2mg/kg, i.p., a non selective dopamine receptor antagonist), SCH23390 (0.05mg/kg, subcutaneously, s.c., a dopamine D(1) receptor antagonist), sulpiride (50mg/kg, i.p., a dopamine D(2) and D(3) receptor antagonist) but was not reversed by prazosin (1mg/kg, intraperitoneally, i.p., an alpha(1)-adrenoceptor antagonist) and caffeine (3mg/kg, i.p., a nonselective adenosine receptor antagonist). Monoamine oxidase-A and -B (MAO-A and MAO-B) activities were neither inhibited in the whole brain nor in specific brain regions of mice treated with tramadol. These data demonstrated that the antidepressant-like effect caused by oral administration of tramadol in the mouse FST is mediated by the noradrenergic system, dopaminergic and imidazoline receptors.
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Antidepresivos/uso terapéutico , Receptores de Imidazolina/fisiología , Norepinefrina/fisiología , Receptores Dopaminérgicos/fisiología , Tramadol/uso terapéutico , Animales , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Depresión/psicología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Receptores Adrenérgicos/fisiología , Tramadol/farmacologíaRESUMEN
The brain noradrenergic system has been implicated in the expression of defensive behaviors elicited by acute stress. The dorsal periaqueductal gray area (dPAG) is a key structure involved in the behavioral and cardiovascular responses elicited by fear and anxiety situations. Although there are noradrenergic terminals in the dPAG, few studies have investigated the role of noradrenaline (NA) in the dPAG on anxiety modulation. The aim of this study was to evaluate the effect of NA microinjection into the dPAG of rats subjected to two animal models of anxiety, the elevated plus-maze and the Vogel conflict test. Male Wistar rats implanted with a guide cannula aimed at the dPAG received microinjections of NA (3, 15, or 45 nmol/0.05 microl) or artificial cerebral spinal fluid into the dPAG immediately before being exposed to the elevated plus-maze or the Vogel conflict test. NA increased the exploration of the open arms and the number of enclosed arm entries in the elevated plus-maze. The increase in open arm exploration remained significant after being subjected to an analysis of covariance using the latter variable as covariate. Moreover, the NA microinjection into the dPAG did not increase general exploratory activity of animals subjected to the open-field test, indicating that the increase in open arm exploration cannot be attributed to a nonspecific increase in exploratory activity. In the Vogel test, the NA microinjection into the dPAG increased the number of punished licks without changing the number of nonpunished licks or interfering with the tail-flick test. The results, therefore, indicate that the NA microinjection into the dPAG produces anxiolytic-like effects, suggesting its possible involvement in the anxiety modulation.
Asunto(s)
Ansiedad/fisiopatología , Conflicto Psicológico , Conducta Exploratoria/efectos de los fármacos , Norepinefrina/fisiología , Sustancia Gris Periacueductal/fisiopatología , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/farmacología , Ansiedad/metabolismo , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Masculino , Microinyecciones , Norepinefrina/administración & dosificación , Norepinefrina/farmacología , Sustancia Gris Periacueductal/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
OBJETIVO: Revisar os artigos sobre substratos neurobiológicos dos transtornos do controle dos impulsos. O jogo patológico é o foco central desta revisão na medida em que a maioria dos estudos biológicos dos formalmente classificados como transtornos do controle dos impulsos examinou este transtorno. MÉTODO: Foi feita uma busca no banco de dados Medline de artigos publicados de 1966 até o presente para identificar aqueles relevantes para serem revisados neste artigo. DESFECHOS: Estudos pré-clínicos sugerem que a neuromodulação das monoaminas cerebrais está associada à tomada de decisões impulsivas e aos comportamentos de risco. Os estudos clínicos implicam diversos sistemas de neurotransmissores (serotoninérgico, dopaminérgico, adrenérgico e opióide) na fisiopatologia do jogo patológico e de outros transtornos do controle dos impulsos. Estudos de neuroimagem preliminares têm indicado o córtex pré-frontal ventromedial e o estriato ventral como atuantes na fisiopatologia do jogo patológico e de outros transtornos do controle dos impulsos. As contribuições genéticas para o jogo patológico parecem substanciais e os estudos iniciais têm relacionado esse transtorno a polimorfismos alélicos específicos, ainda que os achados de varredura genômica ainda tenham que ser publicados. CONCLUSÃO: Mesmo que tenham sido logrados avanços significativos em nossa compreensão sobre os transtornos do controle dos impulsos, mais pesquisas são necessárias para ampliar o conhecimento existente e traduzir esses achados em avanços clínicos.
OBJECTIVE: To review the neurobiological substrates of impulse control disorders. Pathological gambling is a main focus of the review in that most biological studies of the formal impulse control disorders have examined this disorder. METHOD: The medical database Medline from 1966 to present was searched to identify relevant articles that were subsequently reviewed to generate this manuscript. RESULTS: Preclinical studies suggest that differential brain monoamine neuromodulation is associated with impulsive decision-making and risk-taking behaviors. Clinical studies implicate multiple neurotransmitter systems (serotonergic, dopaminergic, adrenergic, and opioidergic) in the pathophysiology of pathological gambling and other impulse control disorders. Initial neuroimaging studies have implicated the ventromedial prefrontal cortex and ventral striatum in the pathophysiology of pathological gambling and other impulse control disorders. Genetic contributions to pathological gambling seem substantial and initial studies have implicated specific allelic polymorphisms, although genome-wide analyses have yet to be published. CONCLUSION: Although significant advances have been made in our understanding of the neurobiology of impulse control disorders, more research is needed to extend existing knowledge and translate these findings into clinical advances.