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S E File

Publications and source records attributed to S E File.

At least 109 records · Page 6Linked to original sources
PubMed1988

Reversal of increased anxiety during benzodiazepine withdrawal: evidence for an anxiogenic endogenous ligand for the benzodiazepine receptor.

Rats were injected daily for 21 days with water or with chlordiazepoxide hydrochloride (10 mg/kg) and then tested in the elevated plus-maze 24-30 hr after the last of their chronic injections. At this time, rats withdrawn from chlordiazepoxide showed a significant decrease in the % of time spent on the open arms, compared with controls, thus indicating enhanced anxiety. The benzodiazepine antagonist, flumazenil (Ro 15-1788, 4 mg/kg, IP 20 min before test) significantly (p less than 0.01) reversed this withdrawal anxiety, and was without effect in the control group. The partial inverse agonist, FG 7142 (5 mg/kg IP 30 min before test) had no significant effect on the withdrawal anxiety. Possible mechanisms underlying the enhanced anxiety displayed by rats in withdrawal from chlordiazepoxide are discussed. It is concluded that a likely explanation is that chronic benzodiazepine treatment leads to an increased production and release of an endogenous ligand for the benzodiazepine receptor, with inverse agonist properties.

Animals↗
PubMed1988

Myoclonic seizures in the mouse induced by alphaxalone and related steroid anaesthetics.

The anaesthetic steroids alphaxalone. 5 beta-alphaxalone and pregnanolone each caused myoclonic jerks in mice in a dose-related manner between 4 and 16 mg kg-1 i.v. There was no loss of righting reflex at these doses. The veterinary product Saffan, which contains alphaxalone and alphadalone, also caused myoclonic jerks at 2 mg kg-1 i.v., and a loss of righting reflex at doses of 4 mg kg-1 and above. These effects appear to be unrelated to the wide spectrum of potencies at the GABAA receptor complex of the three individual steroids as potentiators of muscimol, or as attenuators of picrotoxin.

Anesthetics↗
PubMed1988

Evidence for simultaneous anxiolytic and aversive effects several hours after administration of sodium phenobarbitone to the rat.

Using a place conditioning paradigm, it was shown that the state experienced by rats 8 h after a 50-mg/kg dose of sodium phenobarbitone had aversive properties. However, at this same time, rats showed an increase in the percentage of time spent on the open arms of an elevated plus-maze, and an increase in the number of punished licks in a conflict test. These two effects are indicative of an anxiolytic action. It was therefore possible to demonstrate, simultaneously, an anxiolytic effect of sodium phenobarbitone and that it induced an aversive state. Conditioned place aversion could also be demonstrated 1 h after a 20-mg/kg dose of sodium phenobarbitone, but this dose was ineffective in the elevated plus-maze test of anxiety. These results provide further evidence that drugs that reduce anxiety do not necessarily have secondary positive reinforcing properties.

Animals↗
PubMed1988

Kindling with the beta-carboline FG7142 suggests separation between changes in seizure threshold and anxiety-related behaviour.

The aim of this paper was to determine whether the prolonged decrease in seizure threshold produced by chemical kindling was accompanied by behavioural changes in tests of anxiety and aggression. The responses of rats in five tests were examined after chronic treatment with the benzodiazepine inverse agonist FG7142. This treatment caused chemical kindling, so that the originally proconvulsant drug caused full seizures. This effect is very long-lasting, and our previous work with mice had suggested that it might be accompanied by an increase in anxiety-related behavior. In the present work no significant differences were found between the behaviour of FG7142-kindled rats and vehicle-treated controls in social interaction test, elevated plus maze, or the Vogel conflict test of anxiety or in tests of home cage aggression or startle responses. The results therefore show that prolonged changes in seizure threshold can occur without alterations in the apparent level of anxiety.

Aggression↗
PubMed1988

Sodium valproate and chlordiazepoxide in the elevated plus-maze test of anxiety in the rat.

The effects of sodium valproate (25-200 mg/kg i.p.) were investigated in the elevated plus-maze test of anxiety in the rat. No single dose significantly increased the percentage of entries made onto the open arms. Chlordiazepoxide (5 mg/kg) both acutely and after 5 days of administration significantly increased the percentage of entries onto open arms and this anxiolytic effect was neither potentiated, nor antagonised, by sodium valproate (25-200 mg/kg). Chlordiazepoxide also increased the total number of arm entries (indicating a stimulant effect). When valproate (25-100 mg/kg) was given together with acute chlordiazepoxide it produced a dose-related antagonism of this stimulant effect. The group receiving valproate (200 mg/kg) plus acute chlordiazepoxide (5 mg/kg) had a total number of entries significantly lower than the controls. Thus, the combination of 2 non-sedative doses resulted in a significant sedative effect.

Animals↗
PubMed1988

l-fenfluramine in tests of dominance and anxiety in the rat.

l-Fenfluramine (1.25 and 2.5 mg/kg) significantly reduced the success of dominant rats competing with untreated middle rank rats for chocolate. In resident rats, l-fenfluramine (2.5 mg/kg) significantly increased the number of submissions, and the time spent submitting, to untreated rats intruding into their home-cage territory; it also significantly reduced the number of kicks directed at, and the time spent kicking, the intruder; and the incidence of, and time spent in, aggressively grooming the intruder. When the intruder rats were treated with l-fenfluramine the only significantly change was a decrease in the number of wrestling bouts and the time spent wrestling. Since l-fenfluramine did not change other behaviours in this test (e.g. sniffing the opponent) the decrease in dominance behaviours was probably not secondary to nonspecific sedation. In the social interaction test of anxiety, l-fenfluramine (2.5 and 5 mg/kg) significantly reduced the time spent in active social interaction, and decreased motor activity. Analyses of covariance indicated that these were two independent effects. In the elevated plus-maze, l-fenfluramine (1.25-5 mg/kg) significantly decreased the percent number of entries made onto open arms, and (2.5 and 5 mg/kg) significantly decreased the percent of times spent on the open arms. The total number of arm entries was reduced by all doses (0.625-5 mg/kg). Analysis of covariance indicated that the decrease in percent of time spent on the open arms was secondary to the drop in overall activity. Thus there was no evidence of anxiolytic action in either of these tests, the changes indicating, if anything, anxiogenic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression↗
PubMed1987

Anxiety in the rat is associated with decreased release of 5-HT and glycine from the hippocampus.

Rats, implanted with dialysis loops in the dorsal hippocampus, were injected with subconvulsant doses of pentylenetetrazole (PTZ 15 and 30 mg/kg) and a 30-min sample collected for high-performance liquid chromatography (HPLC) analysis of amines and amino acids. Immediately after the sampling period they were given a 5-min test in the elevated plus-maze. On the basis of their performance in this test, they were divided into an 'anxious' and a 'non-anxious' group. The anxious group had significantly lower levels of glycine and serotonin (5-HT) release. Although PTZ decreased the release of noradrenaline, this was not correlated with behavioural differences in the elevated plus-maze.

Animals↗
PubMed1987

Evidence of strain differences in GABA-benzodiazepine coupling.

The effects of a single dose of oxazepam on seizure threshold, receptor occupancy and brain oxazepam concentration were investigated at several time points after drug treatment in two inbred strains of mice (NIH and C3H/HE). The C3H/HE strain showed a greater sensitivity to the effects of both pentylenetetrazol and oxazepam. Furthermore, the C3H/HE strain showed decreases in both receptor occupancy and seizure threshold across time, whereas the NIH strain showed no change in either measure. Although within-strain correlations were observed between seizure threshold and receptor occupancy, the C3H/HE strain had similar seizure thresholds to the NIH strain throughout but lower percentage receptor occupancies, thus a between-strain correlation was not observed. The C3H/HE strain had a higher number of specific benzodiazepine binding sits and these results may reflect a strain difference in GABA-benzodiazepine receptor coupling. In a further experiment, the development of acute tolerance to the effects of oxazepam was investigated. Brain concentrations of oxazepam and receptor occupancies were determined for each strain of mouse, at two different time points (1.5 and 7.5 h after drug treatment), at which equivalent seizure thresholds were obtained by manipulating the starting dose of oxazepam. For each strain, when equivalent seizure thresholds were observed at different time points, equivalent receptor occupancies were also observed. However, a trend towards higher brain concentrations of oxazepam at the later time point was detected for the two strains, suggesting that there may be some decrease across time in the affinity of the receptor for oxazepam.

Animals↗
PubMed1987

Corticotropin-releasing factor has an anxiogenic action in the social interaction test.

The effects of intracerebroventricular (icv) injections of corticotropin-releasing factor (CRF, 100 and 300 ng) were investigated in the social interaction test of anxiety in rats. Both doses of CRF significantly decreased active social interaction without a concomitant decrease in locomotor activity. CRF also significantly increased self-grooming, an effect that was independent of the decrease in social interaction. These results indicate an anxiogenic action for CRF. Chlordiazepoxide (CDP, 5 mg/kg ip) pretreatment reversed the anxiogenic effects of icv CRF (100 ng), but CRF did not prevent the sedative effects of CDP. There were no statistically significant changes due to CRF in locomotor activity or rears or head dipping in the holeboard test. Both doses of CRF significantly increased plasma concentrations of corticosterone. The possible mechanisms of the behavioral effects of CRF are discussed.

Animals↗
PubMed1987

The contribution of behavioural studies to the neuropharmacology of anxiety.

This article reviews animal tests of anxiety and charts the contribution of behavioural studies to the neuropharmacology of anxiety. In particular it has been possible to distinguish several sites of action for anxiogenic drugs. Whilst great progress has been made to knowledge of the functioning of the GABA-benzodiazepine receptor complex, there has been little advance in the understanding of the other neurochemical pathways concerned with mediating changes in anxiety. The claim to have a drug that is a non-sedative anxiolytic should be based on firm behavioural evidence. The extent to which this has been realised for the existing candidates is reviewed.

Adrenocorticotropic Hormone↗
PubMed1987

The effect of chlordiazepoxide on the habituation of exploration: interactions with the benzodiazepine antagonist RO 15-1788.

Rats tested on two occasions in a holeboard apparatus showed between-session habituation of exploratory activity. No habituation was observed on the measure of locomotor activity. Administration of chlordiazepoxide before the first test reduced exploratory behavior in this test and also reduced the degree of between-session habituation. Administration of RO 15-1788 reversed the effect of chlordiazepoxide on exploration in the first test, but failed to reverse the drug's effect on between-session habituation. It is unlikely that state-dependent retrieval could account for these results. The results are discussed in relation to the effects of benzodiazepines on learning and memory.

Animals↗
PubMed1987

Lack of cross-tolerance in mice between the stimulatory and depressant actions of novel anxiolytics in the holeboard.

CL 218,872, tracazolate and tofisopam are compounds that are believed to act at the GABA-benzodiazepine (BDZ) receptor complex in the CNS and that have anxiolytic properties in animals or in man. Doses of each drug were selected to elevate, or to depress, exploratory head-dipping and locomotor activity in the holeboard in mice, and the development of tolerance to these effects was investigated. As previously found with benzodiazepines, tolerance did not develop to the stimulant effects of low doses of these compounds after 10 days pretreatment with either a low (stimulant) or a high (depressant) dose of the same compound. When animals were pretreated with a low (stimulant) dose, tolerance did not develop to the depressant effects of a high test dose. Tolerance was observed only to the depressant effects of a high dose of a drug, and only when animals were also pretreated with a high dose. The results are compared with those obtained with benzodiazepines, and the ability of current theories of tolerance to account for the results is discussed.

Animals↗
PubMed1987

Anxiogenic effects in benzodiazepine withdrawal are linked to the development of tolerance.

Rats were tested in the elevated plus-maze test of anxiety after a probe injection of chlordiazepoxide (CDP 5 mg/kg) following short-term (5 days) or long-term (20 days) pretreatment with 5 or 20 mg/kg/day. After short-term pretreatment with either dose, the probe dose had anxiolytic effects (it increased the % number of entries, and % of time spent, on the open arms). After long-term pretreatment with either dose of CDP there was tolerance to these effects. When the rats were tested 24 hours after their last dose of CDP, there was no indication of spontaneous withdrawal responses in the rats from the short-term pretreatment groups, but the rats in the long-term pretreatment groups showed increased anxiety (decreases in the % number of entries, and the % of time spent, on the open arms, compared with controls). These results support suggestions that the development of tolerance and the incidence of withdrawal anxiety may both be manifestations of the underlying changes occurring during drug dependence.

Animals↗