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S E File

Publications and source records attributed to S E File.

At least 253 records · Page 14Linked to original sources
PubMed1983

Strain differences in mice in the development of tolerance to the anti-pentylenetetrazole effects of diazepam.

The development of tolerance to the protective effects of diazepam (4 mg/kg) against seizures induced by pentylenetetrazole (PTZ) were studied in 3 strains of mice. Significant tolerance developed to protection against myoclonic jerks induced by PTZ (90-100 mg/kg) by day 5 in Tuck No. 1 and by day 10 in C3H/HE and CD-1 mice. Tolerance developed to protection against tonic-clonic convulsions by day 10 in Tuck No. 1 mice and by day 30 in the other strains. Diazepam remained protective against tonic-clonic convulsions (but not against myoclonus) induced by threshold doses of PTZ for 30 days in all 3 strains.

Animals↗
PubMed1983

Methods for the determination of lorazepam and chlordiazepoxide and metabolites in brain tissue. A comparison with plasma concentrations in the rat.

Rapid and sensitive methods are described for determining lorazepam and for determining chlordiazepoxide and its metabolites in brain tissue of the rat. Lorazepam was determined by means of solvent extraction and electron-capture gas-liquid chromatography and concentrations as low as 5 ng/g tissue could be measured. High-performance liquid chromatography with UV detection was used to determine chlordiazepoxide and its metabolites and was sensitive to 0.1 micrograms/g tissue. The methods were used to investigate the brain and plasma pharmacokinetics of these compounds in animals that had been chronically treated with lorazepam or chlordiazepoxide. In both experiments brain and plasma levels of all compounds assayed were found to correlate highly.

Animals↗
PubMed1983

Interactions of ethyl-beta-carboline-3-carboxylate and Ro 15-1788 with CGS 8216 in an animal model of anxiety.

The effect of CGS 8216 (10 mg/kg) alone and in combination with the imidazodiazepine Ro 15-1788 (10 mg/kg) or ethyl-beta-carboline-3-carboxylate (beta-CCE 1 mg/kg) was tested in the social interaction test of anxiety. All 3 compounds were found to have an anxiogenic action. When Ro 15-1788 or beta-CCE was combined with CGS 8216, no mutual antagonism of the drugs' effects was observed. The failure of Ro 15-1788 to antagonize the anxiogenic action of CGS 8216 raises the possibility that CGS 8216 might be acting at a non-benzodiazepine site.

Animals↗
PubMed1983

The behavioural effects of lorazepam are poorly related to its concentration in the brain.

The brain and plasma pharmacokinetics of lorazepam were investigated in rats that had received 5 once daily injections of 0.5 or 1.0 mg/kg of the compound. The sedative effects of the drug were also assessed using a holeboard test. Thirty minutes after the final injection of 1.0 mg/kg lorazepam animals showed a similar degree of sedation to animals tested 90 min after their final injection of 0.5 mg/kg, despite having brain concentrations of lorazepam that were 3 times higher. Four hours after 0.5 mg/kg lorazepam, when the concentration of lorazepam in the brain was very low, animals' head-dipping and locomotor activity scores were still only 60% of the controls' scores. It is concluded that brain concentrations of lorazepam are of little use in predicting the behavioural effects of the compound.

Animals↗
PubMed1983

The anxiogenic action of Ro 5-4864 is reversed by phenytoin.

Ro 5-4864, a selective ligand for the benzodiazepine micromolar and peripheral receptors, had a significant dose-related (5-20 mg/kg) anxiogenic action in the social interaction test of anxiety. This anxiogenic effect was reversed by phenytoin (10 mg/kg), a ligand for the micromolar receptors, but unaffected by the isoquinoline PK 11195 (10 mg/kg), a ligand for the peripheral receptors.

Animals↗
PubMed1983

Functional tolerance to lorazepam in the rat.

The nature of the tolerance that develops to the sedative action of lorazepam was investigated using a hole-board apparatus. Rats treated with lorazepam (0.125, 0.25 and 0.50 mg/kg) once daily for 3 days showed similar degrees of tolerance to the effects of a test dose of 0.25 mg/kg lorazepam. Tolerance was also observed in animals treated once every 2 days with lorazepam (0.50 mg/kg). Measurement of the plasma and brain concentrations of lorazepam immediately after the behavioural test showed that this tolerance was functional and not dispositional. In contrast, the behavioural effects of lorazepam were not reduced as a result of 3 days of treatment with a sedative dose of sodium pentobarbitone (20 mg/kg), although this led to lower brain concentrations of lorazepam at the time of testing.

Animals↗
PubMed1983

Tolerance to the anti-pentylenetetrazole effects of diazepam in the mouse.

The protective effects of acute and chronic diazepam administration (4 mg/kg) against seizures induced by pentylenetetrazole (PTZ) and picrotoxin were investigated. Considering the incidence of tonic-clonic convulsions, tolerance to the protective effects of diazepam was evident by day 5 if the mice were challenged with PTZ (120 mg/kg), by day 10 if the challenge was picrotoxin (8 mg/kg) and by day 20 if the challenge was PTZ (105 mg/kg). Diazepam retained its protective effects against tonic-clonic convulsions induced by PTZ (90 and 60 mg/kg) for 45 days, but the incidence of myoclonic jerks revealed tolerance after 5 days.

Animals↗
PubMed1983

RO5-4864, a ligand for benzodiazepine micromolar and peripheral binding sites: antagonism and enhancement of behavioural effects.

RO5-4864, a ligand for both the peripheral and for the central nervous system micromolar benzodiazepine binding sites, was investigated in the holeboard, alone and in combination with several other drugs. RO5-4864 alone caused a marked reduction in rears and motor activity and reduced head-dipping when objects were placed under the holes. All these reductions were enhanced by picrotoxin (2 and 4 mg/kg) and by CGS 8216 (3 mg/kg). RO15-1788 (10 mg/kg) reversed the reduction in rears and PK11195 (30 mg/kg), a putative antagonist for the peripheral binding site, reversed the reduction in head-dipping. The results are discussed in terms of the various benzodiazepine binding sites and possible non-specific drug effects.

Animals↗
PubMed1983

Output of endogenous monoamine oxidase inhibitor in rats: effect of ethanol, tryptamine and tryptophan.

Contrary to prediction, loading rats with tryptamine, tryptophan or methanol failed to produce any rise in endogenous monoamine oxidase inhibitor output, whilst ethanol administration resulted in a significantly decreased excretion. These findings, which provide no support for the hypothesis that the inhibitor is a beta-carboline, may shed some light on the tranquilizing effect of ethanol in man.

Animals↗
PubMed1983

Cold restraint alters dopamine metabolism in frontal cortex, nucleus accumbens and neostriatum.

The concentrations of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) were assayed in the striatum, nucleus accumbens and frontal cortex of rats following 2 hours of cold restraint. The concentration of DA was significantly decreased in both the striatum (-16%) and nucleus accumbens (-41%) relative to unstressed controls. The content of DOPAC was significantly increased in both striatum (+56%) and frontal cortex (+76%), but not in nucleus accumbens. The DOPAC/DA ratio was increased in all three regions, that in frontal cortex approaching three-fold. These results extend earlier findings of an activation by acute stressors of frontal cortex DA metabolism, but suggest an involvement of other DA systems as well. The finding of the greatest response in frontal cortex, and the previous observations that this was the only region to show significant changes, may be ascribed to the suggested lack of presynaptic autoreceptors in this region.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Prenatal treatment with clomipramine has an anxiolytic profile in the adolescent rat.

The tricyclic anti-depressant clomipramine (3, 10 or 30 mg/kg/day) was administered to pregnant rats between days 8 and 21 of gestation. Male pups were cross-fostered at birth and raised in litters of eight. After weaning (postnatal day 21) the offspring were raised in an enriched environment and were then subjected to a variety of behavioral tests, lasting through adolescence (days 35 to 42), and repeated in adulthood (day 70 onwards). As has been found when imipramine was administered prenatally, the offspring showed decreased rearing and less exploration; however, the latter was entirely due to more rapid habituation to the test environment. The treatment produced an anxiolytic profile when the adolescents were tested in the Social Interaction test of anxiety. Effects did not persist into adulthood, although it may be that this was the result of repeated testing.

Age Factors↗
PubMed1983

Quinolines and anxiety: anxiogenic effects of CGS 8216 and partial anxiolytic profile of PK 9084.

The effects of three quinoline derivatives, PK 8165 07.5 mg/kg). PK 9084 (7.5 mg/kg) and CGS 8216 (1 and 10 mg/kg), alone and in combination with chlordiazepoxide (5 mg/kg), were investigated in the social interaction test of anxiety. PK 8165 had no effect on social interaction but both PK 8165 and PK 9084 in combination with chlordiazepoxide produced sedation. PK 9084 exhibited a partial anxiolytic profile reflected by a drug x light interaction in the familiar test conditions. CGS 8216 (1 mg/kg) showed no significant effects on social interaction, but did counteract the sedative effect of chlordiazepoxide. The 10 mg/kg dose of CGS 8216 reduced social interaction between pairs of animals in familiar test conditions which is indicative of an anxiogenic effect. These intrinsic anxiogenic properties of CGS 8216 demonstrate that it cannot be considered an inert benzodiazepine antagonist.

Animals↗
PubMed1983

Variability in behavioral responses to benzodiazepines in the rat.

The effects of chlordiazepoxide (10 mg/kg) were assessed in a holeboard by the reductions in head-dipping, rearing and locomotor activity; the correlations among all these measures were significant. Test-retest correlations were significant for all but the time spent head-dipping. On the basis of their behavioral responses to chlordiazepoxide six "strong" and six "weak" responders were identified and used for an in vitro electrophysiological study. There were no differences between the two groups in the extent to which flurazepam potentiated muscimol, but picrotoxin showed a greater antagonism of muscimol in slices from "strong" responders and flurazepam showed a greater reduction of picrotoxin potency. There was a significant correlation between the in vitro picrotoxin shift and the chlordiazepoxide-induced reduction in locomotor activity. The correlations between behavioral responses to chlordiazepoxide and the plasma benzodiazepine concentrations were low and only one (for locomotor activity) reached significance.

Animals↗
PubMed1983

Social and exploratory behaviour in the rat after septal administration of ORG 2766 and ACTH4-10.

The time spent in active social interaction by pairs of male rats in a dimly-lit, familiar test arena, was decreased significantly after intraseptal injection of ACTH4-10 (250-500 ng). In contrast, the time spent in active social interaction was increased significantly after intraseptal injection of the tri-substituted ACTH4-9 analogue ORG 2766 (250-500 pg). Neither ACTH4-10 (250 ng) nor ORG 2766 (250 pg) affected exploration or locomotor activity measured in a holeboard, after intraseptal injection. Intraseptally administered ACTH4-10 (250 ng) increased aggression measured in a colony intruder model, but ORG 2766 (250 pg) was without effect.

Adrenocorticotropic Hormone↗
PubMed1983

Dose tolerance to lorazepam develop with once weekly dosing?

The effect of once weekly administration of lorazepam (2.5 mg) to benzodiazepine-naive student volunteers was assessed in a number of performance tests and on self-ratings. Tolerance developed to the effects of lorazepam on finger-tapping and on self-ratings of dizziness. No tolerance was observed to the drug-induced impairment in a nonsense-syllable paired associate learning test or to the effects on self-ratings of sedation or on heart rate. It is suggested that the reduced impairment in the digit-symbol substitution test observed in weeks 2 and 3 of lorazepam treatment was due to a 'masked' practice effect rather than to tolerance. Test-retest correlation coefficients were calculated for all the tests used. The effect of lorazepam in each test was also correlated with its effect in the other tests. There were significant correlations in performance on placebo in the finger-tapping (r = 0.66), digit-symbol substitution (r = 0.94), symbol copying (r = 0.96) and nonsense-syllable learning (r = 0.74) tests. It is suggested that benzodiazepine experience should be given to drug-naive subjects before they are used in cross-over experiments that involve this class of compound, since the major change in impairment occurred between the first and second exposure to lorazepam.

Adult↗
PubMed1983

Sedative effects of PK 9084 and PK 8165, alone and in combination with chlordiazepoxide.

1 The sedative effects in rats of two phenylquinolines, PK 9084 and PK 8165 (5-50 mg/kg), were examined in a holeboard: both when given alone and when given in conjunction with chlordiazepoxide (5 mg/kg). 2 Both phenylquinolines produced significant dose-related decreases in locomotor activity and rearing, with an ED50 about twice that for chlordiazepoxide. 3 When the phenylquinolines were combined with chlordiazepoxide the degree of sedation was equal to that seen with either drug given alone, whichever produced the greater sedation; the sedative effects of the two drugs were never additive. 4 PK 9084 (10 and 50 mg kg) significantly reduced rectal temperature, as did chlordiazepoxide (5 mg/kg), but there was no addition nor interaction of their effects. 5 Both phenylquinolines also reduced exploratory head-dipping, as did chlordiazepoxide, but in combination they antagonized each other's effects. 6 The classification of the phenylquinolines as non-sedative anxiolytics, acting as agonists at the benzodiazepine receptors needs revision.

Animals↗