摘要:

AbstractThe effect of glutamate on c‐fosexpression in oligodendrocyte progenitors was investigated by Northern blot analysis. Glutamate caused rapid and transient induction. Both 6‐cyano‐7‐nitro‐quinoxaline‐2,3‐dione (CNQX) and 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX), two competitive non‐NMDA ionotropic receptor antagonists, reduced glutamate‐induced c‐fosexpression, whereas the NMDA antagonist MK‐801 was ineffective. In addition, the glutamate receptor agonists (±)‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid hydrobromide (AMPA) and kainate strongly induced c‐fos. However, the metabotropic receptor agonisttrans‐(±)‐1‐amino‐(1S,3R)‐cyclopentanedicarboxylic acid (trans‐(±)‐ACPD) did not increase c‐fosmRNA level and the antagonist L‐(+)‐2‐amino‐3‐phosphonopropionic acid did not block glutamate‐induced c‐fosmRNA. These findings indicate that c‐fosinduction in oligodendrocyte progenitors is mediated through the AMPA/kainate receptors, while NMDA and metabotropic receptor subtypes are not involved. Chelation of extracellular calcium by EDTA prevented glutamate‐induced c‐fosexpression. Similarly, the protein kinase C inhibitor 1‐(5‐isoquinoline‐sulphonyl)‐2‐methylpiperazine dihydrochloride (H7) and down‐regulation of protein kinase C by prolonged exposure to phorbol‐12‐myristate 13‐acetate blocked c‐fosinduction. These results suggest that induction of c‐fosthrough AMPA/kainate receptors is dependent on extracellular calcium influx and involves downstream activation of phorbol ester‐sensitive protein kinase C. The effect of glutamate on oligodendrocyte progenitor proliferation was assessed by [3H]thymidine incorporation. Glutamate and the agonists kainate and AMPA, but nottrans‐(±)‐ACPD, caused a dose‐dependent decrease in [3H]thymidine incorporation. All these pharmacological agents were not toxic to oligodendrocyte progenitors. CNQX reversed the inhibitory effects produced by glutamate and the various agonists. These results

ISSN:0953-816X    

DOI:10.1111/j.1460-9568.1995.tb01032.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractThe effect of iontophoretically applied cholecystokinin (CCK) on neurons of the neostriatum was studied in rats anaesthetized with urethane. The most frequently observed effect of the sulphated octapeptide (CCK‐8S) on striatal neurons was excitation. Spontaneously active neurons responded more often to CCK‐8S than quiescent cells. Silent, primarily non‐responsive neurons could often be stimulated with CCK‐8S using glutamate to induce an ongoing discharge. Thus, 45.8% of the 177 neurons studied changed their discharge rate by more than 30%. Certain CCK receptor antagonists could prevent the effect of CCK‐8S, fully or at least partly, in the majority of CCK‐responsive neurons. The data suggest that cholecystokinin modulates the firing of active neostriatal neurons via the CCKA or the CCKB receptor type. Furthermore, we compared neuronal responses to glutamate with those recorded during concomitant administration of CCK‐8S in order to study the interaction of both transmitters, which may be colocalized in striatal afferents. CCK‐8S mainly enhanced the excitatory effect of glutamate on striatal neurons, but in several neurons the response to glutamate was reduced. The CCKB receptor antagonist could prevent CCK‐8S from increasing the glutamate

ISSN:0953-816X    

DOI:10.1111/j.1460-9568.1995.tb01033.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractThe entorhinal cortex is a gateway to the hippocampus; it receives inputs from several cortical associative areas as well as subcortical areas. Since there is evidence showing that noradrenaline reduces the epileptic activity generated in the entorhinal cortex, we have examined the action of noradrenaline in the superficial layer of the entorhinal cortex, which is the main source of afferents to the hippocampus. In a previous study we showed that noradrenaline hyperpolarized layer II entorhinal cortex neurons and reduced global synaptic transmission via α2‐adrenoreceptors. Here we present a detailed analysis of the effect of noradrenaline on membrane resistance and on the pharmacologically isolated postsynaptic potentials in layer II entorhinal cortex neurons of mice. Noradrenaline (50 μM) hyperpolarized most layer II entorhinal cortex neurons. This hyperpolarization corresponded to an outward current with a reversal potential following the Nernst equilibrium potential for potassium. The hyperpolarizing effect of noradrenaline was blocked by 10 μM yohimbine. These observations suggest that noradrenaline activates a potassium conductance via an α2‐adrenoreceptor. Noradrenaline (10–50 μM) reversibly reduced the amplitude of the pharmacologically isolated excitatory potentials mediated by both NMDA and α‐amino‐3‐hydroxy‐5‐methyl‐isoxazole‐propionic acid (AMPA) receptors, the former being more strongly affected. Again this effect was blocked by 10 μM yohimbine. In contrast, GABAA‐mediated synaptic transmission was virtually unaffected by noradrenaline. Thus, noradrenaline appears to strongly inhibit the glutamate‐mediated synaptic transmission in the entorhinal cortex without affecting inhibitory post‐synaptic potentials. These observations suggest that α2‐adrenergic receptor agonists may exert a beneficial effect in the control of hyperexc

ISSN:0953-816X    

DOI:10.1111/j.1460-9568.1995.tb01034.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractThe free calcium concentration, [Ca2+]c, in fura‐2‐loaded rat cerebellar granule cells was investigated by digital imaging during trains of uniform field stimuli in order to compare the ability of calcium channels in somata and neurites to respond to brief, physiologically relevant depolarizations. Very few somata responded to 20 Hz trains of 1 ms pulses, while virtually all neurites showed an extensive increase which was rapidly reversed when stimulation was terminated. In contrast, both somata and neurites responded when cells were depolarized with 50 mM KCl. The field stimuli evoked a tetrodotoxin‐sensitive increase in Na+concentration in both somata and neurites. When 4‐aminopyridine, which inhibits delayed K+currents in these cells, was present during the field stimulus both somata and neurites increased their [Ca2+]c, suggesting that prolongation of the duration of depolarization is required for somatic Ca2+channel activation. The neurite response did not depend on the orientation of the neurite relative to the applied field. The neurite response was insensitive to nifedipine (1 μM) and ω‐agatoxin‐IVA (30 nM) but was uniformly inhibited by ω‐conotoxin‐GVIA (30% inhibition at 1 μM) and ω‐conotoxin‐MVIIC (44% inhibition at 5 μM). The two inhibitors were not additive. The neurite [Ca2+]cresponse was insensitive to the combination of ionotropic glutamate receptor antagonists. Field stimulation caused the exocytosis of the fluorescent probe FM1‐43 previously loaded during KCl depolarization, suggesting that presynaptic Ca2+channels contribute to the fi

ISSN:0953-816X    

DOI:10.1111/j.1460-9568.1995.tb01035.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractAcute ammonia toxicity is mediated by activation of NMDA receptors and is prevented by chronic moderate hyperammonaemia. The aim of this work was to assess whether the protective effect of chronic hyperammonaemia is due to impaired activation of the NMDA receptor. It is shown that chronic hyperammonaemia in rats decreases the binding of [3H]MK‐801 to synaptosomal membranes from the hippocampus but not the amount of NMDAR1 receptor protein as determined by immunoblotting. In primary cultures of cerebellar neurons, long‐term treatment with 1 mM ammonia also decreased significantly the binding of [3H]MK‐801. These results suggest that ammonia impairs NMDA receptor activation. To confirm this possibility we tested the effect of long‐term treatment of the cultured neurons with 1 mM ammonia on three well known events evoked by activation of the NMDA receptor: neuronal death induced by glutamate, increase in aspartate aminotransferase activity and increase in free intracellular [Ca2+]. Long‐term treatment with ammonia prevented noticeably the effects of glutamate or NMDA on all these parameters. These results indicate that long‐term treatment of neurons with 1 mM ammonia leads to impaired function of the NMDA receptor, which cannot be activated by glutamate or NMDA. Activation of protein kinase C by a phorbol ester restored the ability of the NMDA receptor to be activated in neurons treated with ammonia. This suggests that ammonia impairs NMDA receptor function by decreasing protein kinase C‐dependent ph

ISSN:0953-816X    

DOI:10.1111/j.1460-9568.1995.tb01036.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractStudies of cell lines and some cultured neurons have demonstrated potential cross‐talk between neurotrophins and their receptors; high concentrations of neurotrophins can exhibit either agonist or antagonistic actions on heterologous neurotrophin receptors. We have studied neurotrophin discrimination among the sensory neurons of the embryonic chicken trigeminal system. We show that nerve growth factor (NGF) at a concentration that is six orders of magnitude greater than that required to promote the survival of NGF‐dependent dorsomedial trigeminal ganglion (DMTG) neurons has no effect on the survival of brain‐derived neurotrophic factor (BDNF)‐dependent trigeminal mesencephalic nucleus (TMN) neurons and does not affect the dose‐response relationship of these neurons to BDNF. A similar high level of neurotrophin‐3 neither promotes the survival of BDNF‐dependent ventrolateral trigeminal ganglion neurons nor affects the dose response of these neurons to BDNF. High levels of BDNF have a negligible effect on the survival of mid‐embryonic DMTG neurons. These results show that some neurons are able to discriminate completely between neurotrophins at very high concentrations, indicating that neurotrophin responses can be far more highly specific than previou

ISSN:0953-816X    

DOI:10.1111/j.1460-9568.1995.tb01037.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractIntracellular recording from lumbar motoneurons of the neonatal rat isolated spinal cord bathed in standard saline solution was used to study membrane potential oscillations which accompanied the decay phase of excitatory postsynaptic potentials (EPSP) induced by single electrical pulses to an adjacent dorsal root. About 60% of motoneurons displayed rhythmic oscillations of 10 ± 2 mV maximal amplitude and 7 ± 0.5 Hz frequency. Ability to generate oscillations could not be correlated to the cell membrane properties or to the age of the preparation (5–13 days). The oscillation frequency was independent of membrane potential (‐100 to ‐45 mV) or of the intensity of dorsal root stimuli. The oscillation amplitude was linearly related to the cell potential within the same voltage level. Fast Fourier transform analysis showed that the power spectrum of oscillations peaked at ˜8 Hz. Electrically evoked activities and spontaneous events displayed similar cut‐off frequencies. When the cell membrane potential was steadily depolarized, a hyperpolarizing pulse applied during the decay phase of the EPSP promptly revealed the presence of oscillatory behaviour. Pharmacological block of neurokinin‐1 orN‐methyl‐D‐aspartate receptors depressed the decay phase of the EPSP and the associated oscillatory responses. It is suggested that rhythmic oscillations were probably due to summated synaptic potentials generated at the premotoneuron level and are perhaps of functional relevance to mo

ISSN:0953-816X    

DOI:10.1111/j.1460-9568.1995.tb01038.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractIntracellular recording from lumbar motoneurons of the neonatal rat spinal cordin vitrowas used to study how recently developed non‐peptide antagonists such as SR‐140333 and SR‐48698, known to block distinct subtypes of tachykinin receptors peripherally, might affect synaptic transmission elicited by electrical stimulation of dorsal root fibres. SR‐140333 (1 μM) preferentially antagonized responses mediated by an exogenously applied agonist acting on the NK1receptor subclass, while SR‐48968 (0.5 μM) preferentially reduced responses mediated by an exogenously applied agonist acting on the NK2receptor subclass. SR‐48968 did not affect fast or slow excitatory postsynaptic potentials (EPSPs) or ‘wind‐up’responses induced by repetitive, low‐frequency stimulation (mimicking certain types of nociceptive input); binding studies using this radiolabelled ligand disclosed specific binding activity (21 fmol/mg protein) selectively displaced by an NK2receptor agonist. SR‐140333 reduced the late component of fast and slow EPSPs, and of wind‐up. Pharmacological block of ionotropic glutamate receptors abolished all dorsal root‐evoked EPSPs. In comparison to glutamate receptor blockers, SR‐140333 was a weaker antagonist of slow synaptic responses, though it displayed preferential antagonism towards some components of the wind‐up phenomenon. The present results provide evidence obtained with a novel NK1antagonist that a neuropeptide (presumably substance P), although not directly released by primary afferents onto motoneurons, is a neurotransmitter (acting via NK1receptors) in the pathway mediating slow synaptic responses of motoneurons, and is presumably involved in signalling nocice

ISSN:0953-816X    

DOI:10.1111/j.1460-9568.1995.tb01039.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractA combinedin vivomicrodialysis/biotelemetry method in freely moving rats was used to study the effects of an endotoxic challenge on brain neurotransmission, hypothalamic‐pituitary‐adrenocortical (HPA) axis activity, autonomic functions and behaviour. Rats were equipped with a microdialysis probe in the preoptic area and a transmitter for biotelemetry in the peritoneal cavity. Time‐dependent changes in noradrenergic and serotonergic neurotransmission, and HPA axis activity were monitored by measuring noradrenaline, serotonin, their metabolites and free corticosterone concentrations in dialysates. Core body temperature, heart rate and locomotion were measured simultaneously by biotelemetry. In addition, total behavioural activity was scored by measuring the time during which rats were active. Intraperitoneal administration of endotoxin (lipopolysaccharide; 100 μg/kg body weight) caused a pronounced increase in preoptic extracellular concentrations of noradrenaline and its metabolite 3‐methoxy‐4‐hydroxyphenylglycol (MHPG; 500 and 400% of baseline respectively). No effect was found on preoptic concentrations of serotonin, although the levels of its metabolite 5‐hydroxyindoleacetic acid were slightly elevated (120% of baseline). Intraperitoneal lipopolysaccharide caused a marked increase in corticosterone levels, a decline in behavioural activity, and biphasic rises in body temperature and heart rate. Analysis of the time curves revealed that noradrenaline rose in parallel with the first increase in body temperature and the increase in corticosterone levels. Moreover, maximum noradrenaline levels were reached ˜60 min earlier than the peak in body temperature and corticosterone concentrations. Intraperitoneal pretreatment with the cyclo‐oxygenase inhibitor indomethacin prevented the lipopolysaccharide‐induced changes in body temperature, heart rate and behavioural activity, whereas the changes in noradrenaline, MHPG and corticosterone were largely, but not completely, reduced. Taken together, the results show that an endotoxic challenge results in a highly differentiated response in brain neurotransmission. We postulate that the profound increase in preoptic noradrenergic neurotransmission may be related to the lipopolysaccharide‐evoked induction of fever and/or activ

ISSN:0953-816X    

DOI:10.1111/j.1460-9568.1995.tb01040.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractThe neuropathology of Parkinson's disease is characterized by the degeneration of dopaminergic neurons in the substantia nigra. We have recently shown that the activation of protein kinase A improves the survival of dopaminergic neurons in culture and, furthermore, protects them from the dopaminergic neurotoxin, 1‐methyl‐4‐phenylpyridinium ion (MPP+)in vitro.We have now analysed the potential of phosphodiesterase inhibitors to increase cAMP levels in dopaminergic neurons, to improve their survival in culture and to protect them from the toxicity of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)in vivo.Increasing intracellular cAMP with phosphodiesterase type IV‐specific inhibitors enhanced the survival of dopaminergic neurons in culture. Inhibitors of other phosphodiesterase types were not active.In vivo, phosphodiesterase type IV inhibitors reduced the MPTP‐induced dopamine depletion in the striatum of C57BL/6 mice. Furthermore, the loss of tyrosine hydroxylase‐immunopositive neurons in the substantia nigra of these animals was diminished. After Nissl staining, a similar reduction of the MPTP‐induced loss of neurons was observed in the substantia nigra. The protective effect of protein kinase A activation did not appear to be due to the blocking of MPP+uptake into dopaminergic neurons. This was not decreased after treatment with forskolin or 8‐(4‐chlorophenylthio)‐cAMP. Thus, protein kinase A regulates the survival and differentiation of dopaminergic substantia nigra neuronsin vivo, implicating a therapeutic potential for substances which regulate c

ISSN:0953-816X    

DOI:10.1111/j.1460-9568.1995.tb01041.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY