Biomedical subjects

S E File

Publications and source records attributed to S E File.

At least 235 records · Page 13Linked to original sources

PubMed1984

On the convulsant action of Ro 5-4864 and the existence of a micromolar benzodiazepine binding site in rat brain.

The benzodiazepine Ro 5-4864 (60 mg/kg) produced convulsions in mice that could be antagonised either by diazepam (2-4 mg/kg) or by Ro 15-1788 (10-20 mg/kg). In mice and rats subconvulsant doses of Ro 5-4864 were proconvulsant when combined with subconvulsant doses of picrotoxin or pentylenetetrazole. Ro 15-1788 antagonised the tonic convulsions triggered by the drug combinations when it was given at the same time as Ro 5-4864; this antagonism was not observed when the drugs were injected at different times. In contrast to a previous report, we could find no evidence that Ro 5-4864 antagonised seizures induced by electroshock. Using two different ligand-binding techniques, no evidence was seen for the existence in rat brain of the previously reported "micromolar" benzodiazepine receptor, a suggested site of action of Ro 5-4864.

Animals↗

PubMed1984

Prenatal treatment with clomipramine: effects on the behaviour of male and female adolescent rats.

The tricyclic anti-depressant clomipramine (7.5 or 15 mg/kg/day) was administered to pregnant rats between days 8 and 21 of gestation. Between postnatal days 31 and 47, both male and female offspring received three behavioural test. Prenatal clomipramine (15 mg/kg/day) increased baseline acoustic startle in females, but not in males; both sexes showed greater between-day response decrements if they had received clomipramine. In the social interaction test of anxiety, males prenatally exposed to clomipramine (both dosages), and females prenatally exposed to 7.5 mg/kg/day, revealed a similar profile to that seen after chronic administration of benzodiazepines in the adult. The likelihood that differences in within-session habituation could underlie the changes in social interaction that have been found in this and other studies is assessed.

Aging↗

PubMed1984

Multiple sites of action for anxiogenic drugs: behavioural, electrophysiological and biochemical correlations.

This review describes animal models of anxiety that are able to identify an anxiogenic drug effect. Evidence is reviewed for the anxiogenic action of several drugs that act at the GABA-benzodiazepine-chloride ionophore complex in the brain. The effects of their combinations with various other drugs thought to act at the same sites are discussed. The classification of these drugs on the basis of their behavioural profiles is compared with their classification based on biochemical and electrophysiological studies.

Action Potentials↗

PubMed1984

The nature of lorazepam-induced amnesia.

The effect of lorazepam (2.5 mg) was assessed in two tests of short-term retention (digit-span and Benton Visual Retention), and in verbal learning and picture recognition tests. Lorazepam was without effect in a test of digit-span, but it impaired performance in the Benton Visual Retention and picture recognition tests. In the verbal learning test lorazepam caused a severe anterograde amnesia. Increasing arousal during the presentation of material partially overcame this effect, but also improved the performance of controls. Lorazepam-treated subjects were able to learn a backwards-reading task at a rate no different from controls. The deficits caused by lorazepam are similar to those that have been observed in patients with the amnesic syndrome.

Adult↗

PubMed1984

Behavioural effects of pentylenetetrazole reversed by chlordiazepoxide and enhanced by RO 15-1788.

The effects of low doses of pentylenetetrazole (PTZ) on exploratory behaviour and locomotor activity in the rat, were measured in the holeboard apparatus. PTZ (30 mg/kg) significantly reduced exploratory head-dipping, an effect that was significantly reversed by chlordiazepoxide (5 mg/kg) and enhanced by RO 15-1788 (20 mg/kg). RO 15-1788 (20 mg/kg) also significantly enhanced the reduction in locomotor activity produced by PTZ (30 mg/kg); although this reduction was not reversed by chlordiazepoxide (5 mg/kg) the reduction in locomotor activity with the drug combination was no greater than that with either drug alone. The results are discussed with respect to a coupling between the benzodiazepine receptors and the site at which PTZ acts.

Animals↗

PubMed1984

A pharmacokinetic study of CGS-8216, a benzodiazepine receptor ligand, in the rat.

A rapid and sensitive method is described for the determination of CGS-8216 (a pyrazoloquinoline that displaces benzodiazepines from their binding sites in the brain but which reverses some of the behavioural actions of the benzodiazepines) in plasma using high-performance liquid chromatography with ultraviolet detection. CGS-9896 serves as the internal standard. The method is applied to a pharmacokinetic study of CGS-8216 in the rat. CGS-8216 was not detectable in plasma 24 h after a single IP administration of a 10 mg/kg dose. Animals treated with five once-daily injections of CGS-8216 had plasma concentrations 30 min after the final injection that were approximately four-times those observed 30 min after a single treatment. This suggests that caution must be used in the interpretation of results from experiments using multiple administrations of CGS-8216. The compound could not be detected in brain tissue at any of the time points studied.

Animals↗

PubMed1984

Do the reductions in social interaction produced by picrotoxin and pentylenetetrazole indicate anxiogenic actions?

The effects of picrotoxin (2 and 4 mg/kg) and of pentylenetetrazole (PTZ 5, 10 and 20 mg/kg) were examined in a social-interaction test of anxiety. Picrotoxin (2 mg/kg) caused a significant reduction in active social interaction, without a concomitant reduction in motor activity, indicating an anxiogenic action. Picrotoxin (4 mg/kg) and pentylenetrazole (20 mg/kg) reduced social interaction by more than 75% and motor activity by 40%. Although it is likely that the reduction in motor activity is secondary to the very low levels of social interaction, an unambiguous interpretation of an anxiogenic effect is not possible. Increased concentrations of corticosterone in plasma following administration of picrotoxin were consistent with the drug being anxiogenic. Chlordiazepoxide (5 mg/kg) significantly reversed the reductions in social interaction and locomotor activity following injection of picrotoxin (4 mg/kg) and PTZ (20 mg/kg).

Animals↗

PubMed1984

Repeated electroconvulsive shock has no specific anxiolytic effect but reduces social interaction and exploration in rats.

Administration of repeated electroconvulsive shock (ECS) to rats did not result in a specific anxiolytic profile in the social interaction test, but did significantly reduce several spontaneous behaviours: social interaction, locomotor activity, exploratory head-dipping and rearing. None of these behavioural changes was reversed by the administration of pentylenetetrazol prior to each seizure, a treatment that abolishes ECS-induced changes in GABA and 5-HT in the brain.

Analysis of Variance↗

PubMed1984

Intrinsic behavioural actions of n-propyl beta-carboline-3-carboxylate.

The behavioural effects of n-propyl beta-carboline-3-carboxylate (beta-CCP) were assessed in the social interaction test of anxiety and in the holeboard test of exploratory behaviour. n-Propyl beta-carboline-3-carboxylate (2 mg/kg) significantly reduced the time spent in social interaction without affecting locomotor activity, indicating an anxiogenic action. This reduction was not significantly reversed by chlordiazepoxide (3 mg/kg). In the holeboard, beta-CCP (4 mg/kg) reduced exploratory head-dipping and rearing; neither of these effects was significantly reversed by chlordiazepoxide (5 mg/kg). The actions of beta-CCP in these two tests are similar to those of the structurally-related compound ethyl beta-carboline-3-carboxylate.

Animals↗

PubMed1984

The stress of intruding: reduction by chlordiazepoxide.

Rats placed as intruders in a long-established colony showed significant elevations of plasma corticosterone after 10-20 minutes of intruding. This rise was prevented by 5 days pretreatment with chlordiazepoxide (5 mg/kg). The rats resident in the colony had significantly higher basal corticosterone concentrations compared with singly housed rats but the same as rats housed in groups of six in a normal cage. The resident rats showed no elevation of plasma corticosterone in response to 20 minutes of an intruder in the colony.

Aggression↗

PubMed1984

Lasting behavioral effects after treating rats with CGS 8216 on postnatal days 9 to 21.

The lasting effects of chronic exposure to CGS 8216 in early postnatal life were studied in the social interaction test of anxiety, the holeboard test of exploratory behavior, a startle test and on convulsions induced by pentylenetetrazole. Male rat pups were treated with CGS 8216 (10 or 20 mg/kg/day) from postnatal day 9 until weaning (day 21), and tested in adulthood. In the social interaction test, the pups that had been exposed to CGS 8216 during development showed increased social interaction in both unfamiliar and familiar test conditions, (particularly the latter), in contrast to the decrease in social interaction that results when CGS 8216 is given acutely to adult animals. Conversely, the developmentally-treated rats were more sensitive to the convulsant effects of pentylenetetrazole, and this effect is in the same direction as that seen in adults after acute administration. No effects of the early treatment were detected in adult animals in the holeboard or startle tests.

Animals↗

PubMed1984

Characteristics of an atypical benzodiazepine, Ro 5-4864.

Ro 5-4864 is a 1,4 benzodiazepine which, atypically, does not bind to the classical CNS benzodiazepine receptors, but has high affinity for the peripheral type of binding site found both in the periphery and in the brain. Biochemical evidence for alternative sites of action for this compound is discussed. We review the behavioral profile of Ro 5-4864 (sedative, convulsant and anxiogenic in rodents) and also describe the behavioral 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). In the light of these interactions and electrophysiological evidence we conclude that the actions of Ro 5-4864 are most likely to be mediated at the GABA-benzodiazepine receptor complex in the CNS.

Animals↗

PubMed1984

Chronic neonatal treatment with CGS 8216: effects on the behaviour of adolescent rats.

The behaviour of male adolescent rats was studied after neonatal administration of CGS 8216 (2.5 or 10 mg/kg/day). The pups were cross-fostered, and drug treatment (in a split-litter design) lasted from postnatal day 7 to day 28; behavioural tests began on day 31. In the social interaction test, neonatally-treated adolescents displayed an unusual profile of behaviour that was the opposite to the profile caused by acute CGS 8216 in adults. Their response to challenge doses of CGS 8216 was not significantly different from that of neonatal controls. In the holeboard test of exploratory behaviour, there was little sign of effects of the neonatal treatment, and the response to challenge doses of Ro 15-1788 or chlordiazepoxide was not differentially affected. However, neonatally-treated animals were less sensitive to the convulsant effects of pentylenetetrazole and picrotoxin. Lasting effects of neonatal CGS 8216 have been detected in adults; the effects seen in adolescents appear not to be identical, since a proconvulsant effect occurs in adults.

Animals↗

PubMed1984

Behavioural pharmacology of benzodiazepines.

Acute injections of benzodiazepines produce sedative effects in the rat that can be detected by decreases in spontaneous motor activity and exploration. The effects are found with low doses, are dose-related and correlate well with plasma concentrations. With repeated daily doses there is tolerance to the sedative effects within 3-5 days even with benzodiazepines with short half-lives and no active metabolites. In the rat there may be some pharmacokinetic tolerance accounting for some of the behavioural tolerance, but pharmacokinetic changes cannot explain the tolerance to low doses of chlordiazepoxide. With chronically treated rats there is no relationship between plasma benzodiazepine concentrations and sedation. There is rapid recovery from tolerance to the sedative effects and if the animals are tested undrugged there is no detectable effect 24 h after the last dose. Anxiolytic effects emerge after a few days of benzodiazepine treatment, but after 10-20 days of treatment there is tolerance to these effects in the social interaction test and in the corticosterone-stress response.

Animals↗

PubMed1984

The effects of the beta-carboline FG 7142, on intracranial self-stimulation in the rat.

The effects of FG 7142 were examined, alone and in combination with chlordiazepoxide, on self-stimulation of the mid-lateral hypothalamus. Rewarding stimuli were delivered according to a 10-sec variable-interval schedule of reinforcement. FG 7142 (1-20 mg/kg) produced a dose-related depression in responding, and chlordiazepoxide (5 mg/kg) enhanced it. When these two drugs were given together, response rates did not differ significantly from control rates.

Animals↗

PubMed1984

Pro- and anti-convulsant properties of PK 11195, a ligand for benzodiazepine binding sites: development of tolerance.

Ro 5-4864 is a benzodiazepine that differs from diazepam only in a p-chloro substituent and yet is inactive at the classical CNS binding sites. However it is a potent ligand for the peripheral type of benzodiazepine binding sites. PK 11195 is an isoquinoline carboxamide derivative that potently displaces [3H]-Ro 5-4864 from its binding sites. PK 11195 (30-60 mg kg-1) significantly reduced the incidence of convulsions caused by Ro 5-4864 (30 mg kg-1). PK 11195 (up to 120 mg kg-1) was ineffective at counteracting seizures caused by the convulsant benzodiazepine Ro 5-3663, although this dose did increase the latency to seize after injection with pentylenetetrazole. PK 11195 had no anticonvulsant actions against picrotoxin, and at 60 mg kg-1 reduced the latency to seize. This possible proconvulsant property of the isoquinoline was further explored. PK 11195 (30-90 mg kg-1) had proconvulsant actions when combined with subconvulsant doses of strychnine and picrotoxin, but had none when combined with pentylenetetrazole. No significant tolerance developed to the anticonvulsant action of PK 11195 (30 mg kg-1) even after 25 days of dosing daily. In contrast, there was rapid tolerance (within 5 days) to the proconvulsant action of PK 11195 (60 mg kg-1) with picrotoxin (3 mg kg-1). There was no cross-tolerance between the anticonvulsant actions of diazepam and PK 11195, which suggests that these two drugs act at different sites, as would be predicted from the results of the binding studies. The possible sites of action and clinical relevance of these effects are discussed.

Animals↗

PubMed1984

Modification of seizures elicited by the benzodiazepine Ro 5-3663--a comparison with picrotoxin.

Ro 5-3663 is a convulsant 1,4-benzodiazepine that does not act at the benzodiazepine, but at the picrotoxin, site. To characterize the behavioural actions of Ro 5-3663, a comparison was made between its effects and those of picrotoxin, when combined with several compounds that act at the GABA-benzodiazepine receptor complex. The quinolines, PK 8165, PK 9084 and CGS 8216 caused myoclonic jerks when combined with subconvulsant doses of Ro 5-3663 or picrotoxin; in combination with picrotoxin they also caused full tonic-clonic convulsions. Ro 15-1788 (1, 10 mg kg-1) caused myoclonic jerks when it was given 10 min before, or at the same time as, subconvulsant doses of either compound. Diazepam (2, 4 mg kg-1) was anticonvulsant against both compounds. However, Ro 15-1788 (10, 20 mg kg-1, 20 min before), PK 8165 (80 mg kg-1) and PK 9084 (60 mg kg-1) were effective only against the convulsions induced by Ro 5-3663. It is not possible to determine whether these differences between Ro 5-3663 and picrotoxin are quantitative or qualitative.

Animals↗

PubMed1984

The anxiogenic action of FG 7142 in the social interaction test is reversed by chlordiazepoxide and Ro 15-1788 but not by CGS 8216.

The effects of FG 7142 were examined in the social interaction test, alone and in combination with chlordiazepoxide, Ro 15-1788 and CGS 8216. The anxiogenic action of FG 7142 (5 mg/kg) was reversed by chlordiazepoxide (5 mg/kg) and by Ro 15-1788 (10 mg/kg), but not by CGS 8216 (10 mg/kg). The profile of FG 7142 in this test and the pattern of its interactions with other compounds is similar to that of beta-CCE, but can be distinguished from that of Ro 15-1788 and CGS 8216. It is concluded that FG 7142, Ro 15-1788 and CGS 8216 may act via different sites to produce their anxiogenic effects.

Animals↗