Biomedical subjects

S E File

Publications and source records attributed to S E File.

At least 37 records · Page 2Linked to original sources

PubMed1990

Handling habituation and chlordiazepoxide have different effects on GABA and 5-HT function in the frontal cortex and hippocampus.

In slices of frontal cortex and hippocampus from rats that had been habituated to handling for 21 days, there was significantly less 20 mM K(+)-evoked release of [14C]GABA ([14C]gamma-aminobutyric acid) compared with rats naive to handling. Handling for 21 days also significantly increased the uptake of [14C]GABA into frontal cortex and hippocampus. The change in uptake in the hippocampus was independent of any changes in release and could account for the apparent change in evoked release; in the cortex there were no independent changes in uptake and K(+)-evoked release. When the changes in uptake were taken into account, there were no independent changes in basal release of GABA in either region. HPLC analysis showed the change in uptake was not due to differences between the groups in endogenous GABA concentrations. Acute administration of chlordiazepoxide (CDP 7.5 mg/kg i.p.) to handling naive rats also significantly reduced K(+)-evoked [14C]GABA release from the cortex and hippocampus, but basal release and GABA uptake were unchanged. Neither handling nor CDP administration significantly changed the K(+)-evoked [3H]5-HT release, however, the uptake of 5-HT and its basal release in both regions were both significantly and independently increased in animals habituated to handling, compared with handling naive animals. In the hippocampus, the endogenous 5-HT concentrations were significantly lower in the rats that had received 21 days of handling, compared with handling naive rats. In the cortex the endogenous 5-hydroxyindoleacetic acid concentrations were significantly lower in the group that had been handled for 21 days. Thus both the GABA and 5-HT systems were responsive to handling habituation.

Animals↗

PubMed1990

Long-lasting effects on habituation and passive avoidance performance of a period of chronic ethanol administration in the rat.

Rats were fed a liquid diet to which an increasing concentration of ethanol was added over a period of 3 weeks; a concentration of 10% ethanol was then maintained for a further 4 weeks. The rats were then returned to a normal ad libitum diet of rat pellets. In order to assess the long-term effects of this ethanol diet, the performance of different groups of rats was assessed 3 and 5 months after the normal diet was resumed. At both times, the ex-ethanol-treated rats showed significantly impaired between-day habituation of exploratory head-dipping at holes that were empty, but normal between-day habituation of head-dipping at the hole with the same object underneath on all 3 days. The ex-ethanol-treated rats also showed a reduced response to the introduction of an object at a previously empty hole and, following this, a subsequent disruption of between-day habituation of head-dipping at this hole. Within-session habituation of head-dipping was unimpaired. There were no deficits in the acquisition or short-term retention of a passive avoidance response, but on retention testing 24 h after training the ex-ethanol-treated rats showed a decreased latency to enter the shocked compartment. On the trials 24 h and 48 h after training the rats tested 5 months after their ethanol treatment showed impaired extinction of the passive avoidance response.

Alcoholism↗

PubMed1990

A theory of benzodiazepine dependence that can explain whether flumazenil will enhance or reverse the phenomena.

Repeated administration of benzodiazepines (BDZs) produces dependence in man and animals and this is reflected in the phenomena of tolerance and withdrawal responses. In BDZ-dependent animals the BDZ-receptor antagonist flumazenil (Ro 15-1788) reverses the increased anxiety and decreased seizure threshold seen when benzodiazepine treatment is withdrawn. In contrast are reports that flumaenil enhances BDZ-withdrawal responses. Indirect influences on the direction of flumazenil's effects on anxiety are the duration and dose of BDZ treatment, whether tolerance has developed to its anxiolytic effect and whether there is an anxiogenic response on drug withdrawal. However, we conclude that the crucial factor is the anxiety level of the animal: when this is high flumazenil becomes anxiolytic; when this is low flumazenil is anxiogenic. These bidirectional effects of flumazenil can be seen in drug-naive and BDZ-dependent animals. We propose a theory of benzodiazepine dependence that can account for anxiogenic responses on drug withdrawal and for flumazenil's bidirectional effects; central to this theory is the assumption that flumazenil normalises the benzodiazepine receptor, returning it to a baseline state. Thus it is whether an animal's score lies above or below this baseline that will determine the direction of flumazenil's effect. The clinical implications of this theory are discussed. We suggest that during the development of benzodiazepine dependence, two independent adaptive biochemical mechanisms are triggered: one underlying the development of tolerance to the anxiolytic responses, the other underlying the incidence of increased anxiety on drug withdrawal. It is only changes in the latter that are induced by the administration of flumazenil.

Animals↗

PubMed1990

Changes in seizure threshold and aggression during chronic treatment with three anticonvulsants and on drug withdrawal.

Sodium phenobarbitone (20 and 70 mg/kg) had a significant anticonvulsant action against pentylenetetrazole-induced seizures, which persisted for 21 days of treatment. On drug withdrawal there was a significant decrease in seizure threshold below control level 24-48 h after the last dose of 70 mg/kg. Phenytoin (40 mg/kg) had a significant anticonvulsant action after 7 days of treatment and this persisted for 21 days of treatment. On drug withdrawal there was a significant decrease in seizure threshold 48 h after the last dose. Lorazepam (0.1 mg/kg) had a significant anticonvulsant action, but the group tested after 21 days of treatment did not differ from the controls, indicating that tolerance had developed to this effect; on drug withdrawal there was a decrease in seizure threshold from 24 to 72 h. The only drug to increase aggressive behaviour was sodium phenobarbitone (70 mg/kg); this reached significance after 14 and 21 days of treatment and occurred 8 h after drug administration; 0.5 h after drug administration phenobarbitone (70 mg/kg) abolished aggressive behaviour. After 7 days of treatment phenobarbitone (70 mg/kg) increased social behaviour 0.5 h after administration and this was still increased after 21 days of treatment. On drug withdrawal, there were no changes in aggressive behaviour, but there were significant decreases in social behaviour 24 and 48 h after phenobarbitone (70 mg/kg) withdrawal and 24, 48 and 72 h after lorazepam (0.1 mg/kg) withdrawal.

Aggression↗

PubMed1990

One-trial tolerance to the anxiolytic effects of chlordiazepoxide in the plus-maze.

Chlordiazepoxide (CDP 7.5 mg/kg) had a significant anxiolytic effect in rats tested on the plus-maze for the first time. On a second trial the control scores did not change, but those of the CDP group did and they no longer differed from controls. Rats previously tested undrugged or after flumazenil (4 mg/kg) also failed to show an anxiolytic response to CDP. Thus this phenomenon of one-trial tolerance depended on prior experience with the plus-maze. It also depended on CDP acting at the benzodiazepine receptors on trial 2, since the joint administration of CDP and flumazenil on trial 2 reversed the phenomenon.

Animals↗

PubMed1990

Characterisation of the phenomenon of "one-trial tolerance" to the anxiolytic effect of chlordiazepoxide in the elevated plus-maze.

In the elevated plus-maze test of anxiety the scores of control animals remain stable over repeated tests. However, a single prior exposure to the plus-maze renders an animal insensitive to the anxiolytic effects of chlordiazepoxide. This phenomenon of "one-trial tolerance" persisted even when the two trials were separated by as much as 2 weeks. It has previously been shown that the drug state of the animal on trial 1 is not important to the development of the phenomenon, but one-trial tolerance did not develop if a very high dose (75 mg/kg) of chlordiazepoxide was given on trial 1; it is suggested that this is due to the amnesic effects of the drug. The learning on trial 1 was not specific to a particular plus-maze and tolerance could be observed even when the maze on trial 1 was made from different material. The crucial experience on trial 1 was experience of an open arm of the maze. Whereas tolerance could be obtained as a result of a previous plus-maze experience, there was no evidence of an anxiogenic withdrawal response when rats were tested the following day undrugged. The phenomenon of one-trial tolerance is explained within our recently proposed two-factor theory of benzodiazepine dependence; it is suggested that one-trial tolerance provides a method for studying the mechanism underlying the development of tolerance to anxiolytic effects, independently from the mechanism underlying the development of withdrawal responses.

Animals↗

PubMed1990

Effects of sodium phenobarbital on motor activity and exploration in the mouse: development of tolerance and incidence of withdrawal responses.

Sodium phenobarbital (20 mg/kg) was without significant effect on exploratory head-dipping, but a higher dose (70 mg/kg) significantly reduced the number of head-dips and the time spent head-dipping 0.5 and 8 hr after acute administration. Tolerance developed rapidly, i.e., by day 7 of treatment, to these reductions. Both doses of phenobarbital significantly increased locomotor activity, the increase was more marked for the 70 mg/kg dose and for this dose was greater 8 hr after administration than 0.5 hr. No tolerance developed over 21 days of treatment to the increase in locomotor activity 0.5 hr after drug administration; some tolerance did develop by day 14 to the increase detected 8 hr after drug administration, but this is likely to be metabolic. After 21 days of treatment, sodium phenobarbital was withdrawn. Twenty-four hours after the last dose of 70 mg/kg there was a significant reduction in the time spent head-dipping; there was also significant reduction in locomotor activity, which peaked 48 hr after the last dose.

Animals↗

PubMed1990

A comparison of the effects of diazepam and scopolamine in two positively reinforced learning tasks.

In a helical maze scopolamine (0.5 and 1 mg/kg) significantly impaired the ability of rats to acquire a spatial learning task using reference memory. In contrast, diazepam (0.5-2 mg/kg) did not impair acquisition of this task and the only effect of diazepam (4 mg/kg) was likely to be secondary to sedative effects. Diazepam (0.5-4 mg/kg) did not impair 8-day retention of the helical maze. In a test of working and reference memory in which spatial processing was minimised, scopolamine (0.5 and 1 mg/kg) significantly impaired acquisition and increased the number of reference memory errors. Diazepam (1 and 4 mg/kg) did not impair acquisition of this task, but when a delay was interposed in the middle of a trial the diazepam-treated rats were slower to complete the task than the controls and made more errors of both working and reference memory. In contrast, when the rats were tested with a change of context, the diazepam-treated rats completed the task more quickly than the controls and made fewer errors of both working and reference memory.

Animals↗

PubMed1990

Interactions of anxiolytic and antidepressant drugs with hormones of the hypothalamic-pituitary-adrenal axis.

Changes in hormones of the hypothalamic-pituitary-adrenal (HPA) axis in patients suffering from anxiety and depressive disorders are reviewed, and the changes that occur when animals are exposed to test situations used preclinically to model anxiety or depression. The effects of exogenous administration of HPA hormones both clinically and in animal tests is discussed and the effects of clinically used anxiolytics and antidepressants on hormones of the HPA axis. The final section discusses stress-induced changes in the CNS.

Animals↗

PubMed1990

The history of benzodiazepine dependence: a review of animal studies.

This article provides a historical review of the animal literature relating to the development of tolerance to the behavioral effects of benzodiazepines, and the incidence of biochemical and behavioral changes that result from termination of benzodiazepine treatment (spontaneous withdrawal responses). It charts the slow emergence of a pertinent animal literature and highlights conclusions that were prevalent in 1963 (at the introduction of diazepam), 1973 (at the introduction of lorazepam), 1980 and the present day. For 25 years the animal literature has lagged behind the clinical literature, but recent studies into the neurochemical mechanisms of benzodiazepine dependence and possible treatments for withdrawal responses suggest that, at last, animal experiments may be about to make a substantial contribution.

Alcoholism↗

PubMed1990

Chronic diazepam treatment in rats causes long-lasting changes in central [3H]-5-hydroxytryptamine and [14C]-gamma-aminobutyric acid release.

The effects of chronic diazepam administration to rats on the central release of [3H]-5-hydroxytryptamine ([3H]-5-HT) and [14C]-gamma-aminobutyric acid ([14C]-GABA, ex vivo) were examined. Chronic (5 and 21 days) administration of diazepam (4 mg kg-1 i.p. daily for 21 days) reduced the K-evoked (20 mM KCl) release of [3H]-5-HT from frontal cortex by approximately 50%. Remarkably, this decrease was still present 1 week after diazepam withdrawal. Chronic diazepam treatment did not significantly affect hippocampal [3H]-5-HT release but after 21 days the K-evoked release of [14C]-GABA was more than doubled and remained elevated 30 h after withdrawal; it returned to control levels after 1 week, and decreased below control levels after 2 weeks. This study indicates that chronic diazepam treatment produces striking changes in transmitter release in rats that persist long after treatment has ceased.

Animals↗

PubMed1990

New strategies in the search for anxiolytics.

This article discusses the need for animal behavioural tests in the search for novel anxiolytics and describes in detail those tests that are ethologically-based (the social interaction, elevated plus-maze, light-dark transitions, and rat pup isolation-induced calling tests). The extent to which different animal tests might be sensitive to different types of anxiety is also discussed, with particular reference to possible differences between generalised anxiety and panic disorder.

Animals↗

PubMed1989

Antagonistic effects of caffeine and yohimbine in animal tests of anxiety.

The effect of a combination of caffeine and yohimbine was investigated in the social interaction, elevated plus-maze and punished-drinking tests of anxiety. Caffeine (40 mg/kg i.p.) had anxiogenic-like effects in the social interaction and plus-maze tests. Yohimbine (2.5 mg/kg i.p.) was anxiogenic-like in the plus-maze and displayed anticonflict activity. Unexpectedly, caffeine and yohimbine antagonized each others' effects in the social interaction and elevated plus-maze tests.

Animals↗

PubMed1989

The role of the benzodiazepine receptor in mediating long-lasting anticonvulsant effects and the late-appearing reductions in motor activity and exploration.

The number of head-dips, the time spent head-dipping, the number of rears and the locomotor activity of mice placed in a holeboard was reduced by lorazepam (0.25 mg/kg) 1 and 1.5 h after oral administration and these reductions were reversed by the benzodiazepine antagonist flumazenil (1 mg/kg). Activity returned to control levels at 3 and 4.5 h for head-dipping, and between 3 and 12 h for rearing and locomotor activity. However, significant late-appearing reductions were found for the number of head-dips and the time spent head-dipping (6 h) and rearing and locomotor activity (15 h) and these decreases could not be reversed by flumazenil. Similar results were found after oral administration of oxazepam (7 mg/kg). Oxazepam reduced the number of head-dips and time spent head-dipping at 1, 1.5 and 3 h and these reductions were reversed by flumazenil (1 mg/kg). Head-dipping activity returned to normal at 4.5 h. Significant reductions were also found for both measures at 1, 6 and 7.5 h and these late reductions could not be reversed by flumazenil. This suggests that the late-appearing reductions in holeboard behaviours, resulting from lorazepam or oxazepam administration to mice, is not mediated by the benzodiazepine receptor. This conclusion was supported by the results from in vivo binding, which showed no change in the % receptor occupancy 3-15 h after administration of lorazepam or oxazepam. In contrast to the holeboard behaviours, the anticonvulsant effects of the two drugs showed good correlations with receptor occupancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Flumazenil prevents the development of chlordiazepoxide withdrawal in rats tested in the social interaction test of anxiety.

Rats were chronically treated with chlordiazepoxide (CDP 10 mg/kg/day) or vehicle for 27 days. Twenty-four hours after their last dose, they received flumazenil (4 mg/kg) or vehicle and were tested in the social interaction test, in a low-light, familiar arena. CDP withdrawal significantly reduced the time spent in social interaction compared with controls, indicating an anxiogenic withdrawal response. This was completely reversed by flumazenil. A second group received CDP for 27 days and, in addition, received a single dose of flumazenil (4 mg/kg) 6 days before testing. Flumazenil prevented the development of the anxiogenic withdrawal response in these rats.

Animals↗

PubMed1989

Lack of effects of 5HT3 receptor antagonists in the social interaction and elevated plus-maze tests of anxiety in the rat.

The effects of three 5HT3 receptor antagonists: BRL 43964 (0.1 and 1 mg/kg, oral), GR 38032F (0.1 and 1 mg/kg, oral), and zacopride (0.01, 0.1 and 1 mg/kg, IP) were examined in low light test conditions of the social interaction test. None of the three 5HT3 receptor antagonists had a significant effect on social interaction. In contrast, in two experiments chlordiazepoxide (7.5 mg/kg) significantly increased social interaction and this effect was greatest in the unfamiliar test condition. In a third experiment, the effects of GR 38032F (0.1 and 1 mg/kg, oral) and zacopride (0.01, 0.1 and 1 mg/kg, oral) were investigated in the high light test conditions of the social interaction test; neither compound had a significant effect. In the elevated plus-maze, chlordiazepoxide (7.5 mg/kg oral or IP) significantly increased both the per cent number of entries made onto open arms and the per cent of time spent on the open arms, indicating an anxiolytic action. Zacopride (0.01, 0.1 and 1 mg/kg, oral or IP) had no significant effect in this test. The effect of the baseline rate of responding in the social interaction test on the effects of 5-HT3 antagonists is discussed. The results from the present experiment and those from other animal tests of anxiety caution against the conclusion that 5HT3 receptor antagonists are anxiolytic.

Animals↗

PubMed1989

Flumazenil but not nitrendipine reverses the increased anxiety during ethanol withdrawal in the rat.

After 7 day's gradual introduction of ethanol, rats were maintained for a further 4 weeks on a liquid diet containing 10% ethanol (mean daily dose 11.8 +/- 0.2 g/kg/day). Control-treated rats received liquid diet alone. Pairs of rats were tested in the social interaction test of anxiety 8 h after withdrawal. Withdrawal from ethanol significantly reduced the time spent in social interaction compared with controls, indicating an anxiogenic withdrawal response. Nitrendipine (50 mg/kg) had no effect on, whereas flumazenil (4 mg/kg) significantly reversed, this withdrawal response. This reversal appeared to be long-lasting as there was still no evidence of increased anxiety when rats were again withdrawn after 3 more days of ethanol diet.

Animals↗

PubMed1989

Effects of a single or repeated administration of the benzodiazepine inverse agonist FG7142 on behaviour and cortical adrenoceptor binding in the rat.

We have reported previously an increase in the number of beta-adrenoceptors in mouse cerebral cortex 7 days after kindling of seizures by repeated once-daily administration of the benzodiazepine receptor inverse agonist, FG7142. In subsequent experiments, an even larger increase in beta-adrenoceptor number was found 7 days after a single injection of this compound. The present experiments investigated whether FG7142-induced changes in adrenoceptor binding are also found in the rat and whether the effects of a single and repeated injections of this drug differ quantitatively. In view of the anxiogenic effects of FG7142, we have also tested for parallel changes in behaviours associated with anxiety and exploration. Nine days after a single injection of FG7142, the number of beta-adrenoceptors in the cerebral cortex was greater than that found after repeated administration of this compound; this difference was statistically significant. There was no difference in beta-adrenoceptor binding to tissues from chronically FG7142-treated and vehicle-injected animals and there were no changes in alpha 2-adrenoceptor binding or noradrenaline levels after either a single or repeated FG7142 treatment. Neither single nor repeated FG7142 treatment modified spontaneous behaviour in either the elevated plus-maze test of anxiety or the holeboard test of exploration. The behavioural effects of yohimbine and clenbuterol in these tests were also unaffected by FG7142. We discuss the possibility that the difference in the effects of a single and repeated administration of FG7142 on beta-adrenoceptor binding is related to the expression of kindled seizures.

Animals↗