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T W Stone

Publications and source records attributed to T W Stone.

At least 145 records · Page 8Linked to original sources
PubMed1990

Distribution of NADPH-diaphorase positive cells in the rat brain.

1. Recent work suggests that neurones in vivo and in culture which contain neuropeptide Y and somatostatin and which stain positively for the enzyme NADPH-diaphorase may be resistant to excitotoxins. 2. We have therefore examined the distribution of the enzyme throughout the rat brain. 3. Neurones were found intensely or moderately stained at all levels of the neuraxis, but with particularly dense clusters of cells in the periaqueductal grey area and dorsal raphe nucleus of the hindbrain, the pedunculopontine and interpeduncular nuclei, and the dorsal spinal trigeminal nucleus. 4. Intensely stained cells occurred with no clear pattern in neocortical and striatal areas, and in nucleus basalis. 5. The observed distribution of staining is consistent with previous studies in other species of limited regions of the CNS. 6. While no consistent functional or neurochemical correlate of the NADPH-diaphorase distribution could be proposed, the work provides a basis for more detailed investigations of neuronal sensitivity to excitotoxins.

Amygdala↗
PubMed1990

Dihydropyridines alter adenosine sensitivity in the rat hippocampal slice.

1. The effects of adenosine and a range of adenosine analogues, which are resistant to uptake processes, were studied in the presence of dihydropyridines and verapamil on the population spike potential recorded from the CA1 area of the hippocampal slice. 2. Nifedipine and Bay K 8644, a calcium channel antagonist and activator respectively, enhanced the inhibitory action of adenosine in a concentration-dependent manner. This was in contrast to their effect on adenosine analogues where the inhibition of the population potential was significantly attenuated. Similar interactions between the adenosine compounds and the dihydropyridines were also displayed in studies on spontaneous epileptiform activity in the CA3 region. 3. This effect of nifedipine and Bay K 8644 was not shown by the dihydropyridines, nimodipine or nitrendipine, or by the phenylalkylamine, verapamil. 4. Addition of the adenosine uptake blocker dipyridamole reversed the action of nifedipine on adenosine, so that inhibition by adenosine was now attenuated by nifedipine in a similar manner to that observed with the adenosine analogues. 5. These results can be explained with reference to binding studies that show displacement of adenosine analogues from the adenosine receptor by dihydropyridines. An action at the adenosine uptake site by the dihydropyridines explains the enhancement of adenosine inhibition. 6. The possible sites for this interaction are discussed.

2-Chloroadenosine↗
PubMed1990

The inhibitory adenosine receptor at the neuromuscular junction and hippocampus of the rat: antagonism by 1,3,8-substituted xanthines.

1. The ability of 1,3,8-substituted xanthines to antagonize the inhibitory effects of adenosine receptor agonist on the amplitude of nerve-evoked twitches of the rat phrenic-diaphragm and on the amplitude of orthodromically-evoked population spikes, recorded from the CA1 pyramidal cells of rat hippocampal slices, was investigated. 2. 1,3-Dipropyl-8-cyclopenthylxanthine (DPCPX), 1,3-dipropyl-8-(carboxymethyloxyphenyl)xanthine (XCC), 1,3-dipropyl-8-(4-[2-aminoethyl)amino)carbonylmethyloxyphenyl)x ant hine (XAC), 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX), 8-phenyltheophylline (8-PT), 1,3-diethyl-8-phenylxanthine (DPX) and PD 115,199, in concentrations virtually devoid of effect on neuromuscular transmission, shifted to the right in a near parallel manner the log concentration-response curve for the inhibitory effect of 2-chloroadenosine (CADO) on nerve-evoked twitches of the phrenic-diaphragm. Linear Schild plots with slopes near to unity were obtained for all the xanthines. 3. The order of potency of the xanthines as antagonists of the effect of CADO in the phrenic-diaphragm was DPCPX (Ki = 0.54 nM) greater than XCC (Ki = 10 nM), XAC (Ki = 11 nM), PACPX (Ki = 13 nM) greater than DPX (Ki = 22 nM), 8-PT (Ki = 25 nM) greater than PD 115,199 (Ki = 57 nM). The potency of DPCPX in antagonizing the inhibitory effects of R-N6-phenylisopropyladenosine (R-PIA) and 5'-N-ethylcarboxamide adenosine (NECA) on nerve-evoked twitch response was not statistically different from its potency in antagonizing the inhibitory effect on CADO. 4. In the hippocampal slices, DPCPX, XCC and XAC, used in concentrations virtually devoid of effect on population spike amplitude, shifted to the right in a near parallel manner the log concentrationresponse curve for the inhibitory effect of CADO on the amplitude of the population spikes. The Schild plots were linear with slopes near unity. 5. The potencies of DPCPX (K, = 0.45 nM) and XAC (K, = 11 nM) in antagonizing the inhibitory adenosine receptor at the hippocampus were similar to their potencies for antagonism of the inhibitory adenosine receptor at the phrenic-diaphragm. XCC was only slightly more potent (K, = 5.4 nM) as an antagonist of the adenosine receptor in the hippocampus than in the phrenic-diaphragm. 6. The results suggest that the inhibitory adenosine receptors in the phrenic-diaphragm and in the hippocampus of the rat are similar, and that according to the antagonist potencies, these receptors belong to the A1-adenosine receptor subtype.

Animals↗
PubMed1990

Sensitivity of hippocampal neurones to kainic acid, and antagonism by kynurenate.

1. The sensitivity to kainic acid of neurones in the CA1 and CA3 regions of rat hippocampal slices has been examined by microiontophoresis and by superfusion methods. 2. When the iontophoretic currents needed to produce comparable plateaux of firing were compared, neurones in the pyramidal cell layer of the CA3 region were approximately 5 times more sensitive than cells in the CA1 region. No difference was noted in sensitivity to N-methyl-D-aspartate (NMDA) or quisqualate. 3. When kainate was superfused at known concentrations, the threshold for eliciting excitation in CA1 was 2.1 microM. The threshold concentration in CA3 was 0.24 microM. 4. Two weeks after the stereotaxic intrahippocampal injection of colchicine, the granule cells of the dentate gyrus and thus the mossy fibre projections to CA3 were destroyed. In slices prepared from animals thus treated the threshold concentration of kainate for eliciting excitation had risen to 1.64 microM. 5. Kainate was less effective in promoting the development of epileptiform bursts of neuronal firing in colchicine-treated slices than in controls. 6. Kynurenic acid antagonized the excitation of CA1 neurones elicited by kainate, NMDA or quisqualate. In the CA3 region kynurenate antagonized selectively responses to microiontophoretic NMDA, with little effect on responses to kainate or quisqualate. 7. In slices taken from colchicine-treated rats kynurenate was able to block responses to kainate in the CA3 area in parallel with responses to NMDA. 8. Taken together the results suggest that the excitatory responses to kainate in the CA3 region may be partly due to a presynaptic action on mossy fibre terminals to release endogenous amino acids. The differential action of kynurenate in normal and lesioned slices may, therefore, indicate that the postsynaptic kainate receptors are sensitive to antagonism by this compound whereas the presynaptic receptors are resistant to kynurenate.

Animals↗
PubMed1989

Quinolinic acid neurotoxicity: protection by intracerebral phenylisopropyladenosine (PIA) and potentiation by hypotension.

In the present study we have used the purine agonist R-phenylisopropyladenosine (PIA) which suppresses excitatory amino acid release to assess its effect on quinolinate toxicity. Quinolinic acid was injected into the rat hippocampus alone or with PIA and the animals allowed to recover. After 4 days the brain was removed for histological examination. The extent of neuronal degeneration was assessed blind by an independent observer on a scale of 0 (no damage) to 10 (complete degeneration). Co-administration of PIA protected against the toxicity, and this protective action of PIA was blocked by a xanthine adenosine receptor antagonist. However, systemic injections of PIA or the non-purine ganglion blocking drug trimetaphan, both of which caused significant depression of blood pressure, potentiated quinolinate toxicity. The results may indicate an interaction between endogenous excitotoxins and episodes of hypotension which may be critical in determining cell death in the CNS.

Adenosine↗
PubMed1989

Possible subtypes of ATP receptor producing contraction of rat vas deferens, revealed by cross-desensitisation.

1. Adenosine triphosphate (ATP), alpha beta-methylene ATP and the dinucleotides P1P4diadenosine tetraphosphate (AP4A) and P1P5-diadenosine pentaphosphate (AP5A) have been applied to preparations of the rat vas deferens in vitro in preliminary experiments designed to assess the feasibility of using such nucleotides to detect subtypes of the ATP receptor causing smooth muscle contractions. 2. Desensitisation to the dinucleotides induced a change in the profile of the response to ATP with the preferential loss of an early transient component. 3. Desensitisation to low concentrations of alpha beta-methylene ATP produced a greater loss of the later, slower component of contraction to ATP. 4. It is suggested that these components may therefore involve pharmacologically distinguishable nucleotide receptors.

Adenosine Triphosphate↗
PubMed1989

Increase in kynurenic acid in Huntington's disease motor cortex.

Huntington's disease is a neurological disorder characterised by a progressive chorea and dementia. Recent evidence has suggested that dysfunction involving endogenous excitatory amino acids may be important in the pathogenesis of this disease. Following the recent demonstration that kynurenic acid is present in the brain, we examined the levels in various areas of brain from patients who died with Huntington's disease and from age/sex-matched controls. Blocks (100-500 mg) of cortex (Brodmann's areas 4 and 10) and caudate nucleus and globus pallidus (lateral and medial parts) were obtained from the Cambridge Brain Bank. The tissue was then processed for the extraction and analysis of kynurenic acid. Whereas no differences in the content of kynurenic acid were observed in the caudate nucleus, lateral or medial globus pallidus, or prefrontal cortex (area 10) between controls' brains and those from patients who died with Huntington's disease, there was a 94% (p less than 0.01; n = 5) increase in the kynurenic acid content in the motor cortex (area 4) from Huntington's disease brains, relative to those of controls. Some time ago we suggested that a subtle change in the relative concentrations of quinolinic and kynurenic acids might be important in the pathogenesis of neurodegeneration. It is possible that the observation of raised kynurenic acid levels supports this supposition. Further work is now in progress to determine whether the change in kynurenic acid is a primary effect or a compensatory response to an increase in excitatory activity.

Aged↗
PubMed1989

Effect of changing extracellular levels of magnesium on spontaneous activity and glutamate release in the mouse neocortical slice.

1. The mouse neocortical slice preparation, maintained in a two compartment, grease gap bath, exhibits spontaneous depolarizing activity (with or without rhythmic after potentials) after perfusion with magnesium-free artificial cerebrospinal fluid. 2. If the magnesium concentration is decrementally lowered over an extended time period, then incrementally raised following a similar time course, the spontaneous depolarizing shift activity shows a hysteresis (with regard to both frequency and amplitude), the depolarizing shifts being more resistant to magnesium during the incremental period. 3. The amino acid content of the perfusing fluid was analysed by high performance liquid chromatography (h.p.l.c.). Although a basal efflux of 6 amino acids was quantifiable, only glutamate levels increased following superfusion of the preparation with magnesium-free, artificial cerebrospinal fluid. 4. Glutamate release increased to 266% of the resting release in the presence of magnesium within the first 12 min of the change into magnesium-free artificial cerebrospinal fluid. This increase in release preceded the onset of spontaneous depolarising activity. The release of glutamate remained elevated at 182% of control up to 60 min after perfusion with magnesium-free buffer, when depolarizing activity was well established. 5. A model is presented and discussed for the genesis and maintenance of the spontaneous depolarizing shifts. It is suggested that the maintenance of this spontaneous activity reflects a long term enhancement of neocortical neurone excitability which may be related to long term potentiation in the hippocampus.

Amino Acids↗
PubMed1989

Absence of P2-purinoceptors in hippocampal pathways.

1. Many apparent actions of adenosine 5'-triphosphate (ATP) are mediated by adenosine produced by enzymatic hydrolysis of the nucleotide. Previously described actions of ATP in the CNS have been partly due to this phenomenon. In the present study analogues of ATP, which are not hydrolysed to adenosine, were used to seek responses to activating nucleotide (P2) receptors in the hippocampus. The analogues used were L-adenosine-5'-(beta,gamma-methylene)-triphosphonate and 2-methylthioadenosine-5'-(beta,gamma-difluoromethylene)-triphosphonat e. 2. Neither of the stable nucleotides had any effect on orthodromically evoked synaptic potentials in the CA1 region of rat hippocampal slices. Adenosine and ATP had inhibitory actions that could be prevented by the P1-receptor blocker 8-phenyltheophylline. 3. The stable nucleotides had no consistent effects on the firing rate of single neurones in stratum pyramidale of the CA1 region, although adenosine and ATP produced a xanthine-sensitive inhibition. 4. Adenosine selectively reduced the sensitivity of CA1 neurones to microiontophoretically applied carbachol whereas stable nucleotides did not. 5. It is concluded that there are neither P2x- nor P2y-receptors for adenine nucleotides on rat hippocampal CA1 pyramidal cells at the Schaffer collateral and commissural terminals in stratum radiatum.

Action Potentials↗
PubMed1988

Rhythmic digastric activity in the naloxone-treated decerebrate rabbit pup.

In decerebrate rabbit pups (greater than 1 and less than 7 days postnatal), exhibiting a digastric reflex with a latency of 20-25 ms, the administration of naloxone was followed by depression of the 25 ms latency reflex and the appearance of rhythmic EMG activity (10-18 Hz) with a latency of 45-90 ms. Such a frequency is not consistent with the normal rhythms of feeding but may relate to tooth grinding behaviour. In contrast, spontaneous rhythmic activity occurring after naloxone had a lower frequency, consistent with the normal rhythm of feeding.

Animals↗
PubMed1988

Interactions of adenosine and magnesium on rat hippocampal slices.

The potency of adenosine in reducing orthodromically evoked population potentials elicited in area CA1 of rat hippocampal slices was greatly reduced by removal of magnesium from the bathing medium. Removal of magnesium increased cell excitability, but this did not account for the loss of potency as the addition of (+/-)-2-amino-5-phosphonovaleric acid (2-APV), or a reduction in extracellular calcium failed to restore adenosine inhibition. However, addition of cobalt (500 microM) did restore inhibition. The results may indicate a requirement for magnesium, or a similar divalent cation, at the A1-inhibitory adenosine receptor. The observation of excitation by adenosine in zero magnesium/low calcium may suggest an A2-excitatory receptor interaction in the absence of adenosine inhibition.

2-Chloroadenosine↗
PubMed1988

Purine modulation of cholinomimetic responses in the rat hippocampal slice.

Iontophoretic application of carbachol caused excitation of CA1 neurones and decreased the amplitude of antidromic CA1 population spikes recorded extracellularly. Adenosine, adenosine triphosphate (ATP) and the purine analogues N-ethylcarboxamide adenosine (NECA) and R- and S-phenylisopropyladenosine (PIA) reduced the effects of carbachol on single cell firing and on the population spike. Responses to excitatory amino acids were unaffected by adenosine except for a small depression of kainate and N-methyl-D-aspartate responses at high concentrations. The rank order of potency for the purine reduction of carbachol responses was R-PIA = S-PIA = NECA much greater than adenosine greater than ATP. The actions of purines and purine analogues were antagonized by 8-phenyltheophylline (8-PT) and other xanthine antagonists. Application of 8-PT and other xanthines without prior exposure to purines frequently resulted in marked potentiation of carbachol responses. Thus in the hippocampus, responses to the cholinomimetic carbachol are markedly and selectively reduced by purines acting at the P1 purine receptor type and it appears that endogenous levels of adenosine limit the effects of cholinergic agents.

Acetylcholine↗
PubMed1988

Comparison of kynurenic acid and 2-APV suppression of epileptiform activity in rat hippocampal slices.

The N-methyl-D-aspartate (NMDA) receptor blocker 2-amino-5-phosphonovaleric acid [+/-)-2-APV) and kynurenic acid both suppressed spontaneous epileptiform burst discharges in the CA3 region of rat hippocampal slices. When the bursts were induced by perfusion with magnesium-free medium (+/-)-2-APV was the more potent inhibitor (ED50 66 microM for (+/-)-2-APV and 110 microM for kynurenate). When bursts were induced by picrotoxin, kynurenate was more potent with an ED50 of 132 microM, compared with 290 microM for (+/-)-2-APV. Both antagonists were selective inhibitors of responses to NMDA when examined against excitations induced by NMDA, kainate and quisqualate applied by microiontophoresis onto CA3 pyramidal cells. The results may indicate a complex receptor profile for endogenous compounds involved in epileptiform bursts, or the existence of non-pyramidal cells bearing non-NMDA receptors sensitive to kynurenic acid.

2-Amino-5-phosphonovalerate↗
PubMed1988

Purine receptors and kynurenic acid modulate the somatosensory evoked potential in rat cerebral cortex.

Adenosine and analogues, and antagonists to adenosine and putative excitatory amino acid transmitters were topically applied to the cerebral cortex of urethane-anaesthetised rats and their effects on the somatosensory evoked potentials (SEPs) examined. 2-Chloro-adenosine decreased the amplitude of the SEPs whereas adenosine did not. Both L-(-)N6-phenyl-isopropyladenosine (L-PIA) and 5'-N-ethylcarboxamide adenosine (NECA) depressed the SEPs; the effect of L-PIA was more marked than that of NECA. 8-p-Sulphophenyl theophylline increased the amplitude of the SEPs and also inhibited the effects of 2-chloro-adenosine and L-PIA. Kynurenic acid decreased the amplitude of the SEPs. The results suggest that the initial component of the SEP is a post-synaptic event and that endogenous adenosine probably modulates thalamo-cortical synaptic transmission.

2-Chloroadenosine↗
PubMed1988

Kynurenic acid and AP5 distinguish between NMDA receptor agonists.

Quantitative analysis of responses to amino acids in mouse cortical slices has indicated that the antagonists kynurenate and 2-amino-5-phosphonopentanoic acid distinguish between ibotenate and both N-methyl-D-aspartate (NMDA) and quinolinate. This result is consistent with the existence of NMDA-receptor subtypes.

2-Amino-5-phosphonovalerate↗
PubMed1988

Presynaptic actions of adenosine are magnesium-dependent.

Reducing the extracellular magnesium concentration of medium bathing a rat hippocampal slice preparation greatly reduced the ability of adenosine to inhibit the synaptically evoked population potential. This loss of potency does not appear to be mediated by increased NMDA receptor activity or increased calcium influx. The results suggest that magnesium is required at the A1 adenosine receptor for its interaction with adenosine.

Adenosine↗