RESUMO
The effect induced by noradrenaline (NA) on the spiking activity evoked by glutamate (Glu) on single neurons of the mesencephalic red nucleus (RN) of the rat was studied extracellularly. Long-lasting microiontophoretic applications of the amine induced a significant and reversible depression of the responsiveness of RN neurons to Glu. This effect was mediated by noradrenergic alpha2 receptors since it was mimicked by application of clonidine, an alpha2 adrenoceptor agonist, and blocked or at least reduced by application of yohimbine, an antagonist of NA for the same receptors. The effect appears homogeneously throughout the nucleus and is independent of the effect of NA on baseline firing rate. Application of isoproterenol, a beta adrenoceptor agonist, either enhanced or depressed neuronal responses to Glu in a high percentage (86%) of the tested neurons. Moreover, application of timolol, a beta adrenoceptor antagonist, was able to strengthen the depressive effects induced by NA application on neuronal responsiveness to Glu. Although these data suggest some involvement of beta adrenergic receptors in the modulation of neuronal responsiveness to Glu, the overall results indicate a short-term depressive action of NA, mediated by alpha2 receptors, on the responsiveness of RN neurons and suggest that stress initially leads to an attenuation of the relay function of the RN.
Assuntos
Ácido Glutâmico/metabolismo , Neurônios/fisiologia , Norepinefrina/metabolismo , Núcleo Rubro/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Masculino , Microeletrodos , Neurônios/efeitos dos fármacos , Ratos Wistar , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos beta/metabolismo , Núcleo Rubro/efeitos dos fármacosRESUMO
Excitatory responses evoked by N-methyl-d-aspartate (NMDA) in the vestibular nuclei (VN) of the rat were studied in vivo during microiontophoretic application of noradrenaline (NA) and/or its agonists and antagonists. Ejection of NA-modified excitatory responses mediated by NMDA receptors (NMDAR) in all neurons tested; the effect was enhancement in 59% of cases and depression in the remaining 41%. Enhancements prevailed in all VN with the exception of the lateral vestibular nucleus, where both effects were recorded in an equal number of cases. The enhancing action of NA on NMDAR-mediated responses was mimicked by the noradrenergic beta-receptor agonist isoproterenol, the beta1 specific agonist denopamine and the alpha2 agonist clonidine. These effects were blocked respectively by the generic beta-receptor antagonist timolol, the beta1 antagonist atenolol and the alpha2 antagonist yohimbine. In contrast, application of the alpha1 receptor agonist cirazoline and the specific alpha1 antagonist prazosin respectively mimicked and partially antagonized the depression of NMDAR-mediated excitations induced by NA. Double-labeling immunohistochemical techniques demonstrated broad colocalization of NMDAR (specifically NR1 and NR2 subunits) with noradrenergic receptors (alpha1, alpha2 and beta1) in many VN neurons; only minor differences were found between nuclei. These results indicate that NA can produce generalized modulation of NMDAR-mediated excitatory neurotransmission in VN, which may in turn modify synaptic plasticity within the nuclei.
Assuntos
Neurônios/fisiologia , Norepinefrina/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Núcleos Vestibulares/metabolismo , Animais , Fenômenos Eletrofisiológicos , Imuno-Histoquímica , Masculino , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Norepinefrina/agonistas , Norepinefrina/antagonistas & inibidores , Ratos , Ratos Wistar , Receptores Adrenérgicos/análise , Receptores Adrenérgicos/metabolismo , Receptores de N-Metil-D-Aspartato/análise , Núcleos Vestibulares/efeitos dos fármacosRESUMO
The authors describe the case of a child with craniofrontonasal syndrome (CFNS) (MIM 304110), the diagnostic process performed, the identification of the main clinical features in the proband (hypertelorism, facial asimmetry, bifid nasal tip, corpus callosum hypoplasia, broad thumb, curly and wiry hair), and the comparison with known data in literature. They also describe the detection, through gene sequencing of EFNB1, of responsible mutation and its correlation with the phenotypic variants. They explain the etiophatogenetic basis of the "unusual" inheritance pattern of CFNS: X-linked disease that occurs with greater severity in heterozygous females than hemizygous males. Finally, attention is placed on the need for careful genetic counseling for patients with CFNS, with special care in familial anamnesis taking. In the studied case, the presence of abnormalities of thumbs in the proband's mother and in two of her cousins, orientates principally toward a mutation of maternal origin or to a suspected somatic and germline mosaicism by creating a recurrence risk greater than general population. Because patients with CFNS reported in the literature are few, the AA consider that the observed case may help to improve understanding of the mechanisms of gene expression responsible for the syndrome, of its peculiar phenotypic manifestations and of its frequency in the population with known and easy to assign phenotypes, and possible mosaicisms that are difficult to detect.
Assuntos
Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/diagnóstico , Feminino , Humanos , Recém-Nascido , Linhagem , FenótipoRESUMO
AIM: To verify the involvement of free radicals in tumor progression and to investigate the effects of an ethanolic extract of Ruta Chalepensis L. and of rutin in blood of patients with colon cancer. MATERIALS AND METHODS: Leaves of Ruta Chalepensis L. were collected in the area around Catania (Italy). For the preparation of the ethanol extract of leaves, an exhaustive extraction of 100 g of the drug was carried out in Soxhlet with 800 ml of 95% ethanol. Fifty-six patients with colorectal cancer were randomly selected for this study; among these, 34 were affected by an early stage (T1 N0 M0 according to scale), while 22 were affected by an advanced stage (T4, N1-2, M0) of cancer. Data obtained from these patients were compared with those of a control group consisting of 20 healthy subjects. Plasma of each sample was used for determining non-proteic antioxidant capacity, thiol groups, lipid hydroperoxides and nitrite/nitrate levels, evaluated by spectrophotometric tests. In addition, percentage of haemolysis was evaluated incubating (for 2 hours at 37 degrees C) erythrocyte suspension with a free radical donor (50 mM 2,2'-azobis-amidino propane chloridrate), in the presence or absence of ethanolic extract of Ruta Chalepensis L. (250 microg/ml) or rutin (1 mM). RESULTS: Non-proteic antioxidant capacity was significantly lower in cancerous patients than in healthy subjects (p < 0.001). This decrease was stage-related. In fact, non-proteic antioxidant capacity resulted lower in advanced than in early colorectal cancer (p < 0.001). The same significant stage-related decrease was observed in plasma thiol groups (p < 0.001). Coherently with the decrease in non-proteic antioxidant capacity and thiol groups, higher levels of lipid hydroperoxides and nitrite/nitrate were observed in patients with colorectal cancer with respect to healthy subjects (p < 0.001) and the increase in these markers of oxidative stress was related to the cancer stadiation. Neoplastic patients also showed an increased percentage of oxidative hemolysis respect to controls and the haemolytic damage was correlated with the stage of colon cancer. Both the extract of Ruta Chalepensis L. and rutin were able to protect erythrocytes from oxidative stress induced by the free radical donor, but the extract of Ruta Chalepensis L. was more effective than rutin. This protective effect was significant only in erythrocytes from patients with early colorectal group, whereas no significant modification was induced by Ruta Chalepensis L. or rutin in red blood cells from advanced colorectal cancer patients exposed to the same experimental conditions. CONCLUSION: Oxidative stress correlates with colon cancer stadiation and both the extract of Ruta chalepensis and rutin are able to protect red blood cells from radical-induced damage. However, their effects are significant in early stages of cancer. So these natural antioxidants might be usefull to prevent carcinogenesis and/or tumor progression.
Assuntos
Antioxidantes/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Ruta , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse OxidativoRESUMO
This article reports the case of newborn with multiple dimorphisms (microcephaly, hypertelorism, wide and flat nasal bridge, small nose, long philtrum, microretrognathia, malformed and low-set ears, short neck, redundant nuchal skin, genital anomalies), admitted in the hospital after two days from delivery for torpor, poor food and cyanosis. Babies were affected, at color-Doppler echocardiography, by coarctation of the aorta (CoA) with aortic arch hypoplasia. CoA is often associated to genetic and environmental factors that interact frequently. In this study the anamnestic absence of teratogen noxae and the presence of facial and genital anomalies suggest a genetic study to provide appropriate genetic information to parents. G-banding chromosomic analysis revealed a 46, XX der 4t(4;11) karyotype with partial 11q trisomy confirmed with FISH chromosome painting 4;11 and with FISH subtelomere specific 4(p/q)11(p/q). These techniques showed that derivative chromosome 4 was constituted by chromosome 4 with partial deletion in the q35 region and by 11q21 translocation. This rare anomaly is often inherited by an unbalanced segregation of a balanced translocation, present in one of the two parents. In the present study, the father carried a t(4q;11q) balanced translocation. A CGH-array analysis was executed to the child for the breakpoints definition. As 11q trisomy cases reported in literature are still few, this case can contribute to improve our knowledge on the genotype-phenotype correlation in this rare genetic anomaly.
Assuntos
Aorta Torácica/anormalidades , Coartação Aórtica/complicações , Deleção Cromossômica , Coartação Aórtica/genética , Cromossomos Humanos Par 11 , Feminino , Humanos , Recém-Nascido , Fenótipo , TrissomiaRESUMO
The effects of noradrenaline (NA) on the inhibitory responses to GABA were studied in vivo in neurons of the vestibular nuclei of the rat using extracellular recordings of single unit electrical activity and a microiontophoretic technique of drug application in loco. NA application influenced GABA-evoked inhibitions in 82% of tested neurons, depressing them in 42% and enhancing them in 40% of cases. The more frequent action of NA on GABA responses was depressive in lateral and superior vestibular nuclei (50% of neurons) and enhancing in the remaining nuclei (56% of neurons). The most intense effect of NA application was the enhancement of GABA responses induced in a population of lateral vestibular nucleus neurons, characterized by a background firing rate significantly higher than that of other units. The alpha(2) noradrenergic receptor agonist clonidine mimicked the enhancing action of NA on GABA responses; this action was blocked by application of the specific alpha(2) antagonist yohimbine. The beta adrenergic agonist isoproterenol induced either depressive or enhancing effects on GABA responses; the former more than the latter were totally or partially blocked by application of the beta antagonist timolol. It is concluded that NA enhances GABA responses by acting on noradrenergic alpha(2) and to a lesser extent beta receptors, whereas depressive action involves beta receptors only. These results confirm the hypothesis that the noradrenergic system participates in the regulation of the vestibulospinal and the vestibulo-ocular reflexes and suggest that conspicuous changes of NA content in brain due to aging or stress could lead to a deterioration in the mechanisms of normal vestibular function.
Assuntos
Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Norepinefrina/farmacologia , Núcleos Vestibulares/citologia , Ácido gama-Aminobutírico/farmacologia , Potenciais de Ação/efeitos dos fármacos , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Clonidina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Iontoforese/métodos , Isoproterenol/farmacologia , Ratos , Ratos Wistar , Timolol/farmacologia , Ioimbina/farmacologiaRESUMO
The effects induced on neuronal firing by microiontophoretic application of the biological amines noradrenaline (NA) and 5-hydroxytryptamine (5-HT) were studied "in vivo" in ventral-anterior (VA) and ventrolateral (VL) thalamic motor nuclei of anaesthetized rats. In both nuclei the amines had a mostly depressive action on neuronal firing rate, the percentage of units responsive to NA application (88%) being higher than to 5-HT (72%). Short-lasting (less than 2 min) and long lasting (up to 20 min) inhibitory responses were recorded, the former mostly evoked by NA and the latter by 5-HT ejection. In some cases 5-HT application had no effect on the firing rate but modified the firing pattern. NA-evoked responses were significantly more intense in VL than in VA neurons. Short-lasting inhibitory responses similar to NA-induced effects were evoked by the alpha2 adrenergic receptor agonist clonidine and to a lesser extent by the beta adrenergic receptor agonist isoproterenol. Inhibitory responses to 5-HT were partially mimicked by application of the 5-HT(1A) receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) and of the 5-HT2 receptor agonist alpha-methyl-5-hydroxytryptamine (ALPHA-MET-5-HT). The latter evoked excitatory responses in some cases. Both 5-HT agonists were more effective on VA than on VL neurons. The effects evoked by agonists were at least partially blocked by respective antagonists. These results suggest that although both 5-HT and NA depress neuronal firing rate, their effects differ in time course and in the amount of inhibition; besides aminergic modulation is differently exerted on VA and VL.
Assuntos
Potenciais de Ação/fisiologia , Vias Aferentes/metabolismo , Aminas Biogênicas/metabolismo , Neurônios/metabolismo , Núcleos Ventrais do Tálamo/metabolismo , Potenciais de Ação/efeitos dos fármacos , Antagonistas Adrenérgicos/farmacologia , Animais , Gânglios da Base/fisiologia , Aminas Biogênicas/farmacologia , Cerebelo/fisiologia , Locus Cerúleo/metabolismo , Córtex Motor/fisiologia , Movimento/fisiologia , Neurônios/efeitos dos fármacos , Norepinefrina/metabolismo , Norepinefrina/farmacologia , Núcleos da Rafe/metabolismo , Ratos , Ratos Wistar , Serotonina/metabolismo , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologiaRESUMO
The effects of 5-hydroxytryptamine (5-HT) on neuronal firing rate were studied in the reticular gigantocellular nucleus (GRN) and, for a comparison, in the interstitial (IRN), the parvicellular (PRN) and the lateral (LRN) nuclei, sharing some of GRN functional characteristics. Unitary extracellular recordings performed in anesthetized rats demonstrated that microiontophoretic application of 5-HT modulated the background firing rate in 92% of GRN, in 100% of IRN and LRN, and in 77% of PRN tested neurons. In GRN, 5-HT application induced excitatory responses in 49% of the neurons tested and inhibitions in 43% of them. Both types of effects were dose dependent and appeared scattered throughout the nucleus. Enhancements and decreases of firing rate in response to 5-HT application were also recorded in IRN (58% and 42% respectively), LRN (43% and 57%) and PRN (36% and 41%). The 5-HT(1A) receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) mimicked 5-HT evoked inhibitions in all the nuclei tested and induced weak inhibitory responses also in neurons excited by 5-HT. The 5-HT2A receptor agonist alphamethyl-5-hydroxytryptamine (alpha-me-5-HT) mimicked excitatory as well as inhibitory responses to 5-HT, the former prevailing in GRN and the latter in the remaining reticular nuclei. Both excitatory and inhibitory responses to 5-HT were partially or totally blocked by the application of 5-HT2 receptor antagonist ketanserin. It is concluded that an extended, strong and differentiated control is exerted by 5-HT on the electrical activity of bulbar reticular neurons. Both 5-HT(1A) and 5-HT(2A) receptors mediate these effects, but the involvement of other receptors appears probable.
Assuntos
Potenciais de Ação/fisiologia , Bulbo/fisiologia , Neurônios/fisiologia , Formação Reticular/fisiologia , Serotonina/fisiologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/fisiologia , Bulbo/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Formação Reticular/efeitos dos fármacos , Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
The pituitary hormone prolactin (PRL) is a multifunctional polypeptide which exerts a role on cell proliferation and may also contribute to cell differentiation. PRL is also produced by immune cells and is regarded as a key component of the neuroendocrine-immune loop and as a local regulator of macrophage response. The involvement of PRL in regulating monocyte/macrophage functions is suggested by the presence of PRL receptors in these cells. It has been shown that PRL possess both angiogenic and antiangiogenic effects. Recently, we revealed that augmentation of HO-1 activity enhances PRL-mediated angiogenesis in human endothelial cells. Since macrophages are key participants in angiogenesis our objective was to investigate the effect of PRL also in human macrophages. In vitro treatment of macrophages with PRL was found to increase both heme oxygenase-1 (HO-1) expression and protein synthesis in a time and dose dependent manner as quantified respectively by reverse-transcriptase real-time polymerase chain reaction and Western blot analysis. PRL-treated macrophages also showed an enhanced release of vascular endothelial growth factor (VEGF) as demonstrated by ELISA assay. Furthermore, to determine whether PRL-induced HO-1 activity was required for VEGF production by macrophages, the effect of PRL on the induction of VEGF was studied in the presence of an inducer stannic chloride (SnCl(2)) and of an inhibitor stannic mesoporphyrin (SnMP) of HO activity. Our observations suggest that PRL may regulate monocyte activation and influences not only immune function but also angiogenesis.
Assuntos
Heme Oxigenase (Desciclizante)/metabolismo , Macrófagos/efeitos dos fármacos , Prolactina/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Western Blotting , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Heme Oxigenase-1 , Humanos , Macrófagos/metabolismo , Proteínas de Membrana , Metaloporfirinas/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxidos/metabolismo , Compostos de Estanho/farmacologiaRESUMO
Human chitotriosidase (Chit), a chitinolytic enzyme, is a member of the chitinase family. In human's plasma Chit activity have been proposed as a biochemical marker of macrophage activation in several lysosomal diseases. Recently we found that Chit activity is higher in patients affected by Plasmodium falciparum malaria infection suggesting that chitotriosidase may induce an immunological response. The pituitary hormone prolactin (PRL) is a multifunctional polypeptide also produced by immune cells and represents a key component of the neuroendocrine-immune loop. The presence of PRL receptors in macrophage suggests that PRL is involved in regulating functions in these cells. Our objective in this study was to investigate the effect of PRL in human monocyte-derived macrophages (HMMs) on Chit production. Administration of PRL in HMMs was found to increase both expression and activity of Chit in a time and dose dependent manner as quantified, respectively, by real time PCR and Chit activity assay. PRL-treated monocyte-derived macrophages showed also an enhanced release of superoxide anion (O2-) release. Our observations confirm that PRL regulates HMMs activation and suggest, for the first time, that it influences immune function also through the induction of Chit activity.
Assuntos
Hexosaminidases/biossíntese , Macrófagos/enzimologia , Prolactina/farmacologia , Células Cultivadas , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Hexosaminidases/genética , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Monócitos/citologia , Prolactina/fisiologia , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Oxigênio Singlete/análiseRESUMO
In mesencephalic red nucleus (RN), GABA-induced inhibition of neuronal firing is modulated by noradrenaline acting on alpha2- and beta-adrenoceptors. Since both GABAA and GABAB receptors are present in the rat RN, we have recorded the firing activity of RN neurons in vivo from anaesthetized rats to study how GABAA- and GABAB-mediated effects are modulated by either alpha2- or beta-adrenoceptor activation. Both the GABAA agonist isoguvacine and the GABAB agonist baclofen depressed the firing of RN neurons. During simultaneous application of clonidine, an alpha2-adrenoceptor agonist, half of the isoguvacine- and baclofen-mediated responses were modified: isoguvacine-mediated inhibition was enhanced by 97% without any change in effect duration, whereas baclofen responses were either increased or slightly reduced in the same number of cases. Application of isoprenaline, a beta-adrenoceptor agonist, increased isoguvacine effect in 66% of neurons without modifying effect duration; the amount of increase (43%) was significantly lower than that induced by clonidine. On the other hand, in the presence of isoprenaline, baclofen response was reduced in 72% of neurons with respect to both the amount (52%) and the duration (34%) of effect. Taken together, these results indicate that alpha2-adrenoceptors mainly enhance GABAA-induced inhibition and induce mixed effects on GABAB response; on the other side, beta-adrenoceptors exert an opposite modulation on GABA effects, respectively, enhancing and depressing GABAA- and GABAB-mediated responses.
Assuntos
Inibição Neural/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Receptores Adrenérgicos beta/fisiologia , Receptores de GABA-A/fisiologia , Receptores de GABA-B/fisiologia , Núcleo Rubro/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Agonistas de Receptores Adrenérgicos alfa 2 , Animais , Clonidina/farmacologia , Isoproterenol/farmacologia , Masculino , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Wistar , Núcleo Rubro/efeitos dos fármacosRESUMO
The excitatory responses evoked by glutamate and its agonists in secondary vestibular neurons of the rat were studied during microiontophoretic application of 5-hydroxytryptamine (5-HT). Ejection of 5-HT modified neuronal responsiveness to glutamate in 86% of the studied units, the effect being a depression of the excitatory responses in two-thirds of cases and an enhancement in the remaining third. 5-HT was also effective in modifying 94% of the responses evoked by N-methyl-d-aspartate (NMDA), inducing a depressive effect in 76% of cases and an enhancement in the remaining ones. Quisqualate-evoked effects were depressed and enhanced by 5-HT in about the same number of cases; in contrast, kainate-evoked responses were enhanced. The depressive action of 5-HT was mimicked by application of alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT), a 5-HT(2) receptor agonist, whereas the enhancing effect could be evoked by application of 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT(1A) receptor agonist. The 5-HT(2) receptor antagonist ketanserin was able to reduce, but not to block totally, the depressive action of 5-HT on glutamate- or NMDA-evoked responses. No significant difference was detected between neuronal responses in the lateral and the superior vestibular nucleus. These results indicate that 5-HT is able to modulate the responsiveness of secondary vestibular neurons to excitatory amino acids. Its action is mostly depressive, involves 5-HT(2) receptors, and is exerted on NMDA receptors. A minor involvement of other 5-HT receptors (at least 5-HT(1A)) and other glutamate receptors (for quisqualate and kainate) in the modulatory action of 5-HT is plausible.
Assuntos
Ácido Glutâmico/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Serotonina/farmacologia , Núcleos Vestibulares/efeitos dos fármacos , Núcleos Vestibulares/fisiologia , Animais , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/fisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Ácido Caínico/farmacologia , N-Metilaspartato/farmacologia , Ácido Quisquálico/farmacologia , Ratos , Ratos Wistar , Receptores de Aminoácido/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Núcleos Vestibulares/citologiaRESUMO
The effects of 5-hydroxytryptamine (5-HT) on the inhibitory responses evoked by gamma-aminobutyric acid (GABA) in neurons of the red nucleus (RN) were studied using a microiontophoretic technique. Extracellular unitary recordings performed in anesthetized rats demonstrated that 5-HT ejection influenced GABA-evoked inhibition in 94% of RN neurons, enhancing them in 52% and depressing them in 46% of cases. Both effects were specific and dose-dependent,although enhancements or depressions of the GABA responses were respectively inversely and directly related to the doses of 5-HT applied. The type of modulation exerted by 5-HT on the GABA responses was independent of the action of the amine on background firing. In fact, 5-HT induced an enhancement of the GABA responses in neurons mostly located in the rostral RN and a depression in those in the caudal RN. The application of 8-hydroxy-2(di-n-propylamino)tetralin, a specific 5-HT(1A) receptor agonist, enhanced GABA responses, whereas alpha-methyl-5-hydroxytryptamine, a 5-HT(2A) receptor agonist, depressed them. Both the 5-HT(2) antagonist methysergide and the 5-HT(2A) selective antagonist ketanserin were able to block partially or totally the depressive action of 5-HT on GABA responses. In contrast, the same 5-HT antagonists mimicked the enhancing action of 5-HT on the GABA responses or were ineffective. Application of bicuculline, a GABA(A) receptor antagonist, enhanced the excitatory action of 5-HT on the background firing and slightly reduced the inhibitory action. It is concluded that 5-HT is able to modulate GABA-evoked responses in RN neurons by acting on both 5-HT(1A) and 5-HT(2A) receptors. The functional significance of a serotonergic control on GABAergic inhibitory effects in RN is discussed.
Assuntos
Inibição Neural/fisiologia , Neurônios/metabolismo , Núcleo Rubro/metabolismo , Serotonina/metabolismo , Ácido gama-Aminobutírico/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Mapeamento Encefálico , Relação Dose-Resposta a Droga , Antagonistas GABAérgicos/farmacologia , Antagonistas de Receptores de GABA-A , Iontoforese , Inibição Neural/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Receptor 5-HT2A de Serotonina , Receptores de Serotonina/efeitos dos fármacos , Receptores 5-HT1 de Serotonina , Núcleo Rubro/citologia , Núcleo Rubro/efeitos dos fármacos , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Ácido gama-Aminobutírico/farmacologiaRESUMO
The electrical activity of neurons from the red nucleus, a mesencephalic structure involved in motor control, is under the influence of several neurotransmitters released from afferent fibers and/or from local interneurons. We have investigated the combined effects of gamma-aminobutyric acid (GABA) and noradrenaline (NA), both present at high levels in the red nucleus, on the firing activity of single rubral neurons recorded extracellularly in vivo on anesthetized adult rats. NA inhibited the firing activity of a large part of rubral neurons and induced excitatory or biphasic inhibitory/excitatory effects in a smaller group of cells. Neuronal firing was also inhibited by GABA in all the cells studied. When the effect of GABA was tested during continuous applications of NA, the magnitude of GABA response was modified in 58% of the cells: the effect of GABA was potentiated by NA in half of the responding neurons and was decreased in the remaining half. NA-induced potentiation of GABA response was mimicked by the alpha(2)-adrenoceptor agonist clonidine and was abolished by the alpha(2)-adrenoceptor antagonist yohimbine. On the other side, the decrease of GABA response was reproduced by the beta-adrenoceptor agonist isoprenaline and was blocked by timolol, an antagonist of beta-adrenoceptors. Neuronal firing activity was reduced by nipecotic acid, an inhibitor of GABA reuptake mechanism, and was instead increased during application of the GABA(A) receptor antagonist bicuculline, suggesting that rubral neurons in vivo were under tonic control by endogenous GABA. Both the inhibitory and the excitatory effects of NA were reduced in the presence of nipecotic acid and were instead potentiated during application of bicuculline, suggesting that NA responses were modified by endogenous GABA. Taken together, our results indicate a reciprocal modulation between the effects of GABA and NA on neuronal firing activity in the red nucleus of the rat: GABA depresses the responsiveness of rubral neurons to NA, whereas NA is able either to potentiate or to decrease the effects of GABA by activation of alpha(2)- and beta-adrenoceptors, respectively. The functional significance of such interaction, as well as the possible implication in diseases affecting motor control, will be discussed.
Assuntos
Neurônios/metabolismo , Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Núcleo Rubro/metabolismo , Ácido gama-Aminobutírico/metabolismo , Potenciais de Ação/efeitos dos fármacos , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Bicuculina/farmacologia , Clonidina/farmacologia , Sinergismo Farmacológico , Antagonistas GABAérgicos/farmacologia , Iontoforese , Isoproterenol/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Neurotransmissores/farmacologia , Ácidos Nipecóticos/farmacologia , Norepinefrina/farmacologia , Ratos , Ratos Wistar , Núcleo Rubro/efeitos dos fármacos , Timolol/farmacologia , Ioimbina/farmacologia , Ácido gama-Aminobutírico/farmacologiaRESUMO
Electromyographic responses (EMGs) of limb muscles were studied during microiontophoretic application of 5-hydroxytryptamine (5-HT) into the lateral vestibular nucleus (LVN) or the spinal vestibular nucleus (SpVe) of anaesthetized rats. The aim was to ascertain whether the level of 5-HT in these nuclei was able to modulate muscle responsiveness. Increased levels of 5-HT in LVN (and to a weaker extent in SpVe) enhanced the EMGs of proximal extensor muscles and depressed those of flexors. The 5-HT2A receptor antagonist ketanserin, applied into the LVN, prevented 5-HT effects on EMG-evoked responses. It is concluded that 5-HT can modulate the motor output via the vestibulospinal pathway, exerting a differential control over flexor and extensor muscles.
Assuntos
Eletromiografia/efeitos dos fármacos , Serotonina/farmacologia , Núcleos Vestibulares/fisiologia , Animais , Membro Anterior/fisiologia , Iontoforese , Ketanserina/farmacologia , Movimento/efeitos dos fármacos , Movimento/fisiologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Núcleos Vestibulares/efeitos dos fármacosRESUMO
The effects of 5-hydroxytryptamine (5-HT) on the responses of red nucleus (RN) neurones to glutamate (glu) and its agonists were studied using a microiontophoretic technique in anaesthetised rats. Extracellular unitary recordings of RN neuronal activity showed that 5-HT application induced a significant and reversible depression of glu-evoked excitations in 85% of the RN units tested. This effect was independent of the action of the amine on background firing, which appeared enhanced in the majority of cases but was either depressed or uninfluenced in other cases. Microiontophoretic 5-HT also depressed the excitatory responses evoked in RN neurones by electrical stimulation of sensorimotor cortex. Methysergide application, which prevented the enhancing effects of 5-HT on the background firing, was scarcely effective in antagonising the depression of glu responses. In contrast, the serotonergic effects on the glu responses were reduced by the iontophoretically applied antagonist of 5-HT1A receptors, NAN-190. Microiontophoretic 5-HT was also able to influence the neuronal responses evoked by glu agonists quisqualate (quis) and N-methyl-D-aspartate (NMDA), acting on non-NMDA and NMDA receptors respectively. In fact 5-HT depressed quis-evoked excitations and induced mixed effects on NMDA responses, which were reduced in 45%, enhanced in 34% and unmodified in 21% of the units tested. These results suggest that 5-HT is able to modulate the motor glutamatergic input to RN by acting mostly on non-NMDA receptors. The modulation of non-NMDA and NMDA receptors by 5-HT in the RN appears significant and its functional meaning is discussed.
Assuntos
Ácido Glutâmico/farmacologia , Neurônios/efeitos dos fármacos , Núcleo Rubro/efeitos dos fármacos , Serotonina/farmacologia , Animais , Estimulação Elétrica , Iontoforese , Masculino , Ratos , Ratos Wistar , Receptores de AMPA/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacosRESUMO
We have investigated the effects of noradrenaline (NA) on the spontaneous firing activity of red nucleus (RN) neurons recorded extracellularly in anesthetized rats by using an in vivo electrophysiological technique. Microiontophoretic applications of NA (5-100 nA for 30 s) modified the background firing rate in 99 out of 124 neurons and three different patterns of response were observed in distinct cells. In 61% of the responding neurons NA decreased the mean firing rate, whereas 22% of the neurons responded to NA application with an increase of their spiking activity; in a smaller group of cells (17%) NA exerted a biphasic inhibitory/excitatory effect on the spontaneous firing rate. The effects of NA were reversible and dose-dependent. From histological examination, the neurons responding to NA with a purely inhibitory effect were scattered throughout the RN. On the other hand, the neurons responding to NA with an excitation were found to be more numerous in the dorso-medial part of the RN, whereas the neurons in which NA induced biphasic effects appeared to be segregated in the outer lateral portion of the RN. The alpha 2-adrenoceptor antagonist yohimbine completely blocked the inhibitory effect of NA but was unable to antagonize the excitatory response. In addition, the inhibitory effect of NA was mimicked by clonidine, a selective agonist of alpha 2-adrenoceptors; clonidine had no effect on those cells which responded to NA with an increase of the mean firing rate. The excitatory effect of NA was mimicked by the beta-receptor agonist isoprenaline and was antagonized by timolol, a selective antagonist of beta-adrenoceptors. Isoprenaline was ineffective in those cells in which NA exerted inhibitory responses. Taken together, our results indicate that the inhibitory effect of NA on the firing activity of rat RN neurons were mediated by alpha 2-adrenoceptors, whereas beta-adrenoceptors were responsible for the excitatory effects.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Neurônios/efeitos dos fármacos , Norepinefrina/farmacologia , Núcleo Rubro/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Anestésicos , Animais , Masculino , Ratos , Ratos Wistar , Núcleo Rubro/citologiaRESUMO
The effects of dorsal raphe (DR) electrical stimulation on the neuronal activity of vestibular nuclei were studied in anaesthetized rats. The aim was to establish whether the central systems classically involved in nociceptive functions are able to influence vestibular secondary neurons. DR activation induced modifications of the firing in 70% of the tested neurons, the percentage being similar in the lateral (LVN), superior (SVN), and spinal (SpVN) vestibular nuclei. Three different types of responses were recorded: long-lasting modifications (generally enhancements) of the mean firing rate (43%), short-latency response patterns (14%), both (43%). Short-latency response patterns were more numerous in LVN than in SVN. Iontophoretic applications of 5-HT antagonists Methysergide and Ketanserin blocked long-lasting effects but were scarcely effective on the short-latency response patterns evoked by DR stimulation. It is concluded that DR exerts a double control on secondary vestibular neurons: a generalised excitatory influence by serotoninergic fibers and a specific action mostly targeted on LVN, by nonserotoninergic pathways.
Assuntos
Neurônios/fisiologia , Núcleos da Rafe/fisiologia , Nervo Vestibular/fisiologia , Animais , Estimulação Elétrica , Eletrofisiologia , Iontoforese , Ketanserina/farmacologia , Masculino , Metisergida/farmacologia , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Wistar , Serotonina/fisiologiaRESUMO
The effects of microiontophoretic 5-hydroxytryptamine (5-HT) on the firing rate of red nucleus (RN) neurons were studied in urethane-anesthetized rats. The background discharge rate of almost all the neurons tested (97%) was modified by 5-HT, and generally increased (89%). Responses were dose dependent. Twenty-three percent of the excitatory responses were preceded by a short inhibitory phase. No significant difference in the effect of 5-HT was found between those RN neurons that project to the spinal cord and those that do not The excitatory responses to 5-HT were blocked or greatly reduced by the 5-HT antagonists methysergide and ketanserin, and were even reversed in some cases. The 5-HT2/5-HT1A antagonist spiperone, in small doses, also blocked the transient inhibitory phases in addition to the excitatory effects. In RN neurons exhibiting a short-lasting inhibition in the response to 5-HT, the 5-HT1A agonist 8-hydroxy-2(di-n-propyl-amino)tetralin (8-OH-DPAT) induced inhibitory effects. These results support the hypothesis that 5-HT exerts control throughout the RN, mostly by acting on 5-HT2 receptors. Furthermore, an influence of this amine on the electrical activity of small groups of RN neurons by 5-HT1A receptors, and eventually by different mechanisms, appears probable. The functional significance of serotoninergic control of RN neuronal activity is discussed.
Assuntos
Neurônios/fisiologia , Núcleo Rubro/efeitos dos fármacos , Serotonina/farmacologia , Potenciais de Ação/fisiologia , Animais , Estimulação Elétrica , Eletrofisiologia , Iontoforese , Masculino , Vias Neurais/citologia , Vias Neurais/fisiologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Núcleo Rubro/citologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Medula Espinal/citologia , Medula Espinal/fisiologiaRESUMO
The effects of microiontophoretic application of 5-hydroxytryptamine (5-HT) on the neuronal firing rate of the medial vestibular nucleus (MVN) were studied in anaesthetized rats. Ninety-three % of the units modified their background activity following 5-HT iontophoresis, enhancements of the firing rate being recorded in 42%, decreases in 38% and biphasic effects in 13%. 5-HT antagonists methysergide and ketanserin blocked the excitatory but not the inhibitory responses to 5-HT. These latter were, however, mimicked by 5-HT agonists 5-methoxy-N,N-dimethyltryptamine (5MeODMT) and 8-hydroxy-2(di-n-propyl-amino)tetralin (8-OH-DPAT). It is concluded that 5-HT can variously influence the background activity of MVN neurons and that 5-HT2 and probably 5-HT1A receptors are involved in the responses.