NMDA receptors and ligands in the vertebrate CNS.
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Action Potentials↗
Biomedical subjects
T W Stone
Publications and source records attributed to T W Stone.
Interactions of carbamazepine, chlormethiazole and pentobarbitone with adenosine on hippocampal slices.
1. The effects of the anticonvulsants carbamazepine, chlormethiazole and pentobarbitone and their interactions with adenosine have been studied in rat hippocampal slices. 2. Neither chlormethiazole nor pentobarbitone changed the evoked population spike in CA1 stratum pyramidale, while carbamazepine produced a gradual decline of this potential at concentrations of 100 microM or greater. 3. This effect was not prevented by 8-phenyltheophylline. 4. Only carbamazepine (greater than 20 microM) produced any change of adenosine responses: a slowly developing reduction of the inhibitory action. 5. None of the anticonvulsants altered responses to the amino acid excitant N-methyl-aspartate, or kynurenic acid.
2-Chloroadenosine↗
Effects of anticonvulsants on responses to excitatory amino acids applied topically to rat cerebral cortex.
1. Five clinically used anticonvulsants were examined to find out if they block the effects of excitatory amino acids in the cerebral cortex of urethane anaesthetised rats. 2. Compounds were tested by topical application to the cortical surface and following their intraperitoneal injection at anticonvulsant doses. 3. Pentobarbital and diphenylhydantoin blocked the effect of quisqualic acid but only at concentrations higher than the therapeutically relevant levels. 4. Pentobarbital and diphenylhydantoin did not alter the effects of N-methyl-D,L-aspartic acid (NMDLA) or kainic acid. 5. Diazepam prevented the kainic acid-induced development of distorted somatosensory evoked potentials (SEPs) at therapeutically relevant levels. 6. Diazepam had no effect on NMDLA or quisqualic acid. 7. Carbamazepine and chlormethiazole had no effect on NMDLA, kainic acid or quisqualic acid. 8. The anticonvulsive effects of these drugs, with the exception of diazepam, probably do not involve antagonism of endogenous EAAs.
Administration, Topical↗
Pharmacologically induced changes in the latency of digastric reflexes in 1-7 day old rabbits.
1. The naturally occurring change in latency of the digastric reflex from long (40-70 msec) to short (15-35 msec) in the first week of life was studied in rabbits using drugs known to affect GABAergic and glycinergic transmission. 2. Usually the long or the short latency reflex response appeared alone but after strychnine both appeared together. 3. The long latency responses were favoured by the GABA blockers bicuculline and picrotoxin; periodically rhythmic activity was also elicited. 4. The short latency responses were favoured by the GABA agonists pentobarbitone and diazepam.
Animals↗
A quantitative pharmacological analysis of some excitatory amino acid receptors in the mouse neocortex in vitro.
1. The effects of 2-amino-5-phosphonovalerate and kynurenate, either alone or in combination, were tested on responses evoked by the excitatory amino acid agonists quinolinate, ibotenate, N-methyl-D-aspartate and N-methyl-DL-aspartate by use of an in vitro preparation of mouse neocortex and artificial cerebrospinal fluid nominally free of magnesium. 2. Schild plots for 2-amino-5-phosphonovalerate, using each of the excitatory amino acids, were linear and had a slope not significantly different from one. The apparent pA2 values for 2-amino-5-phosphonovalerate using each of the excitatory amino acids were 4.98 (quinolinate), 5.00 (N-methyl-DL-aspartate), 4.92 (N-methyl-D-aspartate) and 5.05 (ibotenate). The apparent pA2 obtained using ibotenate was distinct from that of N-methyl-D-aspartate but there were no significant differences between pA2 estimates for quinolinate, N-methyl-D-aspartate or N-methyl-DL-aspartate. 3. Schild plots for kynurenate, using each of the excitatory amino acids, were linear and had a slope of 1.36 +/- 0.03, significantly greater than one. The estimated apparent pA2 values for kynurenate were 3.65 (quinolinate), 3.71 (N-methyl-DL-aspartate), 3.65 (N-methyl-D-aspartate) and 3.89 (ibotenate). The apparent pA2 obtained using ibotenate was distinct from that of the other agonists. 4. Experiments using combinations of 2-amino-5-phosphonovalerate and kynurenate indicated that both antagonists apparently acted competitively at receptors activated by ibotenate or by quinolinate. 5. These results indicate that ibotenate acts at a site distinct form that of quinolinate, N-methyl-D-aspartate and N-methyl-DL-aspartate.
2-Amino-5-phosphonovalerate↗
Excitatory amino acid antagonists and endogenous aspartate and glutamate release from rat hippocampal slices.
1. The effect of excitatory amino acid agonists and antagonists on the efflux of endogenous aspartate and glutamate from the rat hippocampus in vitro was studied. 2. None of the compounds tested had any effect on the basal efflux of endogenous aspartate and glutamate. 3. 2-Amino-5-phosphonovaleric acid (APV), 2-amino-7-phosphonoheptanoic acid (APH) and MK-801 all reduced the potassium-evoked efflux of aspartate and glutamate by between 14.9% and 34.3% (P less than 0.05). 4. The depression of efflux brought about by APV was still observed in the presence of tetrodotoxin. 5. Neither N-methyl-D,L-aspartate nor quinolinic acid had any effect on the potassium-evoked efflux of aspartate and glutamate. 6. These results imply the existence of presynaptic amino acid receptors that are capable of modulating the efflux of endogenous aspartate and glutamate.
2-Amino-5-phosphonovalerate↗
Quinolinic acid effects on amino acid release from the rat cerebral cortex in vitro and in vivo.
1. The effect of quinolinic acid, N-methyl-D,L-aspartate (NMDLA) and kainate on the release of endogenous and exogenous amino acids from the rat cerebral cortex in vitro and in vivo was studied. 2. Neither quinolinic acid nor NMDLA had any effect on the basal or potassium-evoked release of [3H]-D-aspartate from slices of rat cerebral cortex either in the presence or absence of magnesium. Kainic acid failed to modify the basal efflux of [3H]-D-aspartate but significantly inhibited (by 34.4% +/- 0.04%, P less than 0.05) the potassium-evoked release. 3. Neither quinolinate nor NMDLA had any effect on the basal efflux of endogenous amino acids from rat cortical slices either in the presence or absence of magnesium ions at concentrations between 10 microM and 5 mM. 4. Both NMDLA (1 mM) and quinolinate (5 mM) produced an efflux of endogenous aspartate (371.4% +/- 11.6%; 389.3% +/- 12.1%) and glutamate (405.4% +/- 13.6%; 430.1 +/- 8.7%) respectively from the rat cerebral cortex in vivo (P less than 0.01). The quinolinic acid-evoked efflux was abolished by the NMDLA antagonist, 2-amino-5-phosphonovaleric acid (200 microM). 5. Kainic acid also caused an efflux of endogenous amino acids from the rat cerebral cortex in vivo. However, the profile of this release was different from that produced by quinolinate and NMDLA. 6. The results add further support to the suggestion that quinolinic acid acts at the NMDLA-preferring receptor and may also explain the requirement for intact afferent projections for the neurotoxic effects of quinolinate to be manifested.
2-Amino-5-phosphonovalerate↗
Amino acid pharmacology in neocortical slices: evidence for bimolecular actions from an extension of the Hill and Gaddum-Schild equations.
1. The equivalent circuit of the cortical slice preparation has been analysed to show that the measured d.c. voltages can be used to estimate the Hill coefficient for ligands acting on the pyramidal cell bodies. 2. The Gaddum-Schild equation for agonist-antagonist interactions has been modified for applications in which the Hill coefficient is not equal to 1. 3. The equations obtained have been applied to recent data of Burton et al. (1988). The results provide evidence for a bimolecular action of the agonists N-methyl-D-aspartate (NMDA) and quinolinic acid and the antagonists kynurenic acid and 2-amino-5-phosphono-pentanoic acid at NMDA receptors on mouse neocortical pyramidal cells.
2-Amino-5-phosphonovalerate↗
Actions of amrinone and milrinone on the guinea-pig ileum.
The pharmacological activity of the cardiotonic agents amrinone and milrinone has been examined on the isolated guinea-pig ileum. Both compounds antagonised the presynaptic inhibitory action of adenosine on electrically evoked contractions, milrinone being the more potent. Higher concentrations of amrinone or milrinone produced contractions of the ileum which were prevented by atropine. Contractile responses to adenosine 5'-monophosphate were not inhibited by atropine. It is concluded that amrinone and milrinone can antagonise some effects of purines but this does not represent their only pharmacological action.
Amrinone↗
Involvement of N-methyl-D-aspartate receptors in the augmenting response in rat neocortex.
The augmenting response was elicited in the neocortex of anaesthetized rats by 10 Hz stimulation of thalamic nuclei. The N-methyl-aspartate (NMA) antagonists 2-amino-5-phosphonopentanoate or 2-amino-7-phosphonoheptanoate were applied topically to the exposed cortex by replacement of fluid in a small plastic cylinder lying on the pial surface. The antagonists delayed the development of augmentation and hastened its decline. It is suggested that this may indicate the involvement of NMA receptors in the augmenting phenomenon in cortex.
2-Amino-5-phosphonovalerate↗
Direct excitatory effects of neuropeptide Y (NPY) on rat hippocampal neurones in vitro.
Intracellular recordings from granule cells of the rat dentate gyrus show neuropeptide Y (NPY) applied by pressure ejection from pipettes containing 1.2-12 microM by pressures of less than 200 kPa for 1-5 s in duration to consistently evoke membrane depolarisations accompanied by a reduction in membrane resistance. The depolarisations were accompanied by an increase in excitability. Since the depolarisations evoked by NPY were not attenuated by either tetrodotoxin or kynurenic acid a direct excitatory action of NPY is postulated.
Action Potentials↗
Endogenous excitotoxic agents.
Although glutamate and aspartate are among the most likely compounds to function as central neurotransmitters, and both can produce cell death in neonatal animals, the efficient uptake systems for these amino acids mean that exceptionally high concentrations are required for toxicity in adults. A better candidate for an endogenous neurotoxin is quinolinic acid, which produces cell death via activation of the N-methyl-aspartate receptors. Several differences of detail between the activity of quinolinate and N-methyl-aspartate may indicate the existence of subpopulations of the N-methyl-aspartate receptor. Another compound in the same 'kynurenine' pathway as quinolinate, kynurenic acid, is an antagonist of the excitatory and neurotoxic actions of quinolinate, and the overall excitability of the central nervous system and the occurrence of cell death may therefore result from a balance between the concentrations of quinolinate and kynurenate.
Animals↗
Interactions between topically applied excitatory amino acids on rat cerebral cortex: discrimination by pentobarbitone.
The interaction between the effects of topically applied excitatory amino acid receptor agonists on the somatosensory evoked potentials (SEPs) were examined in urethane-anaesthetised rats. Preceding application of N-methyl-D, L-aspartic acid (NMDLA) prevented the effects of quinolinic acid or kainic acid but not those of carbachol or KCl. Similarly, quisqualic acid prevented the effects of NMDLA or kainic acid but not that of carbachol. Pentobartitone suppressed the inhibitory effect of quisqualic acid on NMDLA responses without altering the NMDLA response itself. It is concluded that an apparent desensitisation phenomenon occurs between the excitatory amino acids, distal to the receptor site.
Administration, Topical↗
Injection of baclofen into the ventromedial hypothalamus stimulates gastric motility in the rat.
Injection of 2 micrograms (+/-)-baclofen into the ventromedial hypothalamus (VMH) of urethane-anaesthetized rats resulted in an increase in gastric tone and amplitude of contractions. This effect was curtailed by administration of atropine methyl nitrate (20 mg/kg i.p.) or bilateral cervical vagotomy. These results provide evidence for a hypothalamic modulation of gastric motility by the vagus. Baclofen, possibly acting on receptors insensitive to gamma-aminobutyric acid (GABA), may be mimicking a vagal activation system, located within the ventro-medial hypothalamus.
Animals↗
The mouse neocortical slice: preparation and responses to excitatory amino acids.
1. An improved method of preparing wedges of cerebral cortex and corpus callosum from 500 microM thick coronal sections using mouse brain is described. 2. The characteristics of mixing in the two compartment baths is fully reported. 3. Cortical tissue could be depolarized relative to callosal tissue by superfusion of N-methyl-D-aspartate (NMDA), quinolinate, kainate or quisqualate. 4. At higher concentrations of agonists the depolarization was followed by a small hyperpolarization. This hyperpolarization was abolished by 5 microM ouabain. 5. Neither TTX (1 microM) nor bicuculline (50-62.5 microM) significantly affected the amplitude of the responses to the excitatory amino acids. 6. Responses to NMDA and quinolinate were selectively reduced by magnesium ions, 2-amino-5-phosphonovalerate or ketamine.
Amino Acids↗
Adenosine reduces agonist-induced production of inositol phosphates in rat aorta.
In rat aortic strips rendered permeable with digitonin, inositol trisphosphate induced an efflux of 45Ca from the tissue. This release was not affected by adenosine. In tissues not treated with digitonin the contents of inositol trisphosphate (IP3) and its metabolite inositol 1-phosphate (IP1) were significantly enhanced by noradrenaline in the lithium-treated rat aorta. Adenosine was without effect on levels of IP1 or IP3 in tissues which had not been pretreated with noradrenaline, however, the noradrenaline-enhanced tissue content of IP1 was reduced by adenosine in a dose-dependent manner. The reduction in IP1 content by adenosine was enhanced by the uptake blocker dipyridamole (10 microM) and was blocked by the adenosine receptor antagonist 8-phenyltheophylline (10 microM). Adenosine may therefore lower production of inositol phosphates and thus reduce the stimulated release of calcium from intracellular stores. It is proposed that a reduction in phosphatidylinositol turnover may play a role in adenosine-mediated relaxation of blood vessels.
Adenosine↗
The effects of adenosine on receptor sensitivity in the rat vas deferens.
In the guinea-pig isolated vas deferens adenosine augments the contractile response to noradrenaline (NA). Adenosine also augments the contractile response to NA and phenylephrine in the prostatic portion of the transversely bisected rat vas deferens. However, adenosine appeared to neither augment nor diminish the responses to carbachol, 5HT or high K+. Repetitive exposure of the vas to various agonists induced a desensitisation specific to the particular agonist used. The rate of return of responsiveness (the rate of resensitization) was investigated and, in particular, the effect of adenosine on that rate. In the rat vas deferens the rate of resensitization of responses to NA was retarded by adenosine and this effect was abolished by 8-phenyltheophylline and by yohimbine, but not by atropine or propranolol. Neither 8-phenyltheophylline, yohimbine, propranolol nor atropine by themselves affected the rate of resensitization of the rat alpha-adrenoceptor. Adenosine had no effect on the rate of resensitization of responses to phenylephrine, 5HT, carbachol or high K+. It is considered that the potentiation of catecholamine responses by adenosine involves solely alpha 1-receptors but that the retardation of resensitization may involve alpha 2-receptors which do not contribute directly to contraction.
Adenosine↗
The effect of kainic, quinolinic and beta-kainic acids on the release of endogenous amino acids from rat brain slices.
It has been suggested that the neurotoxic properties of quinolinic acid and kainic acid may, at least in part, involve an indirect action on nerve terminals containing glutamate. In the present study it is confirmed that kainate causes the release of endogenous glutamate from rat hippocampal slices, but that quinolinic acid does not share this activity. In addition beta-kainic acid was found to depress the potassium evoked release of endogenous glutamate at relatively high concentrations and this effect may underlie the anticonvulsant properties of this substance.
Amino Acids↗