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Publications and source records attributed to S E File.

At least 217 records · Page 12Linked to original sources
PubMed1985

What can be learned from the effects of benzodiazepines on exploratory behavior?

The purpose of this review is to assess the value of using tests of exploratory behavior to study the actions of benzodiazepines. The methods of measuring exploration and the factors influencing it are briefly described. The effects of benzodiazepines on exploratory behavior of rats and mice are reviewed; and the dangers of interpreting the results of such tests in terms of any of the clinical effects of the benzodiazepines is stressed. Finally, the interactions between benzodiazepines and other drugs acting at the GABA-benzodiazepine receptor complex are described. The results of these experiments caution against global classification of compounds as benzodiazepine "antagonists."

Animals↗
PubMed1985

Tolerance to the behavioral actions of benzodiazepines.

The evidence for tolerance to the behavioral effects in animals of benzodiazepines is reviewed. Tolerance develops rapidly (within 3-5 days) to the sedative effects and from 5 days of treatment to the anticonvulsant effects. In general, tolerance has not been found to anxiolytic effects after 7-15 days of treatment, although in the social interaction test it was found after 25 days. Tolerance has not been found to the locomotor stimulant effects up to 20 days of treatment. Dispositional tolerance does not occur following treatment with low doses and nor is there clear evidence of changes in benzodiazepine binding. Such changes could not account for the very different rates of tolerance to the different behavioral effects, but these could be explained if learned adaptation were to underlie tolerance or to influence the rate at which it develops. Whether the mechanism of learned adaptation is one of instrumental conditioning, classical conditioning or habituation will depend on the formal aspects of the test. It is therefore suggested that the different rates of tolerance are a function of the detailed arrangement of the experimental situation and not of the particular behavior measured or of the clinical effect the test is meant to reflect.

Animals↗
PubMed1985

Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat.

A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated + -maze consisting of two open arms and two enclosed arms. The use of this test for detecting such drug effects was validated behaviourally, physiologically, and pharmacologically. Rats made significantly fewer entries into the open arms than into the closed arms, and spent significantly less time in open arms. Confinement to the open arms was associated with the observation of significantly more anxiety-related behaviours, and of significantly greater plasma corticosterone concentrations, than confinement to the closed arms. Neither novelty nor illumination was a significant contributor to the behaviour of the rats on the + -maze. A significant increase in the percentage of time spent on the open arms and the number of entries into the open arms was observed only within clinically effective anxiolytics (chlordiazepoxide, diazepam and, less effectively, phenobarbitone). Compounds that cause anxiety in man significantly reduced the percentage of entries into, and time spent on, the open arms (yohimbine, pentylenetetrazole, caffeine, amphetamine). Neither antidepressants nor major tranquilisers had a specific effect. Exposure to a holeboard immediately before placement on the + -maze showed that behaviour on the maze was not clearly correlated either with exploratory head-dipping or spontaneous locomotor activity.

Analysis of Variance↗
PubMed1985

No cross-tolerance between the stimulatory and depressant actions of benzodiazepines in mice.

Doses of the benzodiazepines chlordiazepoxide and diazepam were selected that elevate, or that depress, exploratory and locomotor behaviour in the holeboard in mice, and the development of tolerance to these effects was investigated. Tolerance did not develop to the stimulant effects of low doses of these compounds after 10 or 20 days pretreatment with either a low (stimulant) dose or a high (depressant) dose of each. When animals were pretreated with a high (depressant) dose of the benzodiazepines, tolerance developed to the depressant effects of a high test dose, and in fact, after 20 days a stimulatory effect on head-dipping had developed with this dose. In contrast, however, after pretreatment with a high (depressant) dose, there was no tolerance to the stimulatory effects of a low test dose of the benzodiazepines, even after 20 days. The ability of current theories is concluded that behavioural theories of tolerance, such as an instrumental conditioning model, may be the most appropriate to explain the present results.

Animals↗
PubMed1985

A comparison of the effects of lorazepam with those of propranolol on experimentally-induced anxiety and performance.

In a double-blind cross-over study the effects of propranolol (80 mg) and of lorazepam (1 or 2.5 mg) were assessed in normal student volunteers using a number of performance tests and mood-rating and bodily symptom questionnaires. Drug effects on experimentally-induced anxiety were also studied. The high dose of lorazepam impaired performance in digit-symbol substitution, symbol copying and verbal learning tests, and increased subjects' ratings of dizziness. Both lorazepam and propranolol increased simple reaction time. Lorazepam but not propranolol increased ratings of sedation. Although the stressor increased subjects' ratings of anxiety, neither drug altered anxiety ratings. Propranolol decreased and lorazepam increased subjects' pulse. These changes were not reflected in subjects' self-ratings - lorazepam caused a reduction in ratings of palpitations. The results suggest that if administered acutely, neither drug is beneficial in the treatment of short-term anxiety associated with intellectual stress.

Adult↗
PubMed1985

The effects of triazolobenzodiazepines in two animal tests of anxiety and in the holeboard.

In addition to possessing anti-anxiety activity in man, triazolobenzodiazepines have been reported to have antidepressant and antipanic properties. In this they differ from classical 1,4-benzodiazepines that have only anti-anxiety activity. The purpose of the present study was to examine the effects of the triazolobenzodiazepines in two animal tests of anxiety and in the holeboard, to see whether clear differences could be observed between them and the 1,4-benzodiazepines. After acute administration, U-43,465 (16 mg kg-1) had a significant anxiolytic effect in the social interaction test. Neither adinazolam (1-3.5 mg kg-1) nor alprazolam (0.125-2 mg kg-1) had a significant effect. It is suggested that this is because, with adinazolam and alprazolam, doses at which anxiolytic effects can be observed are close to those at which sedative effects can be observed. U-43,465 (8-16 mg kg-1) and alprazolam (1-2 mg kg-1) had significant anxiolytic effects in the elevated plus-maze test of anxiety. U-43,465 (8-32 mg kg-1), adinazolam (0.5-5 mg kg-1) and alprazolam (0.2-2.0 mg kg-1) caused dose-related reductions in exploratory head-dipping, locomotor activity and rearing in the holeboard. In general the results seen in the three tests with the triazolobenzodiazepines alprazolam and adinazolam were similar to those seen with classical 1,4-benzodiazepines. With U-43,465, however, an anxiolytic effect was observed in the social interaction test after acute treatment; chronic treatment is required to see an effect with classical 1,4-benzodiazepines. In this U-43,465 resembles the effects of several novel non-benzodiazepine putative anxiolytic compounds that are believed to have less sedative potential than the benzodiazepines.

Alprazolam↗
PubMed1985

Pro- and anti-convulsant drug effects in combination with the convulsant benzodiazepine Ro 5-4864.

The effects of several compounds believed to act at the GABA-benzodiazepine receptor complex and which have anticonvulsant or proconvulsant properties when administered in combination with picrotoxin and pentetrazol (leptazol, pentylenetetrazole) were investigated in combination with the convulsant benzodiazepine Ro 5-4864. Tracazolate (25-100 mg kg-1) failed to affect convulsions induced by Ro 5-4864; however, they were prevented by treatment with CL 218,872 (20 mg kg-1). Compounds having proconvulsant activity in combination with a subthreshold dose of Ro 5-4864 were: CL 218,872 (5 mg kg-1), and CGS 8216 (20 mg kg-1) and FG 7142 (40 mg kg-1), two compounds characterized as 'inverse agonists' at benzodiazepine receptors. The phenylquinolines PK 8165 and PK 9084, originally believed to have anxiolytic properties, had no significant effect in combination with Ro 5-4864 (25-100 mg kg-1). The convulsant profile of Ro 5-4864 is compared with that of picrotoxin and pentetrazol.

Animals↗
PubMed1985

Effects of acute and chronic treatment on the pro- and anti-convulsant actions of CL 218, 872, PK 8165 and PK 9084, putative ligands for the benzodiazepine receptor.

CL 218,872 is a triazolopyridazine that acts at the benzodiazepine binding site. At low doses (0.5-7.5 mg kg-1) it is proconvulsant when combined with subconvulsant doses of picrotoxin but not when combined with pentetrazol (leptazol, pentylenetetrazol). At high doses (20-60 mg kg-1) CL 218,872 counteracted seizures caused by pentetrazol but not those caused by picrotoxin. There was tolerance to the proconvulsant effects after five days of treatment and to the anticonvulsant effects after 15-20 days. Two phenylquinolines, PK 8165 and PK 9084, that also act at the GABA-benzodiazepine receptor complex have proconvulsant actions in combination with picrotoxin. Significant tolerance to these effects had not developed even after 20 days of treatment. It is concluded that three different sites on the GABA-benzodiazepine complex mediate the pro- and anti-convulsant actions of CL 218,872 and the proconvulsant actions of PK 8165 and PK 9084.

Animals↗
PubMed1985

Animal models for predicting clinical efficacy of anxiolytic drugs: social behaviour.

The behavioural, physiological and pharmacological validation of one animal test of anxiety, the social interaction test, is described in detail. The effects of anxiolytic and anxiogenic drugs, and manipulations of catecholaminergic and serotonergic pathways are considered. The test is able to distinguish anxiolytic from sedative effects and is not sensitive to the actions of antidepressants or neuroleptics.

Animals↗
PubMed1985

The anxiolytic but not the sedative properties of tracazolate are reversed by the benzodiazepine receptor antagonist, Ro 15-1788.

The effects of the novel putative anxiolytic, tracazolate, were investigated in the social interaction of anxiety and the holeboard. Tracazolate (5 mg/kg) had an anxiolytic action that was no longer observed at higher doses (10-25 mg/kg); in the holeboard tracazolate produced a dose-related (5-25 mg/kg) depression of exploratory head-dipping, locomotor activity and rearing. The effects of tracazolate in the social interaction test, but not in the holeboard, could be reversed by the benzodiazepine receptor antagonist, Ro 15-1788 (10 mg/kg).

Animals↗
PubMed1985

Does the benzodiazepine antagonist Ro 15-1788 reverse the actions of picrotoxin and pentylenetetrazole on social and exploratory behaviour?

The effects of the benzodiazepine receptor antagonist, Ro 15-1788, were examined in combination with those of picrotoxin and pentylenetetrazole on social and exploratory behaviour in the rat. Both Ro 15-1788 (10 mg/kg) and picrotoxin (2 mg/kg) reduced social interaction, but there was no additive effect of these drugs together. Ro 15-1788 (10 and 20 mg/kg, which had no intrinsic effects in the holeboard alone) antagonized the reductions in exploratory head-dipping and motor activity produced by low (2 mg/kg), but not by high (4 mg/kg), doses of picrotoxin. In contrast, pentylenetetrazole (20 mg/kg) enhanced the reduction in social interaction produced by Ro 15-1788 (10 mg/kg), in accordance with previous findings that the reductions in spontaneous behaviour in the holeboard produced by pentylenetetrazole are enhanced by Ro 15-1788. These results show that there are clear functional interactions between these two compounds at the GABA-benzodiazepine receptor complex in the CNS, and that the nature of these interactions differs for picrotoxin and pentylenetetrazole.

Animals↗
PubMed1984

The anxiogenic action of Ro 15-1788 is reversed by chronic, but not by acute, treatment with chlordiazepoxide.

The benzodiazepine receptor antagonist, Ro 15-1788 (10 mg/kg) is anxiogenic in the social interaction test. Acute administration of chlordiazepoxide (5 or 10 mg/kg) did not reverse the anxiogenic effects of Ro 15-1788; however, in animals pretreated with chlordiazepoxide (5 mg/kg) for 5 days prior to testing, there was a reduction in the anxiety produced by Ro 15-1788.

Animals↗
PubMed1984

Behavioural effects of PK 8165 that are not mediated by benzodiazepine binding sites.

The phenylquinoline, PK 8165 (5-25 mg/kg), produced dose-related reductions in locomotor activity, rearing and exploratory head-dipping in a holeboard. Neither Ro 15-1788 (1, 10 or 20 mg/kg) nor CGS 8216 (1 or 10 mg/kg) was able to reverse the reductions in locomotor activity or rearing. This suggests that at least some of the behavioural effects of PK 8165 are not mediated by a site on the GABA-benzodiazepine receptor complex. This conclusion is supported by the recent report [9] that, whereas PK 8165 potently displaces benzodiazepines from their binding site in vitro, it is without effect in vivo.

Animals↗
PubMed1984

Behavioural actions of Ro 5-4864: a peripheral-type benzodiazepine?

Ro 5-4864 is a 1,4 benzodiazepine lacking typical benzodiazepine behavioural actions, and which has very low affinity for the "classical" CNS benzodiazepine binding sites. However, Ro 5-4864 has very high affinity for the peripheral type of binding site in the periphery and in the brain. Evidence is reviewed that Ro 5-4864 is sedative, convulsant and anxiogenic in rodents. We also describe the effects of combining Ro 5-4864 treatment with benzodiazepines (e.g. diazepam, chlordiazepoxide) and with other drugs that modify the activity of benzodiazepines (Ro 15-1788, CGS 8216, picrotoxin, PK 11195, phenytoin). The binding sites that might be mediating these behavioural actions of Ro 5-4864 are discussed.

Animals↗
PubMed1984

Intracranial self-stimulation distinguishes between two benzodiazepine antagonists.

Low doses of Ro 15-1788 and CGS 8216 were without effect on variable-interval self-stimulation, but completely abolished the enhancement of responding produced by chlordiazepoxide (5 mg/kg). Higher doses of Ro 15-1788, unlike other benzodiazepine receptor antagonists, produced an increase in response rates similar to that found after chlordiazepoxide. This result is consistent with its suggested action as a partial agonist. The combination of a high (benzodiazepine-like) dose of Ro 15-1788 with chlordiazepoxide produced a depression of responding similar to that seen with high doses of benzodiazepines. High doses of CGS 8216 produced a depression of self-stimulation, which was not reversed by chlordiazepoxide (5 mg/kg). Thus, the present procedure is able to distinguish contrasting behavioural effects of benzodiazepine antagonists.

Animals↗
PubMed1984

Interactions of two phenylquinolines with picrotoxin and benzodiazepines in vivo and in vitro.

PK 8165 and PK 9084 are phenylquinolines with high affinity for the benzodiazepine binding site. Both phenylquinolines were proconvulsant in combination with subconvulsant doses of picrotoxin and pentylenetetrazole in mice. Both chlordiazepoxide (10 mg/kg) and the imidazodiazepine, RO 15-1788 (10 mg/kg) prevented these tonic-clonic convulsions. In vitro studies of rat cuneate nucleus indicated that the proconvulsant actions of PK 8165 and PK 9084 could be explained by their direct, albeit slightly different, interactions with the GABA-receptor complex. PK 8165 (100 microM) alone had no effect on responses to the GABA analogue muscimol, but enhanced the potency of picrotoxin as an antagonist of muscimol and reduced the potency of flurazepam as a potentiator of muscimol. PK 9084 (100 microM) alone caused a small antagonism of muscimol, but did not affect the potency of picrotoxin; flurazepam reversed the effect of PK 9084.

Animals↗
PubMed1984

Pharmacokinetic studies on Ro 15-1788, a benzodiazepine receptor ligand, in the brain of the rat.

Methods for determining Ro 15-1788 in brain tissue were developed using gas chromatography with nitrogen-phosphorus detection, and using reverse-phase high performance liquid chromatography. Application of the methods to pharmacokinetic studies in the rat found the elimination half-life of Ro 15-1788 from rat brain to be 16 min. Ro 15-1788 was undetectable in rat plasma at the time points studied. Concentrations of Ro 15-1788 in the brain were reduced if chlordiazepoxide was coadministered.

Animals↗