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Biomedical subjects

H J Little

Publications and source records attributed to H J Little.

At least 73 records · Page 4Linked to original sources
PubMed1991

Differential interactions between benzodiazepines and the dihydropyridines, nitrendipine and Bay K 8644.

The effects of the dihydropyridine calcium antagonist, nitrendipine and the calcium channel activator, Bay K 8644, have been compared on the anaesthetic, ataxic and anticonvulsant effects of benzodiazepines. Possible interactions between the peripheral benzodiazepine receptor antagonist, PK11195, and the classical benzodiazepines were also examined. Nitrendipine considerably potentiated the anaesthetic effects of benzodiazepines and increased their ataxic effects but had no effect on the anticonvulsant actions. Clonazepam did not produce anaesthesia, at doses up to 1 g kg-1 or when given with nitrendipine. When given alone, nitrendipine did not cause general anaesthesia. Nitrendipine did not appear to alter the metabolism of midazolam. The calcium channel activator, Bay K 8644, reduced the anaesthetic potency of midazolam and, when given alone, produced ataxia. It did not significantly alter central concentrations of midazolam. The "peripheral" benzodiazepine antagonist, PK11195, did not affect the ataxic or anaesthetic actions of benzodiazepines. These results suggest that dihydropyridine-sensitive calcium channels may be more important to the general anaesthetic than to the anticonvulsant actions of benzodiazepines. The "peripheral" benzodiazepine site did not appear to play a role in either of these properties.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

The benzodiazepines: anxiolytic and withdrawal effects.

Benzodiazepine withdrawal, spontaneous or precipitated by the receptor antagonist, flumazenil, produces anxiety that can be measured in animal models. Benzodiazepine inverse agonists also cause anxiety. Their convulsive effects increase after chronic agonist treatment, but they become anxiolytic. Decreases in GABAA receptor sensitivity occur after chronic benzodiazepine treatment. Flumazenil, given 24h prior to the measurements, prevented both the sensitivity changes and benzodiazepine tolerance in vivo. The anxiety and decreases in seizure threshold during withdrawal were also prevented. It has been suggested that flumazenil causes a prolonged 'resetting' of the benzodiazepine receptor complex. Acute flumazenil decreased anxiety-related behaviour during ethanol withdrawal. Concurrent chronic treatment with verapamil completely prevented anxiety following chronic benzodiazepine treatment.

Animals↗
PubMed1991

The role of neuronal calcium channels in dependence on ethanol and other sedatives/hypnotics.

This review discusses the importance of neuronal calcium currents in dependence on ethanol, barbiturates, benzodiazepines and opiates. The main sections describe the actions of ethanol on control of intracellular calcium and on calcium and calcium-dependent conductance mechanisms. In particular, the effects of both acute and chronic ethanol treatment on dihydropyridine-sensitive, voltage-dependent, calcium channels are described. The later sections cover the effects of barbiturates, benzodiazepines and opiates on these systems. The conclusions suggest that dihydropyridine calcium channel antagonists may offer a new therapeutic approach to the treatment of ethanol and opiate dependence.

Alcoholism↗
PubMed1991

A calcium channel antagonist stereoselectively decreases ethanol withdrawal hyperexcitability but not that due to bicuculline, in hippocampal slices.

1. Extracellular recordings were made from CA1 area of isolated hippocampal slices of the mouse after chronic ethanol administration in vivo, with orthodromic stimulation of the Schaffer collateral/commissural fibres. 2. The (+)-isomer of the calcium channel antagonist PN 200-110 (isradipine) significantly decreased all the recorded signs of hyperexcitability in the slices during ethanol withdrawal. These included increased paired pulse potentiation and decreases in the thresholds for elicitation of single and multiple population spikes. 3. The (-)-isomer of PN 200-100 did not affect ethanol withdrawal hyperexcitability in the slices. 4. Neither isomer of PN 200-110 affected the field potentials in slices from control animals. 5. The gamma-aminobutyric acid (GABA) antagonist, bicuculline, lowered thresholds for eliciting population spikes in hippocampal slices from untreated animals. The active, (+)-isomer of PN 200-110 did not affect this action of bicuculline in hippocampal slices from untreated animals. 6. The stereoisomerism of the action of PN 200-110 on ethanol withdrawal hyperexcitability in the hippocampal slice was therefore the same as that seen in blockade of calcium channels. The results suggested that ethanol withdrawal hyperexcitability recorded in the isolated hippocampal slice involved increased activity of voltage-sensitive calcium channels.

Animals↗
PubMed1991

Chronic dihydropyridine treatment can reverse the behavioural consequences of and prevent adaptations to, chronic ethanol treatment.

1. Chronic treatment with the dihydropyridine calcium channel antagonist, nitrendipine, given concurrently with ethanol, prevented the ethanol withdrawal syndrome in mice, even though the chronic nitrendipine treatment was stopped 24 h or 48 h before the withdrawal testing. 2. This effect was seen in two strains of mice with different methods of ethanol administration. Nitrendipine was effective when given for two weeks but not after only two days' treatment. 3. Two other dihydropyridine calcium antagonists, nimodipine and PN 200-110, given chronically with ethanol, also prevented the withdrawal syndrome. The tests were again made 24 h after the last administration of dihydropyridine. 4. The chronic nitrendipine treatment also prevented the rise in the number of central dihydropyridine binding sites that occurs on chronic ethanol administration. 5. Chronic administration of nitrendipine alone did not cause any withdrawal behaviour. 6. Chronic nitrendipine treatment did not affect the seizure threshold to bicuculline in mice that were not given ethanol. 7. Whole brain concentration measurements showed that the effects were not due to residual nitrendipine in the CNS at the time of withdrawal testing or to differences in central ethanol concentrations during the treatment. 8. It is suggested that the results provide evidence for a functional role for dihydropyridine-sensitive calcium channels in ethanol dependence.

Adaptation, Psychological↗
PubMed1991

Nitrendipine, given during drinking, decreases the electrophysiological changes in the isolated hippocampal slice, seen during ethanol withdrawal.

1. Extracellular recordings were made from mouse isolated hippocampal slices prepared after chronic treatment in vivo with either ethanol or ethanol plus the dihydropyridine calcium channel antagonist, nitrendipine. 2. The withdrawal of ethanol caused a variety of changes in the field potentials, as previously reported, including decreases in the thresholds for eliciting single and multiple population spikes, increases in paired pulse potentiation and shifts to the left of the input/output curves. 3. The addition of nitrendipine to the drinking mixture in the chronic ethanol treatment significantly decreased all the changes in the field potentials that were seen after ethanol withdrawal. 4. Addition of nitrendipine to the perfusion medium also decreased the signs of hyperexcitability seen in the hippocampal slices during ethanol withdrawal. 5. The results provide further evidence that neuronal calcium channels may be involved in ethanol dependence and that the adaptive changes caused by chronic ethanol treatment can be modulated by alterations at dihydropyridine-sensitive sites.

Alcohol Drinking↗
PubMed1990

Patterns of changes in field potentials in the isolated hippocampal slice on withdrawal from chronic ethanol treatment of mice in vivo.

Extracellular recordings were made from isolated hippocampal slices, CA1 area, following withdrawal from chronic ethanol administration to mice of the C57 strain. The field potentials were followed for 7 h from preparation of the slices, in the absence of ethanol. Paired pulse potentiation was increased, and paired pulse inhibition decreased, in slices from ethanol-treated mice during the first four hours of the recording period. Orthodromic thresholds for elicitation of single and multiple population spikes were decreased by the ethanol treatment, in the later part of the recording period. The input/output curves for population spike area and population excitatory postsynaptic potential slope showed a shift to the left for the slices from ethanol-treated animals, but no change in the maximal response. Antidromic stimulation also demonstrated decreases in thresholds for single and multiple population spikes in tissues from ethanol-treated animals, during the later half of the recording period. The results indicate that there are several mechanisms by which neuronal excitability increases on withdrawal from chronic ethanol treatment. The changes follow different time courses and suggest multiple mechanisms underlying the behavioural signs seen during the ethanol withdrawal syndrome.

Alcoholism↗
PubMed1990

Effects of dihydropyridine calcium channel antagonists in ethanol withdrawal; doses required, stereospecificity and actions of Bay K 8644.

The effects of dihydropyridine calcium channel antagonists, and the calcium channel activator, Bay K 8644, were examined on the convulsive behaviour induced by handling in mice following withdrawal from chronic ethanol inhalation. Nimodipine and nitrendipine and PN 200-110 significantly decreased the convulsive behaviour, after intraperitoneal doses of the same order of magnitude as have been found by others to be required for displacement of radiolabelled dihydropyridine in the CNS. The (+) isomer of PN 200-110 was effective, but the (-) isomer, which is ineffective in vitro, had no significant action. Bay K 8644 prevented the actions of nimodipine against the ethanol withdrawal syndrome. The behavioural ratings after nimodipine plus Bay K 8644 were significantly higher than after vehicle treatment. Bay K 8644 alone, when given to naive mice, caused convulsive behaviour resembling that seen in withdrawal from chronic ethanol treatment, but when given during ethanol withdrawal did not significantly increase the behavioural signs.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Action of chlormethiazole in a model of ethanol withdrawal.

Mice withdrawn from exposure for 14 days to ethanol inhalation showed the expected signs of ethanol withdrawal including convulsive behaviour. Injection of chlormethiazole (100 mg/kg) 5 h after the start of withdrawal, at the time that the convulsive behaviour was near maximal, resulted in the virtual disappearance of the withdrawal-induced behaviour within 30 min, with its reappearance by 60 min. A dose of chlormethiazole of 40 mg/kg was without effect. The time course of the effect of chlormethiazole (100 mg/kg) in the withdrawal test was similar to its effect in raising seizure threshold and decreasing locomotor activity. Chlormethiazole did not alter in vitro binding of [3H]-PN 200-110 to the dihydropyridine sensitive Ca2+ channel. Chlormethiazole, a drug used clinically to treat ethanol withdrawal, has therefore been shown to be effective in this animal model of withdrawal. Dihydropyridine calcium antagonists are also active in the model but chlormethiazole is likely to work by a different mechanism and it is suggested that this may be by increasing GABAergic function.

Animals↗
PubMed1990

Adverse effects on rat cardiac function ex vivo after repeated administration of the benzodiazepine partial inverse agonist, FG7142.

1. The Langendorff preparation was used to investigate functional changes in rat heart one week after the last of a course of repeated injections of the benzodiazepine inverse agonist, FG7142 (20 mg kg-1 i.p; three times weekly for five weeks). 2. Under these conditions, FG7142 caused a statistically significant reduction in both cardiac basal tension and the inotropic effect of noradrenaline at doses giving 50 and 100% of the maximum response. 3. Basal heart rate, basal coronary perfusion pressure and the effects of noradrenaline ex vivo on these parameters were all unaffected by repeated administration of FG7142. 4. FG7142 had no intrinsic effects on cardiac function when administered in vitro. 5. We discuss mechanisms which could underlie the effects of FG7142 on cardiac tension ex vivo and consider the possibility that this action may be related to the anxiogenic or proconvulsant actions of this drug.

Animals↗
PubMed1990

Acetylcholinesterase activity in regions of mouse brain following acute and chronic treatment with a benzodiazepine inverse agonist.

1. Chronic administration of the benzodiazepine inverse agonist FG 7142 has previously been shown to induce seizure activity in mice. In the present study we have investigated the effects of acute and chronic treatment with FG 7142 in mice on the levels of acetylcholinesterase activity in cortex, hippocampus, midbrain and striatum. We have also investigated the effects of acute and chronic stress in the form of handling (vehicle-injection) on acetylcholinesterase levels. 2. A single dose of FG 7142 produced a marked elevation of total acetylcholinesterase activities in the hippocampus and midbrain when compared with vehicle-injected control levels, but the levels were not different from those in unhandled animals. 3. Acute stress, in the form of vehicle-injection produced decreases in cortical and hippocampal soluble acetylcholinesterase activity but FG 7142 had no effect upon these stress-induced changes. 4. Total cortical and hippocampal acetylcholinesterase activities were increased by 56% and 16% respectively in the chronic FG 7142-treated mice that exhibited seizure activity (compared with vehicle-injected controls). 5. Soluble acetylcholinesterase activity in the midbrain was decreased to 82% of control levels only in animals that had undergone FG 7142-induced kindling. Smaller or no changes in acetylcholinesterase activity in the midbrain were observed in chronically FG 7142-treated animals that exhibited no seizure activity. 6. Mice that did not demonstrate seizure activity in response to chronic FG 7142 treatment showed alterations in the soluble acetylcholinesterase activities of the hippocampus and midbrain. 7. It is concluded that chronic treatment with the benzodiazepine inverse agonist FG 7142 produces alterations in the acetylcholinesterase activities of various brain regions, in a manner related to the kindling that can be produced by this treatment. 8. Chronic mild stress, in the form of repeated handling (vehicle injection), induced changes in brain activity with decreases in total activity occurring in the cortex and hippocampus, and an increase in soluble acetylcholinesterase activity occurring in the midbrain. 9. All these stress-induced changes appeared to be prevented by administration of FG 7142 at the time of the stress. It would appear therefore that FG 7142 can prevent the effects of chronic stress on brain acetylcholinesterase activity.

Acetylcholinesterase↗
PubMed1990

Nitrendipine decreases benzodiazepine withdrawal seizures but not the development of benzodiazepine tolerance or withdrawal signs.

1. The effects of the calcium channel blocking agent, nitrendipine, were studied on seizures in mice produced during withdrawal from chronic benzodiazepine treatment and on the development of tolerance to benzodiazepines. 2. Nitrendipine produced a dose-dependent decrease in seizure incidence, when seizures were produced by the partial inverse agonist FG7142 during withdrawal from seven days treatment with flurazepam. 3. Nitrendipine did not raise the seizure thresholds in naïve mice to the full inverse agonist methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), or to the gamma-aminobutyric acid (GABA) antagonist, bicuculline. 4. When given concurrently with flurazepam for seven days, nitrendipine did not affect the incidence of seizures during flurazepam withdrawal. 5. When given concurrently with the benzodiazepines, nitrendipine did not prevent the development of tolerance to midazolam general anaesthesia or tolerance to the ataxic actions of flurazepam or midazolam. 6. Chronic treatment with flurazepam for seven days did not affect the Kd or Bmax of [3H]-nimodipine binding in mouse whole brain or cerebral cortex. 7. These results with benzodiazepines are partially in contrast with those for ethanol, where nitrendipine not only decreased ethanol withdrawal seizures when given acutely, but also prevented the development of tolerance and withdrawal signs when given concurrently with ethanol. However, they do confirm the selectivity of nitrendipine for withdrawal-induced seizures.

Animals↗
PubMed1989

Effects of "nitrendipine" on nitrous oxide anesthesia, tolerance, and physical dependence.

Studies with ethanol have indicated that dihydropyridine-sensitive calcium (Ca++) channels may be involved in the adaptation to prolonged exposure to ethanol. This study investigated the effects, in mice, of the dihydropyridine Ca++ antagonist, nitrendipine, on acute tolerance to nitrous oxide after 60 min exposure to anesthetizing concentrations, and also the withdrawal syndrome which occurred following removal from nitrous oxide. Control mice were anesthetized by nitrous oxide concentrations in the range 1.28-1.51 atmospheres. Nitrendipine 10, 50, and 100 mg.kg-1, i.p., produced a dose-dependent potentiation of nitrous oxide anesthesia (P less than 0.05 for nitrendipine 50 and 100 mg.kg-1). Tolerance to nitrous oxide anesthesia developed over 60 min (13% increase in ED50, P less than 0.05). Concurrent administration of nitrendipine at all doses prevented the development of nitrous oxide tolerance. After 60 min exposure to nitrous oxide 1-1.5 atmospheres, all control mice showed handling seizures. Nitrendipine diminished or prevented nitrous oxide withdrawal seizures, in a dose-dependent manner (P less than 0.05 for nitrendipine 50 and 100 mg.kg-1). These results support the importance of the role of dihydropyridine-sensitive Ca++ channels in the mechanism of tolerance and dependence to central depressant drugs. They also suggest that acute and chronic tolerance to sedative drug action may share some common pathways, and that tolerance and physical dependence may share a common mechanism through voltage-operated Ca++ channels.

Anesthesia, Inhalation↗
PubMed1989

Systemically administered glycine protects against strychnine convulsions, but not the behavioural effects of high pressure, in mice.

1. The effects of intraperitoneal administration of glycine were studied on the behavioural effects of raised ambient pressure in mice, compared with the effects of such administration on the actions of chemical convulsants. 2. Glycine did not alter the onset pressures for the occurrence of tremor, myoclonic jerks or clonic convulsions, when the ambient pressure was raised using helium. 3. Glycine showed a protective action against the convulsant effects of strychnine. 4. No protective action of glycine was found against the convulsant actions of pentylenetetrazol or bicuculline. 5. It is suggested that the results provide evidence that the high pressure neurological syndrome and strychnine convulsions have different neurophysiological origins.

Animals↗
PubMed1989

Are changes in neuronal calcium channels involved in ethanol tolerance?

Effects on the development of tolerance to ethanol of concurrent administration of the dihydropyridine calcium channel antagonist, nitrendipine, were investigated. Ethanol tolerance was induced in rats by repeated i.p. injections and measured by performance on the rotarod apparatus. Concurrent injections of nitrendipine prevented the development of tolerance to the ataxic action of ethanol. A similar effect was seen with the calcium channel antagonist PN 200-110 on tolerance to the general anesthetic effects of ethanol in mice. As previously reported, chronic ethanol administration increased the number of dihydropyridine binding sites in rat cerebral cortex. This was also prevented by the nitrendipine treatment; repeated administration of both ethanol and nitrendipine caused a decrease in the number of binding sites. The effect of nitrendipine on the tolerance was not due to alterations in body temperature, changes in blood pressure, differences in brain ethanol concentrations or residual nitrendipine in the brain at the time of testing. The results suggest that alterations in dihydropyridine-sensitive calcium channels may be involved in the adaptations that occur on chronic treatment with ethanol.

Alcoholism↗
PubMed1988

Anticonvulsant profile of the dihydropyridine calcium channel antagonists, nitrendipine and nimodipine.

The effects of the dihydropyridine calcium channel antagonists, nitrendipine and nimodipine, on convulsions produced by different mechanisms have been studied in rats. Nitrendipine and nimodipine significantly raised the thresholds to pentylenetetrazol for up to six hours after their injection. The calcium channel agonist, BAY K 8644, lowered the convulsion threshold to pentylenetetrazol and antagonised the effects of nitrendipine. In contrast, the severity of seizures produced by N-methyl-dl-aspartate (NMA) was increased by nitrendipine. BAY K 8644 also slightly increased the effects of NMA. Nimodipine and nitrendipine caused small, but significant, increases in the threshold pressures for the convulsions caused by raising the atmospheric pressure with helium gas. The compounds had no effect on strychnine convulsions. The conclusion is that the calcium channel antagonists are anticonvulsant against only certain types of convulsions, such as pentylenetetrazol and high pressure (and ethanol withdrawal, reported previously). Others may be increased, such as NMA seizures, or unaffected, such as strychnine-induced convulsions.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1988

Changes in benzodiazepine/GABA receptor complex function in benzodiazepine-tolerant mice.

Mice were given flurazepam, 40 mg k-1, IP, once daily for 7 consecutive days. Twenty-four and forty-eight hours after the last injection measurements were made of the effects on convulsion threshold, body temperature and locomotor activity, of drugs acting on the GABA receptor complex. Significant decreases were seen in the hypothermic and hypomobility effects of progabide at 48 h, but no significant changes were seen in the effects of pentylenetetrazol or pentobarbitone. The actions of picrotoxin in all three types of test and the convulsant action of bicuculline (IP) were significantly decreased at 24 h but not at 48 h. The convulsive, but not the hypothermic, effects of picrotoxin were increased at the 48 h interval. These results may suggest that the chronic benzodiazepine treatment decreased some aspects of GABA receptor function at 48 h after the last dose; however, such an effect probably does not explain the previously reported increases in the effects of inverse agonists following chronic agonist treatment.

Animals↗