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T W Stone

Publications and source records attributed to T W Stone.

At least 199 records · Page 11Linked to original sources
PubMed1985

beta-Kainic acid is not an amino acid antagonist.

beta-Kainic acid has been reported to have anticonvulsant properties. In view of its structural relationship to alpha-kainic acid it has therefore been tested for antagonist activity at excitatory receptors for N-methylaspartate, quisqualate and alpha-kainate using anaesthetized rats and brain slice preparations. No antagonism was found against these three agonists though beta-kainate itself caused excitation. If beta-kainate interferes with excitatory amino acid neurotransmission it probably acts presynaptically.

Amino Acids↗
PubMed1985

The activity of phosphorothioate analogues of ATP in various smooth muscle systems.

Phosphorothioate analogues of adenosine 5'-triphosphate (ATP) have been tested on the rat and guinea-pig vas deferens, the guinea-pig taenia coli and urinary bladder. Adenosine 5'0-(2-thiotriphosphate) (ATP beta S) was more active than adenosine 5'0(1-thiotriphosphate) (ATP alpha S) and ATP in producing contractile responses on the vas deferens of rat and guinea-pig, and guinea-pig bladder, though the difference of potency was less marked for producing relaxation of the carbachol-contracted taenia coli. No differences were observed between the A and B diastereoisomers of ATP alpha S or ATP beta S. Contractions of the vas deferens produced by ATP alpha S were of much longer duration than those produced by ATP beta S. When tested against electrically-evoked twitch responses of the vas deferens the order of potencies was reversed with ATP being most active and ATP beta S least active. These inhibitory effects were blocked by 8-phenyl-theophylline. The calculated pA2 values for ATP, adenosine, beta, gamma-methylene ATP (APPCP) and ATP alpha S were similar, suggesting a common site of action. The results do not reveal any stereoselectivity among the tissues tested, for the diastereoisomers of ATP phosphorothioates; the observed differences of potency may be due to differences between ATP alpha S and ATP beta S in their rates of metabolism to adenosine. The different response profiles to the phosphorothioates may however reflect some differences of receptor mechanisms.

Adenosine↗
PubMed1984

Actions of excitatory amino acids and kynurenic acid in the primate hippocampus: a preliminary study.

Orthodromic evoked potentials of CA1 pyramidal cells were studied in superfused slices of marmoset hippocampus. N-methylaspartate, quinolinic acid and quisqualic acid depressed the responses, but only the former two compounds appeared to be antagonized by 2-amino-5-phosphonovalerate. Kynurenic acid also reduced the orthodromic evoked responses but had no effect on antidromic potentials, the blocking action therefore probably resulting from an interference with synaptic transmission. The study reveals receptors for N-methylaspartate, quisqualate, quinolinate and kynurenic acid in the primate hippocampus broadly comparable with those previously studied in non-primate vertebrates.

Amino Acids↗
PubMed1984

A DNA analysis program designed for computer novices working in an industrial-research environment.

A program designed for DNA sequence analysis by people with no computer background or experience is described. The criteria used in the program design were (i) user friendliness, (ii) ability to handle large DNA files (greater than 10 kilobases), (iii) low storage requirements so that it could be put on a personal computer (IBM), (iv) written in a widely used language (FORTRAN 77) and (v) ability to handle all of the needed tasks for DNA analysis. The program consists of an executive that controls a set of modular subprograms. A file management system using 'SEQ' and 'SITE' files is also in place. SEQ files contain long DNA nucleotide sequences (e.g. restriction enzyme sites). Related SEQ and SITE files are grouped into categories. A SITE category can include related sequences a user wishes to search for in a longer SEQ sequence from a designated category. For example, all of the restriction enzyme recognition sites can group into a single category called 'Enzymes' and can be searched for in a SEQ sequence which has been placed in the SEQ file category 'Plasmids'. Colour graphics is also used as a visual aid.

Base Sequence↗
PubMed1984

The action of gamma-aminobutyric acid (GABA) and ethylenediamine (EDA) on Limulus and Helix central neurones and rat cerebellar and sympathetic ganglion neurones.

Intracellular recordings were made from central Limulus and Helix neurones and extracellular recordings from rat cerebellar Purkinje cells and sympathetic ganglia. The actions of gamma-aminobutyric acid (GABA) and ethylenediamine (EDA) and related analogues on these preparations were investigated. On Limulus neurones inhibited by GABA, EDA and piperazine were 81 and 186 times respectively less potent than GABA. Both the GABA and EDA events were chloride mediated, having similar reversal potentials and were reversibly antagonised by picrotoxinin. The EDA response persisted in high magnesium Ringer. On Helix neurones inhibited by GABA, EDA was 92 times less potent while on neurones excited by GABA, EDA was 9.25 times less potent. The other analogues tested had little or no GABA-like effect on either preparation. On rat cerebellar Purkinje cells, EDA was equipotent with GABA and both compounds were antagonised by bicuculline. Flurazepam only potentiated the action of EDA on 3 out of 23 cells tested while the GABA response of all 23 cells was potentiated by the benzodiazepine. Diaminopropionic acid was a weak inhibitor of cerebellar Purkinje cell firing but flurazepam potentiated this response in 6 out of 10 cells tested. On rat cervical ganglion neurones, EDA was half the potency of GABA and likewise the other analogues were less potent than GABA as depolarising agents. Incubation with glutamic acid decarboxylase inhibitors had no effect on the EDA response. Cross desensitisation between GABA and EDA was demonstrated using the ganglion preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Excitant activity of methyl derivatives of quinolinic acid on rat cortical neurones.

Various synthetic analogues of quinolinic acid have been tested for agonist and antagonist properties when applied by microiontophoresis to neurones in the rat cerebral cortex. Quinolinic acid 2-methylester was a weak antagonist of N-methyl-D-aspartate (NMDA) and quinolinic acid, but also showed agonist activity, being about half as active as quinolinic acid. The excitant effects of the compound could be antagonized by the NMDA receptor blocker, 2-amino-7-phosphonoheptanoic acid (2APH). N-methyl-quinolinic acid 2, 3-dimethylester showed very weak agonist and antagonist activity. Homoquinolinic acid was a potent excitant of cortical neurones, being about five times more active than quinolinic acid and approximately equipotent with NMDA. The excitations were blocked by 2APH or its pentanoate analogue (2APV). Homoquinolinic acid 2-methylester was also active as an agonist. N-methyl-DL-glutamic acid was also tested, since homoquinolinic acid is a rigid analogue of this compound. Although it did cause excitation of 5 of the 16 units tested, N-methyl-glutamate was a weaker agonist than NMDA or homoquinolinate. Phthalic acid, ejected as an anion caused excitation of 14 out of 16 units. It is therefore concluded that the ring nitrogen of quinolinic acid is not essential for excitant activity. Since homoquinolinic acid is a rigid analogue of glutamic acid, but causes excitation by acting apparently on the NMDA receptor, the results are consistent with the suggestion that activation of the NMDA receptor may require the carboxyl groups to be held in a relatively extended configuration.

Animals↗
PubMed1983

Inhibition of adenosine accumulation by a CNS benzodiazepine antagonist (Ro 15-1788) and a peripheral benzodiazepine receptor ligand (Ro 05-4864).

Although benzodiazepines can inhibit adenosine uptake into central neurones, this effect is not antagonized by behaviourally effective 'benzodiazepine antagonists' such as Ro 15-1788. We now report that Ro 15-1788 and the 'peripheral' benzodiazepine ligand Ro 05-4864 themselves inhibit adenosine accumulation by rat brain synaptosomes. The inhibition of adenosine accumulation may thus underlie those behavioural effects of benzodiazepines which are mimicked but not antagonized by Ro 15-1788.

Adenosine↗
PubMed1983

Actions of 6-aminonicotinamide on benzodiazepine receptors in rat CNS.

Since nicotinamide, 6-aminonicotinamide and harmaline can modify the ability of 3-acetylpyridine to cause CNS lesions, and nicotinamide and harmane alkaloids have been proposed as ligands at the benzodiazepine receptor, we have examined the effects of these agents individually or in combinations on [3H]diazepam binding to rat cortex membranes. No interaction was observed between any of the compounds, but 6-aminonicotinamide is over 100-fold more potent than nicotinamide in displacing diazepam.

6-Aminonicotinamide↗
PubMed1983

Actions of TRH and cyclo-(His-Pro) on spontaneous and evoked activity of cortical neurones.

Thyrotrophin releasing hormone (TRH) and its metabolite histidyl-proline diketopiperazine (cyclo-(His-Pro) have been applied by microiontophoresis to neurons in the rat cerebral cortex. Both TRH and cyclo-(His-Pro) had little effect on the spontaneous firing of neurons but both were able to enhance excitatory responses to acetylcholine. Both peptides also caused an enhancement of excitatory responses to quisqualic acid while having little consistent effect on responses to N-methyl-DL-aspartic acid although excitation of a small proportion of cells was enhanced. On 3 cells the increase in size of responses to quisqualate was sufficient to cause overdepolarisation. No antagonism of responses to quisqualate or N-methyl-DL-aspartate was seen.

Acetylcholine↗
PubMed1983

On the interaction of 2-amino-7-phosphono-heptanoic acid and quinolinic acid in mice.

It is shown that (a) peripheral injections of quinolinic acid cause neuronal excitation with a latency much less than that of convulsions due to quinolinic acid and (b) peripherally injected 2-amino-7-phosphono-heptanoic acid (2APH) does antagonise neuronal excitation due to quinolinic acid applied locally by microiontophoresis. It is concluded that the previously reported failure of 2APH to prevent quinolinic acid seizures is a reflection of different modes of action of quinolinic acid in causing neuronal excitation and convulsions, and does not contradict the suggestion that quinolinic acid acts at N-methyl-D-aspartate (NMDA) receptors in the brain.

2-Amino-5-phosphonovalerate↗
PubMed1983

Quisqualic acid excitation of cortical neurones is selectively antagonized by streptomycin.

Although evidence exists for at least 3 kinds of excitatory amino acid receptor in the CNS, responding to N-methyl-D-aspartic acid, kainic acid and quisqualic acid, respectively, only antagonists at the former two sites are currently available. It is now reported that when applied by microiontophoresis to neurones in the rat cerebral cortex, excitatory responses to quisqualic acid can be selectively reduced by streptomycin.

Animals↗
PubMed1983

Benzodiazepine inhibition of adenosine uptake is not prevented by benzodiazepine antagonists.

Uptake of [3H]adenosine into rat cerebral cortex synaptosomes was studied. Hexobendine (10(-5) M) and the benzodiazepine agonists diazepam (10(-5) M) and flurazepam (10(-4) M) significantly inhibited this uptake, but only if the compounds were pre-incubated for 10 min in the case of the benzodiazepines. The benzodiazepine antagonists Ro15-1788 (10(-5) M) and CGS 8216 (10(-5) M) failed to reverse the action of benzodiazepine agonists or hexobendine on [3H]adenosine uptake. The results add weight to the view that inhibition of adenosine uptake processes by benzodiazepines do not contribute to their behavioural effects.

Adenosine↗
PubMed1983

Quinolinic acid: regional variations in neuronal sensitivity.

The excitatory action of quinolinic acid has been examined on neurons in different parts of the rat CNS. When applied by microiontophoresis quinolinic acid excited cells in the cerebral cortex, hippocampus and neostriatum, but even when applied from electrodes which produced responses in these areas, quinolinic acid was ineffective in the cerebellum and spinal cord. Like most excitants tested in other studies, L-glutamate was excitatory to all cells examined. As an endogenous compound, therefore, quinolinic acid may merit special attention as a potential neurotransmitter in brain.

Animals↗
PubMed1983

Neuronal responses to 5-hydroxytryptamine and dorsal raphe stimulation within the globus pallidus of the rat.

The projection from the dorsal raphe nucleus (DRN) to the globus pallidus (GP) was investigated electrophysiologically, in the urethane-anesthetized rat together with the responsiveness of cells in the GP to 5-hydroxytryptamine (5-HT) and noradrenaline (NA). The majority of spontaneously active cells in the GP had high regular firing rates. They were unaffected by both DRN stimulation (69/83 cells) and iontophoretically applied 5-HT (38/63 units) or NA (30/42 units) but were inhibited by GABA. A few cells (N = 10) were recorded from, that were spontaneously active but with a much lower and less regular firing rate, which, however, seemed to be much more responsive to 5-HT. In addition, DL-homocysteic acid (DLH) was used to activate silent cells and all seven cells activated in this manner were inhibited by 5-HT. In addition 5/6 cells that had their firings maintained by DLH were inhibited by stimulation of the dorsal raphe. The results show a lack of responsiveness to both 5-HT and DRN stimulation of the typically regular spontaneously active pallidal neurons. There seems to be a small population of normally quiescent cells, however, that is sensitive to 5-HT and receives an input from the DRN.

Animals↗
PubMed1983

In vivo release of [3H]-purines by quinolinic acid and related compounds.

In vivo release of [3H]-purines from the cortex of anaesthetized rats was measured and the actions of excitatory amino acids and analogues investigated. High KCl, N-methyl-DL-aspartate (NMDLA) and quinolinic acid produced a large increase in basal release of labelled materials. Glutamate, quisqualate and kainate had less effect. The N-methyl-D-aspartic acid (NMDA)-preferring receptor antagonist, 2-amino-7-phosphonohepatanoic acid, significantly reduced the release evoked by NMDLA and quinolinate but not that produced by the other agonists. Kynurenic acid, a compound metabolically related to quinolinic acid, reduced the release due to NMDLA and quinolinate but not glutamate. The results add further support to the suggestion that quinolinic acid acts on the NMDA-preferring receptor.

2-Amino-5-phosphonovalerate↗
PubMed1983

A comparison of the effects of morphine, enkephalin, kyotorphin and D-phenylalanine on rat central neurones.

1 Morphine, Met-enkephalin, kyotorphin and D-phenylalanine have been applied by microiontophoresis to neurones in the globus pallidus and cerebral cortex of rats anaesthetized with urethane. 2 In the pallidum, most cells were inhibited by all the agonists, with a high correspondence between cells inhibited by Met-enkephalin and D-phenylalanine and by Met-enkephalin and kyotorphin. Whereas responses to Met-enkephalin were readily antagonized by naloxone, responses to kyotorphin and D-phenylalanine were not. 3 In the cerebral cortex a high proportion of cells was excited by all four agonists and antagonism by naloxone was less consistent than in pallidum. 4 It is concluded that the naloxone-reversible analgesic effects of kyotorphin and D-phenylalanine may be mediated indirectly, rather through an activation of opiate receptors.

Animals↗