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H J Little

Publications and source records attributed to H J Little.

107 records · Page 6Linked to original sources
PubMed1985

Effects of high-pressure helium on gamma-[3H]aminobutyric acid release from the isolated frog spinal cord.

The application of high pressure in vivo causes a hyperexcitability syndrome involving tremors and convulsions. Drugs that potentiate GABA transmission protect animals against this syndrome. It is possible that changes in gamma-aminobutyric acid (GABA) transmission may underlie the hyperexcitability. We have therefore investigated the effects of pressure on the components of GABA transmission in vitro. After incubation with [3H]GABA, hemisected frog spinal cords were superfused inside a pressure chamber and perfusate fractions were collected every 10 min. Helium, at 50 or 100 atm, did not alter the spontaneous release of GABA, but if electrical stimulation had been applied previously, then pressure caused a prolonged increase in GABA release. Helium at 50 atm did not alter the evoked release during electrical stimulation, but at 100 atm this was increased. This increase was smaller in the absence of calcium. No corresponding changes in [14C]urea efflux were seen, suggesting that the effects were not due to nonselective membrane permeability changes. The results are consistent with the known effects of pressure on neuronal activity, such as repetitive firing, but they do not suggest a selective action on the GABA release process.

Animals↗
PubMed1984

Investigating benzodiazepine receptor function in vivo using an intravenous infusion of DMCM.

A method for measuring seizure thresholds using an intravenous infusion of a convulsant beta-carboline benzodiazepine receptor ligand (DMCM) is reported. Seizure thresholds to DMCM are elevated by the benzodiazepine receptor agonist, flurazepam and antagonist, Ro 15-1788, and the proconvulsant beta-carboline, FG 7142. Various other anticonvulsant also antagonise DMCM seizures. Selectivity for the benzodiazepine/GABA receptor complex is demonstrated since bicuculline and pentylenetetrazol lowered thresholds whereas strychnine and N-methyl DL-aspartate did not.

Animals↗
PubMed1984

Ketamine potentiates the responses of the rat superior cervical ganglion to GABA.

The responses of the rat superior cervical ganglion to gamma-aminobutyric acid (GABA) were recorded in vitro using extracellular electrodes. Ketamine was found to increase the amplitude of these responses by up to 100%. This potentiation was seen at ketamine concentrations as low as 18 microM, reached maximum at 180 microM and then declined as the concentration was raised further. Ketamine (90 microM and over) depressed the nicotinic responses of the ganglia. The log concentration-effect curve to GABA was shifted to the left, and the maximum response increased, by ketamine. Inhibition of glial uptake of GABA did not prevent the effect of ketamine. The effects of 3-aminopropane sulphonic acid, which has a very low affinity for this GABA uptake mechanism, were also increased by ketamine. We conclude that ketamine, at concentrations which are found during general anaesthesia, potentiates the responses of the ganglion to GABA, by a mechanism other than inhibition of uptake, and suggest this may be due to action at the GABA receptor site.

Animals↗
PubMed1984

Differential effects of the benzodiazepine antagonist Ro 15-1788 after "general anaesthetic" doses of benzodiazepines in mice.

The effects of the benzodiazepine antagonist Ro 15-1788 20 mg kg-1 after "general anaesthetic" doses of several benzodiazepines were studied in mice, in order to determine if the effects of the latter were attributable to an action at benzodiazepine receptors. Male CDI mice were used and the end-points for anaesthesia were loss of the righting reflex and loss of the foot pinch reflex. The effects of midazolam, and to a lesser extent those of chlordiazepoxide and of diazepam on these reflexes, were antagonized partially by Ro 15-1788. When the antagonist was given after high doses of flurazepam, convulsions were produced. Calculation of the likely membrane concentrations of the benzodiazepines showed that these fitted the lipid solubility correlation for general anaesthesia. Ro 15-1788 did not decrease the lethal effects of the benzodiazepines. With flurazepam, chlordiazepoxide and diazepam it caused signs of hyperexcitability, which in the case of flurazepam led to the death of the animals.

Anesthesia, General↗
PubMed1984

The effects of benzodiazepine agonists, inverse agonists and Ro 15-1788 on the responses of the superior cervical ganglion to GABA in vitro.

The effects of benzodiazepines and their antagonists on the responses to gamma-aminobutyric acid (GABA) of the superior cervical ganglion of the rat were examined using extracellular recording. Chlordiazepoxide (1 microM to 28.9 microM) and flurazepam (145-725 nM) increased the responses of the ganglion to GABA and the increases were antagonized by Ro 15-1788, at 3.34 microM. The concentration of GABA used was 9.7 microM which gave half-maximal responses. Chlordiazepoxide similarly increased the responses of the ganglion to GABA 38.8 microM in the presence of bicuculline 27.2 microM. This concentration of GABA gave, with bicuculline, responses of a similar magnitude as those to 9.7 microM in the absence of bicuculline. Bicuculline did not affect the actions of chlordiazepoxide or the antagonism by Ro 15-1788. Ro 15-1788 did not affect the increases in GABA response caused by pentobarbitone or by phenobarbitone in the presence of bicuculline. Ethyl beta-carboline-3-carboxylate (beta CCE) (207 nM to 1 microM) significantly decreased the responses to GABA in the presence and in the absence of bicuculline. The decreases were antagonized by Ro 15-1788 (3.34 microM). beta CCE at 2.1 microM and above did not significantly change the responses to GABA. Methyl beta-carboline-3-carboxylate (beta CCM) at 88 to 440 nM significantly decreased the responses to GABA. The decreases were antagonized by Ro 15-1788 (3.34 microM) and were also seen in the presence of bicuculline. High concentrations of Ro 15-1788 decreased the responses to GABA, 9.7 microM, but increased the responses to GABA 38.8 microM in the presence of 27.2 microM bicuculline. The pattern of effects of the benzodiazepines, beta-carbolines and low doses of Ro 15-1788 on the responses to GABA was similar to the effects of these compounds on seizure threshold and anxiety-related behaviour in vivo.

Animals↗
PubMed1984

Acute and chronic effects of the benzodiazepine receptor ligand FG 7142: proconvulsant properties and kindling.

The effects of the acute and chronic administration of the beta-carboline benzodiazepine receptor ligand, FG 7142 were studied in mice. On acute administration FG 7142 (at doses between 10 and 40 mg kg-1) lowered seizure thresholds to infused pentylenetetrazol (PTZ) but showed an unusual dose-response curve in that higher doses had less effect. The duration of action was considerably longer than that of other beta-carbolines, such as ethyl-beta-carboline-3-carboxylate (beta CCE). During repeated administration, doses of FG 7142 which were initially proconvulsant subsequently produced generalized seizures on average in 60% of animals after 12 once daily treatments. This seemed to be a form of chemical kindling. The effects of different drug administration regimes were studied. Once daily dosage was shown to be the optimum for kindling production, and was therefore used for subsequent experiments. Kindling lasted for at least one month after 12 single once daily doses of 40 mg kg-1 (FG 7142). The administration of the benzodiazepine antagonist Ro 15-1788 concurrent with FG 7142 prevented kindling. When Ro 15-1788 was given to kindled animals along with a challenge dose of FG 7142, it prevented the expression of kindled seizures. These data show that kindling is mediated via the benzodiazepine receptor.

Animals↗
PubMed1983

Ketamine and the guinea-pig ileum: possible opiate agonist and antagonist actions and effects of peptidase inhibition.

The effects of ketamine and its interaction with naloxone were studied on the transmurally stimulated guinea-pig ileum preparation. Ketamine (at concentrations between 10(-4) and 10(-3) M) depressed the contractions of the ileum, showing a very steep log concentration-effect curve. Naloxone partially reversed the depressant effect of ketamine at slightly higher concentrations (between 10 nM and 1 microM) than those normally required to reverse opiate depression in this tissue. Naloxone did not affect pentobarbitone-induced depression, suggesting that ketamine has specific actions on opiate transmission. Phentolamine and propranolol did not affect the ketamine-induced depression, whereas acetylcholinesterase inhibition did not alter the action of naloxone on this depression. Ketamine showed some reversal effect on the depressant action of morphine and caused contractions of the morphine-tolerant ileum, suggesting that it may have opiate antagonist activity. Inhibition of peptidase enzymes by a mixture of dipeptides potentiated the depression after high-frequency stimulation of the ileum, but did not affect the action of ketamine. The results suggest that ketamine may interact with opiate mechanisms in the ileum to produce part of its depressant action and may also have some opiate antagonist activity.

Acetylcholine↗
PubMed1982

The benzodiazepine antagonist, Ro 15-1788, prevents the effects of flurazepam on the high pressure neurological syndrome.

The benzodiazepine antagonist, Ro 15-1788, was used to investigate the anticonvulsant effect of flurazepam on the high pressure neurological syndrome (HPNS). Flurazepam raised the threshold pressures for the onset of tremor and of clonic convulsions caused by high pressure helium. Administration of the benzodiazepine antagonist Ro 15-1788 completely prevented the changes in threshold pressures produced by flurazepam. Alone, Ro 15-1788 did not affect the onset pressures. The concentration of Ro 15-1788 which blocked the actions of flurazepam on the pressure signs was the same as that required to prevent its effects on convulsions due to infusion of bicuculline. It is concluded that the effect of flurazepam on thresholds for the high pressure neurological syndrome is due to action at benzodiazepine receptors and not to a nonspecific effect.

Animals↗
PubMed1982

Drugs that increase gamma-aminobutyric acid transmission protect against the high pressure neurological syndrome.

1 The effects on the high pressure neurological syndrome (HPNS) of drugs which facilitate gamma-aminobutyric acid (GABA) transmission were investigated. Threshold pressures for the onset of the behavioural signs of the HPNS in mice--tremors and convulsions were established. 2 Flurazepam hydrochloride 20 and 10 mg/kg and sodium valproate 800 and 400 mg/kg substantially raised the threshold pressures for both tremor and convulsions. 3 Amino-oxyacetic acid 35 and 25 mg/kg and diaminobutyric acid 600 mg/kg also significantly increased the thresholds. Muscimol 1 mg/kg (and 150 ng i.c.v.) was ineffective at non-toxic doses. 4 These effects paralleled the drugs' ability to raise the convulsion threshold to intravenous infusion of bicuculline in mice. 5 These results demonstrate that drugs with actions more selective than those of the general anaesthetics are effective against the HPNS. It is also possible that there is a GABAergic component to the effects of general anaesthetics on the HPNS.

Anesthetics↗
PubMed1982

Effects of ketamine and of high pressure on the responses to gamma-aminobutyric acid of the rat superior cervical ganglion in vitro.

1 The method of Brown & Marsh (1974) for recording of surface potentials from the rat superior cervical ganglion has been adapted for use in a high pressure chamber in order to study the effects of high pressure of helium and the possible interactions with the effects of general anaesthetics. 2 Helium pressure of 130 atm did not alter the amplitude of the responses recorded from the ganglion in response to gamma-aminobutyric acid (GABA) application (9.7 and 19.4 microM) but the amplitude of responses to a nicotinic agonist were depressed. 3 Ketamine, at concentration between 18 and 180 microM, considerably potentiated the responses of the ganglion to GABA. 4 Helium pressure (130 atm) did not reverse the potentiation of GABA by ketamine. 5 The results are discussed in connection with the ability of ketamine to oppose the behavioural effects of high pressure.

Animals↗
PubMed1980

In vitro actions of NN-dimethyl-2-aminoindane and related compounds.

The actions of 2-aminoindane, 2-amino-1,2,3,4-tetrahydronaphthalene and amphetamine and their N-methyl and NN-dimethyl derivatives on the guinea-pig ileum were compared. All, except the tertiary 2-aminoindane, inhibited the responses to electrical stimulation and it is suggested that this is not fully explained by their sympathomimetic properties. NN-Diemthyl-2-aminoindane increased these responses and caused contractions of the unstimulated ileum due to a nicotine-like action. The indane series was more effective in producing contractions of the ileum than the other compounds. The three tertiary derivatives antagonized competitively the actions of histamine on the ileum and those of 5-hydroxy-tryptamine on the rat uterus.

Acetylcholinesterase↗
PubMed1979

The effects of inert gases and other general anaesthetics on the release of acetylcholine from the guinea-pig ileum.

1 The actions of a range of general anaesthetic agents on the rates of release of acetylcholine from the guinea-pig ileum were tested, by means of a superfusion system designed to maintain the tissues under physiological conditions in a high pressure chamber.2 Anaesthetic pressures of nitrous oxide, nitrogen, argon, sulphur hexafluoride and carbon tetrafluoride caused increases in acetylcholine ouput but the concentrations required did not parallel their general anaesthetic potencies. The changes were not altered by the application of a pressure of helium which reverses their general anaesthetic actions in vivo.3 Urethane (50.5 mM and 101 mM, but not 16.8 mM) decreased acetylcholine release rates and this effect was not reversed by helium pressure.4 Octanol (1.0 mM, but not 0.124 mM or 0.496 mM) decreased the acetylcholine output. This action was not reversed by helium pressure. The lack of effect on acetylcholine release from tetrodotoxin-treated tissues suggested that the changes were produced by blockade of action potential conduction.5 Phenobarbitone (0.4 mM but not 0.2 mM) also decreased acetylcholine output. Although the concentrations required were lower than those which have been previously shown to block axonal conduction, no changes were seen in tetrodotoxin-treated tissues. The decreases were less when helium pressure was applied than at atmospheric pressure but full pressure reversal, as occurs in vivo, was not seen.6 The effects on acetylcholine output exerted by the anaesthetics studied did not reflect their general anaesthetic action in the concentrations required, the direction of the changes produced or in the response to helium pressure. They represent specific actions which are likely to contribute to the individual differences which are seen between the physiological actions of the anaesthetics in vivo.

Acetylcholine↗
PubMedDate not supplied

Correlation between increases in dihydropyridine binding in vivo and behavioural signs of ethanol withdrawal in mice.

Increased ligand binding to dihydropyridine receptors in the central nervous system after chronic ethanol consumption is thought to contribute to the withdrawal syndrome. Previous studies demonstrated such changes when the binding was measured in vitro, which, as the receptors are voltage-sensitive, may not accurately reflect the binding in vivo. In the present study, dihydropyridine binding was measured in vivo in mice, after intravenous administration of the radioligand. The aim was to determine whether there was any correlation between such binding and measurements of behavioural hyperexcitability at different times during the withdrawal phase and after two different methods of alcohol administration. Measurements were made of the binding in vivo of [3H]nitrendipine, at intervals after withdrawal from chronic ethanol administration, and of the severity of withdrawal as measured by response to gentle handling. An increase in the in vivo binding to [3H]nitrendipine was seen after cessation of chronic ethanol consumption by liquid diet. The binding was significantly increased at 4 h, when the behavioural changes were maximal, but not immediately after withdrawal, when the responses to handling were unchanged. By 24 h after cessation of the ethanol treatment, no differences in the binding were found, compared with control values; at this time the withdrawal hyperexcitability had ceased. When alcohol was given chronically by inhalation, the in vivo dihydropyridine binding was increased at 3 h from withdrawal of the ethanol, the time of maximal behavioural hyperexcitability, but no change was seen 30 min after withdrawal, when no changes in the ratings of behaviour were found. There was a significant positive correlation in individual mice between the ratings of handling-induced behaviour at the 3 h interval and the amount of in vivo binding. These data support the hypothesis that the sites labelled by [3H]nitrendipine play an important role in withdrawal hyperexcitability.

Administration, Inhalation↗