Interactions of adenosine and magnesium on neuronal excitability and transmitter sensitivity in the hippocampal slice.
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Adenosine↗
Biomedical subjects
T W Stone
Publications and source records attributed to T W Stone.
Prevention of kainate-induced excitotoxicity by a purine analogue.
The effect of a systematically administered adenosine analogue upon neuronal damage induced by kanic acid has been examined using the binding of a peripheral benzodiazepine receptor ligand as a marker for the gliosis following neuronal death. Intraperitoneal (i.p.) injections of R-phenylisopropyladenosine (R-PIA), at a dose of 100 micrograms kg-1 or 25 micrograms kg-1 reduced substantially the hippocampal neurotoxicity induced by intraperitoneal kainate 100 mg kg-1. The effect of R-PIA was prevented by 8-phenyl-theophylline, confirming the involvement of a purine P1 receptor.
Animals↗
Changes in adenosine sensitivity in the hippocampus of rats with streptozotocin-induced diabetes.
1. Hippocampal slices have been used to assess the sensitivity of the CNS to adenosine and gamma-aminobutyric acid (GABA) in diabetes. The effects of adenosine, 2-chloroadenosine, GABA, muscimol and baclofen were studied on orthodromic synaptic potentials recorded in the CA1 region of slices taken from normal rats or animals made diabetic by the injection of streptozotocin. 2. In diabetic animals the sensitivity to adenosine was increased 4 fold compared with normal rats. The potency of 2-chloroadenosine was unchanged. 3. The nucleoside transport inhibitor, hydroxynitrobenzylthioinosine (HNBTI), increased the potency of adenosine in slices from normal rats but not in slices from diabetic rats. 4. No change was observed in the potency of GABA or muscimol, although a small but significant decrease was detected in the EC50 value for baclofen. 5. Treatment of diabetic animals with insulin restored the potency of adenosine to control levels. 6. It is concluded that the diabetic state is accompanied by substantial changes of adenosine sensitivity due to the loss of nucleoside uptake processes. Secondary neurochemical changes following from this in human diabetic patients may contribute to the reported behavioural changes.
2-Chloroadenosine↗
Release of endogenous adenosine and its metabolites by the activation of NMDA receptors in the rat hippocampus in vivo.
1. The effects of N-methyl-D-aspartate (NMDA), KCl, and veratridine on the release of endogenous adenosine and its metabolites, inosine and hypoxanthine, from the rat hippocampus have been studied by in vivo microdialysis. 2. In the hippocampus of rats anaesthetized with urethane the adenosine level reached a stable state estimated at 0.93 microM during the first 2 h after the implantation of the dialysis probe. NMDA (50 microM to 25 mM) in the perfusate evoked a concentration-dependent release of adenosine, inosine and hypoxanthine with an EC50 of 180 microM. The release was reduced by 93% by the specific NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (2-AP5) at 200 microM, indicating an NMDA receptor-mediated process. In addition, the 100 mM KCl-evoked release of adenosine was also substantially reduced by 77% by 2-AP5, suggesting that a large component of the K(+)-evoked release is NMDA-receptor-mediated. 3. Perfusion with zero-Ca2+ artificial cerebrospinal fluid attenuated the NMDA-evoked release of adenosine only by 16% (not significant) but depressed the K(+)-evoked release by 62%, indicating that most of the NMDA-evoked release is directly receptor-mediated, whereas a large component of the K(+)-evoked release could be via the release of an excitatory amino acid acting at the NMDA receptors.
2-Amino-5-phosphonovalerate↗
Depression of purine induced inhibition during NMDA receptor mediated activation of hippocampal pyramidal cells--an iontophoretic study.
Single pyramidal cells in the rat hippocampal slice preparation were stimulated by iontophoretic application of excitatory amino acids and acetylcholine. The purine adenosine 5'-monophosphate (AMP), applied iontophoretically, readily depressed acetylcholine stimulated cell firing, was less effective on quisqualic acid stimulated cells and virtually ineffective during stimulation by N-methyl-D,L-aspartate (NMA). Inhibition could be restored if the AMP ejection current was increased 3-fold. In contrast, the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) exerted a comparable level of inhibition under all 3 neuroexcitants. These data support previously published results which suggest that purine mediated inhibition may be reduced during NMDA receptor channel activation. This may have important implications for the action of adenosine during seizures and ischaemic events as well as neuronal phenomena such as long term potentiation.
Acetylcholine↗
Effects of quinolinic and kynurenic acids on central neurons.
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Action Potentials↗
The effect of aluminum on rat brain and liver quinolinic acid concentrations.
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Alum Compounds↗
Kynurenine and glycine enhance neuronal sensitivity to N-methyl-D-aspartate.
Neurones in rat hippocampal slices were excited by microiontophoretic applications of N-methyl-D-aspartate (NMDA) and kainate. Responses to NMDA were potentiated by glycine 300 microM or 1 mM in the perfusing medium. A small potentiation of kainate was not observed in the presence of the NMDA antagonist 2-amino-5-phosphonopentanoic acid (2AP5). The potentiation of NMDA responses by glycine was not prevented by strychnine 5 or 30 microM and was also shown by D-serine and L-kynurenine but not L-leucine. If sensitivity to NMDA was reduced by kynurenic acid, glycine and L-kynurenine produced a greater enhancement of NMDA. The requirement of NMDA receptor activation for the occupation of strychnine-resistant glycine sites can thus be demonstrated in complex systems such as brain slices. It is possible that L-kynurenine may also be an endogenous ligand capable of modulating NMDA sensitivity.
Animals↗
The effect of theophylline on essential tremor: the possible role of GABA.
The chronic administration of theophylline was studied in twenty patients with essential tremor in a double-blind cross-over trial. The tremor was improved significantly after four weeks of treatment. In mice the chronic administration of theophylline was compared with propranolol on the modulation by adenosine, 5-HT, (-)isoprenaline or GABA of NMDA-induced depolarisation of neocortical slices. Adenosine depolarisation was abolished by two-weeks treatment with theophylline but not propranolol. Potentiation by (-)isoprenaline of NMDA responses was reduced by theophylline (100 mg/kg/day) and propranolol treatment (25 mg/kg/day), but a lower dose of propranolol further increased it. The enhancement by 5-HT of NMDA-induced depolarisation was unaffected by the pretreatment with theophylline, while the higher dose of propranolol blocked it. GABA caused no significant change of NMDA depolarisation in control slices, but after theophylline treatment (100 mg/kg/day) and propranolol administration at both doses it significantly potentiated NMDA depolarisation. The enhancement of GABA sensitivity might be an important common factor in decreasing the essential tremor after propranolol and theophylline treatment.
Adenosine↗
Receptors for adenosine and adenine nucleotides.
1. A summary is provided of current classifications of receptors for the adenine nucleosides and nucleotides. 2. The origin of the division of nucleoside (P1) and nucleotide (P2) receptors is discussed as well as the subdivisions of these into A1 and A2, determined by structure activity considerations, and P2x and P2y. 3. Further suggestions have been made recently for identifying A1a and A1b, A2a and A2b subtypes of the P1 receptor family, and for proposing distinctive nucleotide receptors on platelets (P2t) and mast cells (P2z). 4. In addition, an A3 site may exist with properties intermediate between A1 and A2, and a novel P2s receptor on some smooth muscle systems and a P3 site.
Adenine Nucleotides↗
Changes in neurotransmitter sensitivity in the mouse neocortical slice following propranolol and theophylline administration.
1. The mouse neocortical slice has been used to examine the sensitivity of neurones to isoprenaline, 5-hydroxytryptamine (5-HT) and adenosine acutely and following chronic treatment of animals with propranolol or theophylline. 2. While having little effect alone, all three agonists enhanced the d.c. depolarizing potential produced by N-methyl-D-aspartate (NMDA). The effect of (-)-isoprenaline (0.2 microM) was shared by (+)-isoprenaline at the much higher concentration of 10 microM. 3. Superfusion of slices with theophylline or 8-phenyltheophylline blocked responses to adenosine with evidence of selectivity. A single injection of theophylline 24 h before slice preparation did not alter agonist sensitivity, but when administered daily at 100 mg kg-1 for 14 days, the xanthine caused a loss of sensitivity to adenosine and (-)-isoprenaline but not 5-HT. The lower dose of theophylline, 10 mg kg-1 daily, also led to a loss of adenosine responses but no change of sensitivity to the amines. 4. Following the 14 day treatment with theophylline at 100 mg kg-1 daily in two groups of mice, responses to adenosine recovered to control levels after 20 days. 5. Propranolol superfusion blocked responses to both isomers of isoprenaline and 5-HT but did not affect sensitivity to adenosine. 6. Chronic treatment with propranolol at 25 mg kg-1 daily for 14 days induced a loss of sensitivity to (-)-isoprenaline and 5-HT but not adenosine. A lower dose of 5 mg kg-1 daily caused no change in responses to adenosine or 5-HT, but yielded an increased sensitivity to (-)-isoprenaline. 7. The results are discussed with respect to reports of receptor up-regulation in binding studies; caution is clearly required in extrapolating from such work to receptor activity in a functional system, especially in the case of theophylline and adenosine.
Adenosine↗
A comparison of excitotoxic lesions of the basal forebrain by kainate, quinolinate, ibotenate, N-methyl-D-aspartate or quisqualate, and the effects on toxicity of 2-amino-5-phosphonovaleric acid and kynurenic acid in the rat.
1. It has been suggested that an NMDA1 receptor subtype might be activated by N-methyl-D-aspartate (NMDA) and ibotenate and an NMDA2 subtype by NMDA or quinolinate, and that the NMDA2 site might be more susceptible to blockade by kynurenic acid. 2. Experiments were carried out to examine the ability of 2-amino-5-phosphonovaleric acid (AP5) and kynurenic acid to antagonize the neurotoxic properties of kainate, ibotenate, NMDA, quinolinate and quisqualate injected into the rat basal forebrain. 3. Following histological analysis of the injection sites, lesion volume was assessed parametrically. Each of the toxins except quisqualate was found to make lesions of parvocellular neurones within the basal forebrain with a relative order of potency: kainate much greater than quinolinate greater than ibotenate = NMDA. 4. Equimolar doses of AP5 abolished the toxicity produced by quinolinate and NMDA; toxicity to kainate and ibotenate was attenuated to approximately 40% of the toxin-alone condition. 5. The antagonistic properties of kynurenate were dose-dependent: equimolar kynurenate had no effect on quinolinate but attenuated the actions of ibotenate, kainate and NMDA; 2 x equimolar kynurenate had no effect on quinolinate or ibotenate but attenuated the toxicity of kainate and NMDA; and 3 x equimolar kynurenate had no effect on the toxicity of kainate or ibotenate, attenuated the actions of NMDA and abolished the toxic action of quinolinate. 6. The results are discussed in terms of the actions of the various toxins at different receptors, differentially sensitive to AP5 and kynurenate.
2-Amino-5-phosphonovalerate↗
Research funding.
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Research Support as Topic↗
Activation of NMDA receptor-coupled channels suppresses the inhibitory action of adenosine on hippocampal slices.
It has previously been found that the sensitivity of hippocampal slices to adenosine depends on magnesium ions. The addition of 2-amino-5-phosphonopentanoic acid (2AP5) in magnesium-free medium, thus blocking receptors for N-methyl-D-aspartate (NMDA) did not modify this dependence. Here it is shown that if 2AP5 is present before the removal of magnesium ions the sensitivity to adenosine is maintained. The channel blocker MK-801 also restores adenosine responsiveness. Superfusing slices with NMDA itself directly suppresses adenosine responses and can reverse adenosine inhibition of synaptic potentials. Increasing neuronal excitability non-selectively with 8.5 mM potassium in the presence of 2AP5 has little effect on adenosine sensitivity, while removing the 2AP5 causes a loss of sensitivity. The results indicate that activation of NMDA receptor-coupled channels causes a reduction of adenosine sensitivity. This sequence of events may be viewed as a positive feedback and may be of fundamental importance in phenomena such as long-term potentiation, seizure generation and kindling.
2-Amino-5-phosphonovalerate↗
Chronic benzodiazepine treatment and cortical responses to adenosine and GABA.
The effects of chronic treatment of mice with clonazepam have been examined on the responses of neocortical slices to adenosine, 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA). Responses to these agonists were measured as changes in the depolarisation induced by N-methyl-D-aspartate (NMDA). Added to the superfusion medium diazepam blocked responses to adenosine but not 5-HT; this effect was not observed with 2-chloroadenosine or in the presence of 2-hydroxynitrobenzylthioguanosine. GABA was inactive in control slices but chronic treatment with clonazepam induced responses to GABA and enhanced responses to adenosine but not 5-HT. It is suggested that the induction of GABA responses may reflect the up-regulation of GABA receptors, but the increase of adenosine responses by clonazepam implies that there is no simple relationship between adenosine receptor binding and functional responses.
Adenosine↗
Inhibition of adenosine responses of rat hippocampal neurones by nifedipine and BAYK 8644.
The application of adenosine to hippocampal slices caused a suppression of evoked population spikes in the CA1 region. This effect was enhanced by nifedipine and BAYK 8644 in control slices but was reduced by these dihydropyridines in the presence of dipyridamole. Several analogues of adenosine which are not substrates for the uptake system also depressed the population spikes in the CA1 region but these responses were inhibited by nifedipine and BAYK 8644. Other dihydropyridines including nimodipine and nitrendipine did not affect sensitivity to adenosine or its analogues. It is concluded that some agonist and antagonist dihydropyridines can inhibit adenosine uptake and thus potentiate its effects but can also antagonise receptor activation. Structural features of nifedipine and BAYK 8644 may be specific for a population of dihydropyridine receptors closely linked functionally with the adenosine receptor.
2-Chloroadenosine↗
Theophylline down-regulates adenosine receptor function.
Chronic treatment of animals with caffeine or theophylline has been reported to increase the number of adenosine receptors in the CNS detected by ligand binding, but few functional studies have been performed. In the present study adenosine enhanced depolarising responses to the excitatory amino acid N-methyl-D-aspartate (NMDA) in slices of mouse cerebral cortex. This effect was blocked acutely by theophylline but not by theophylline given 24 h previously. Twenty-four hours after 2 weeks of treatment with this antagonist, however (10 or 100 mg/kg/day) adenosine was no longer effective, sensitivity recovering subsequently. Theophylline treatment also reduced sensitivity to (-)-isoprenaline but not 5-hydroxytryptamine. It is concluded that changes of adenosine receptor number in the brain do not necessarily reflect the induced changes of receptor function.
Adenosine↗
NMDA-receptor-independent effects of low magnesium: involvement of adenosine.
Perfusion of hippocampal slices with magnesium-free media elicits epileptiform activity attributable partly to the activity of N-methyl-D-aspartate (NMDA) receptors, but recent reports have documented an NMDA-independent enhancement of orthodromic potentials by moderate reductions in magnesium concentration. The present experiments indicate that this enhancement is comparable with that produced by perfusion with an adenosine antagonist, 8-phenyltheophylline, and that superfusion with this compound or adenosine deaminase precludes any enhancement of potential size in low magnesium solutions. The low magnesium enhancement is probably attributable to the recently described magnesium dependency of presynaptic inhibition by adenosine.
Action Potentials↗