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S E File

Publications and source records attributed to S E File.

At least 19 recordsLinked to original sources
PubMed1992

Modification of chlordiazepoxide's behavioural and neurochemical effects by handling and plus-maze experience.

The purpose of the present experiment was to determine how a rat's prior history (of repeated gentle handling and/or of the elevated plus-maze apparatus) modified the behavioural and neurochemical response to chlordiazepoxide. In handled animals one previous exposure to the plus-maze rendered the rats insensitive to the anxiolytic effects of chlordiazepoxide in this test. This phenomenon of 'one-trial tolerance' was not seen in unhandled rats and thus both prior handling and prior maze experience were necessary to abolish the behavioural response to chlordiazepoxide. The effects of chlordiazepoxide on K(+)-evoked [14C]GABA (gamma-aminobutyric acid) release were also modified by the rat's past history. The drug-induced reduction of GABA release in the cortex was abolished by prior plus-maze experience; whereas handling modified chlordiazepoxide's effects on GABA release in the hippocampus (the drug decreased release in unhandled rats and increased release in those given repeated gentle handling). Thus an anxiolytic response to chlordiazepoxide in the plus-maze was accompanied by reduced GABA release in both cortex and hippocampus. The 5-HT system (5-hydroxytryptamine) also proved sensitive to the rats' past history. The effects of chlordiazepoxide on K(+)-evoked [3H]5-HT release from the hippocampus depended on both prior handling and plus-maze experience and could be predicted from the undrugged level of evoked release; when this was low, chlordiazepoxide increased it, when it was high, chlordiazepoxide reduced it. These results raise the possibility that the beneficial effects of a benzodiazepine may depend on the baseline condition of the animals.

Animals↗
PubMed1992

The use of temazepam elixir in surgical dental sedation: a comparison with intravenous midazolam.

Out-patients attending for removal of at least one lower third molar were randomly allocated to treatment with temazepam elixir (n = 7) or intravenous midazolam (n = 8), as well as local analgesia. Patients were tested prior to drug administration and at the end of surgery. Both drugs increased heart rate and midazolam also decreased diastolic blood pressure. The two drugs caused significant, equal increases in ratings of sedation, but the reduction of anxiety was significant only for midazolam. There was significant amnesia for material presented after drug administration, as well as for dental events and this was significantly greater for midazolam. The effects of these drugs in dental patients were compared with those in normal volunteers treated in an identical manner, but without oral surgery. The drugs had similar significant cardiovascular and amnesic effects in the volunteers and the same effects on mood ratings, even though volunteers and patients differed in their pretreatment levels of anxiety and discontent. The dentist's ratings of the sedation and operating conditions were excellent in both cases. Thus temazepam elixir provided a useful sedative for oral surgery, avoiding the complications of intravenous administration. However, for equivalent levels of sedation, midazolam had greater anxiolytic and amnesic effects than temazepam.

Administration, Oral↗
PubMed1992

Acute handling stress downregulates benzodiazepine receptors: reversal by diazepam.

In rats naive to handling, the effects of an acute handling stress led to lower [3H]flunitrazepam binding in the frontal cortex, compared with animals previously habituated to handling for 2 or 21 days. This decreased binding was due to reductions in the number of receptors, not to change in affinity. Pre-incubation with diazepam (0.3, 3.0 or 30 microM) of frontal cortex homogenates taken from naive rats exposed to acute handling stress (followed by extensive washing to remove residual diazepam and endogenous modulators) led to a concentration-dependent increase in the number benzodiazepine receptors, without any change in KD. Acute in vivo administration of diazepam (4 mg/kg) prior to the handling stress was without significant effect in handling-habituated animals, but increased [3H]flunitrazepam binding in handling naive rats. Thus, handling habituation and diazepam treatment have similar actions on benzodiazepine binding and represent two ways of adapting to the stress of handling by increasing the number of benzodiazepine receptors.

Animals↗
PubMed1992

Are there changes in sensitivity to 5-HT3 receptor ligands following chronic diazepam treatment?

Administration of 1-(3-chlorophenyl)-biguanide (mCPB), a 5-HT3 receptor agonist (1 and 10 mg/kg IP), was found to be significantly anxiogenic in vehicle treated rats tested in the plus-maze, while having no significant effect in rats withdrawn for 24 h from 21 days diazepam treatment (2 mg/kg/day), suggesting a decreased agonist action at 5-HT3 receptors following withdrawal from chronic diazepam treatment. In the social interaction test, diazepam withdrawn rats showed a significant decrease in social interaction when compared to the chronic vehicle treated group. This anxiogenic response was reversed by low doses of zacopride (0.0001-0.01 mg/kg IP); in the vehicle treated animals 0.1 mg/kg was significantly anxiogenic. The overall pattern of results with zacopride is explained by suggesting that the anxiogenic effects of high doses of zacopride are detectable at low levels of 5-HT function and are due to an agonist action of the S-isomer in the rat at 5-HT3 receptors. The anxiolytic action of low doses is attributed to the R-isomer acting at the R-zacopride binding site and is enhanced in conditions of high 5-HT function, e.g. in the diazepam withdrawn rats. If this hypothesis is correct, then we would predict the R-isomer alone would be more effective in reversing the anxiogenic effects of diazepam withdrawal than the racemate, used here.

Animals↗
PubMed1992

Concurrent treatment with verapamil prevents diazepam withdrawal-induced anxiety, in the absence of altered calcium flux in cortical synaptosomes.

Rats, chronically treated with diazepam (4 mg/kg/day) for 28 days, displayed increased anxiety when tested in the elevated plus-maze, 42 hr after the last dose. This anxiogenic withdrawal response was entirely prevented by the concurrent administration of the calcium channel antagonist, verapamil. No anxiolytic effect of chronic administration of verapamil was observed in vehicle-treated rats. To investigate the possibility that increased calcium function in nerve terminals might underlie diazepam withdrawal-induced anxiety, the uptake by cortical synaptosomes of 45Ca2+ was studied. Both fast (3-sec) and slow (60-sec) phase uptake were measured. No changes in basal (5 mM), potassium-stimulated (55 mM) or net uptake were observed during either fast or slow phase uptake. It is concluded that increased calcium influx in nerve terminals in the cortex does not underlie the anxiogenic effect of withdrawal of the benzodiazepine but that further studies must be carried out in other regions of the brain.

Animals↗
PubMed1992

Effects of lorazepam on psychomotor performance: a comparison of independent-groups and repeated-measures designs.

The purpose of this study was to compare the sensitivity to the effects of lorazepam (2.5 mg) of a design using independent groups (random allocation of subjects to either a placebo or a lorazepam treatment) with a repeated-measures design (subjects tested both before and after lorazepam treatment). With both designs, it was possible to demonstrate significant and equal effects of lorazepam in tests based upon speed of responding: Lorazepam significantly increased simple reaction time and significantly decreased performance in number cancellation and symbol copying tasks. The independent-groups design was more sensitive (i.e., showed effects at a higher level of significance) to the lorazepam-induced impairment in episodic memory, as assessed in a picture recognition task, and to the lorazepam-induced impairment in a word completion task. Comparisons between the two control condition scores indicated that there were unlikely to be significant group differences with random allocation of a relative homogeneous group of volunteers, such as medical students. While either design would be appropriate for homogeneous populations, for a heterogeneous clinical population where groups cannot be matched the repeated-measures design would be preferable.

Adult↗
PubMed1992

Raised [3H]-5-HT release and 45Ca2+ uptake in diazepam withdrawal: inhibition by baclofen.

The effect of diazepam withdrawal (2 mg/kg/day) on release of [3H]-5-hydroxytryptamine(5-HT) and [14C]-GABA from rat cortical and hippocampal slices was studied. No changes in [14C]-GABA release (basal, K(+)-evoked, uptake) from slices of either region were observed. Similarly, all parameters of [3H]-5-HT release were unchanged in cortical slices. However, during diazepam withdrawal, depolarised [3H]-5-HT release from hippocampal slices was raised with no changes in basal release or uptake into the slices being found. This increase could be prevented by in vivo administration of 1 mg/kg baclofen--this dose having no significant effect on [3H]-5-HT release from hippocampal slices of control rats. To further investigate this effect, 45Ca2+ uptake into hippocampal synaptosomes was examined and found to be increased during withdrawal. This was blocked by in vitro addition of 10 microM (-)baclofen, which had no effect on 45Ca2+ uptake in controls. Inhibition of 45Ca2+ uptake by (-)baclofen was also enhanced in nonwithdrawn diazepam-treated rats, but not in rats treated acutely with diazepam. The results from both studies indicate that chronic diazepam treatment increases neuronal sensitivity to baclofen. These results are discussed with reference to the anxiogenic state during diazepam withdrawal and a recent report of reversal of this behaviour by baclofen.

Animals↗
PubMed1992

Chlordiazepoxide reduces the generalised anxiety, but not the direct responses, of rats exposed to cat odor.

Rats were treated for 5 days with vehicle or chlordiazepoxide (CDP, 5, 10, or 20 mg/kg/day) and then exposed to a cloth impregnated with a neutral or cat odor. Those exposed to cat odor made significantly fewer contacts with the cloth and spent less time in contact with it and more time sheltering than those exposed to the neutral odor. CDP (5 mg/kg) significantly increased the time in contact with both odor cloths, but there were no other significant effects in the cat odor group. Rats previously exposed to cat odor showed significant anxiogenic responses in the social interaction and elevated plus-maze tests that were significantly reversed by CDP. There was no reduction in the responses to the cat odor on a second occasion as a result of the first exposure occurring after treatment with CDP (5 or 20 mg/kg). The anxiogenic effects of pentylenetetrazole (20 mg/kg) as detected in the social interaction and plus-maze tests were unaffected by prior odor experience. It is suggested that during exposure to the cat odor the responses of rats reflect avoidance components of a phobic anxiety state. Benzodiazepines are relatively ineffective against these responses in contrast to their efficacy against the generalised anxiety responses detected in the social interaction and plus-maze tests.

Animals↗
PubMed1992

Effects of nitrendipine, chlordiazepoxide, flumazenil and baclofen on the increased anxiety resulting from alcohol withdrawal.

1. Male hooded Lister rats were fed a liquid diet containing 10% absolute ethanol for 4-5 weeks. Control rats received the liquid diet in amounts controlled to produce equal weight gain. 2. The rats were tested 7.5 h after withdrawal of ethanol and 30 min after i.p. injection with nitrendipine, chlordiazepoxide or baclofen or 20 min after i.p. injection with flumazenil. 3. Nitrendipine (25-100 mg/kg) was unable to reverse the anxiogenic responses detected on withdrawal from ethanol, but the highest dose did reduce withdrawal tremor. 4. Chlordiazepoxide (10 mg/kg), flumazenil (4 mg/kg) and baclofen (1.25 mg/kg) significantly reversed the anxiogenic response detected on withdrawal from ethanol. 5. These reversals of ethanol withdrawal responses are similar to the reversal of the increased anxiety detected on withdrawal from chronic treatment with benzodiazepines. 6. The mechanisms and clinical implications of these drug-induced reversals are discussed.

Animals↗
PubMed1991

Low but not high doses of buspirone reduce the anxiogenic effects of diazepam withdrawal.

After 21 days of treatment with diazepam (2 mg/kg/day IP) rats were tested 24 h after the last injection in the social interaction and elevated plus-maze tests of anxiety. Compared with control-treated rats, they showed significant decreases in social interaction, in the % numbers of entries onto open arms of the plus-maze and in the % of time spent on the open arms, indicating an anxiogenic response on withdrawal from diazepam. Buspirone (200 micrograms/kg SC) significantly increased social interaction in diazepam withdrawn rats and in the plus-maze also this dose significantly reversed the anxiogenic effects of diazepam withdrawal. Buspirone (400 micrograms/kg SC) was without effect in the plus-maze, but buspirone (800 micrograms/kg SC) significantly decreased the % of time spent on open arms in control-treated rats, indicating an anxiogenic effect. In the social interaction test buspirone (800 micrograms/kg SC) was without significant effect. The contrasting effects of the 200 and 800 micrograms/kg doses are discussed in terms of the pre- and post-synaptic actions of buspirone. The findings are consistent with earlier proposals that the increased anxiety during benzodiazepine withdrawal is at least partly caused by an increased release of hippocampal 5-HT.

Animals↗
PubMed1991

Diazepam withdrawal responses measured in the social interaction test of anxiety and their reversal by baclofen.

After 21 days of treatment with diazepam (0.5 or 2 mg/kg/day) rats were tolerant to the effects of diazepam to increase social interaction in the low light unfamiliar test condition of the social interaction test of anxiety. When they were tested 24 h after the last of 21 injections they showed significant decreases in social interaction, indicating an anxiogenic withdrawal response. However, the social interaction scores of rats tested 48 h after withdrawal from diazepam treatment were no longer different from those of the control group. The decreased social interaction, indicating increased anxiety, detected 24 h after withdrawal of diazepam (21 daily injections of 0.5 or 2 mg/kg), could be reversed by the usual daily diazepam dose (0.5 or 2 mg/kg, respectively) or by baclofen (0.5 or 1 mg/kg). Baclofen (2 mg/kg) was sedative in both control treated and diazepam-dependent rats, but was ineffective at reversing the decrease in social interaction seen after diazepam withdrawal. Possible sites of action mediating these effects of baclofen are discussed, and it is suggested that either post-synaptic GABAB sites in the hippocampus are involved or that the reversal of the decreased social interaction detected on withdrawal of diazepam treatment is due to a baclofen-mediated inhibition of 5-HT release in the hippocampus.

Animals↗
PubMed1991

Effects of baclofen and nitrendipine on ethanol withdrawal responses in the rat.

Withdrawal of rats from 5 weeks of a liquid ethanol diet (10%), resulted in anxiogenic responses in the social interaction and elevated plus-maze tests of anxiety. The rats withdrawn from ethanol also showed increased aggression, tremor and rearing. Baclofen (1.25 and 2.5 mg/kg), but not nitrendipine (25-100 mg/kg), reversed the anxiogenic withdrawal responses, without having any effect in control animals and without having significant sedative effects. Baclofen reduced the enhanced aggression during withdrawal of ethanol, but this may have reflected a more general anti-aggressive action. Baclofen (2.5 mg/kg) reduced the withdrawal tremor. Nitrendipine (100 mg/kg) significantly reduced withdrawal tremor, but this dose was sedative, so this was likely to be a non-specific effect. It is proposed that the anxiogenic response during withdrawal of ethanol is due to a reduced GABA function, involving both GABAA and GABAB receptors.

Aggression↗
PubMed1991

Sex differences in animal tests of anxiety.

To explore further the meaning of sexually dimorphic behavior in the open-field test, male and female hooded Lister rats were tested in three tests of anxiety. In the social interaction test, the social interaction scores of the female rats were lower and did not increase as readily following familiarization to the apparatus as those of the male rats. In the elevated plus-maze test, female rats showed a reduced aversion to the open arms compared to male rats; and in a modified Vogel conflict test, the punished licking rates of the female rats were lower than those of the male rats. It is concluded that the behavior of male and female rats differs in these tests, but that firm conclusions concerning sex differences in anxiety levels cannot be made because all three tests did not lead to predictions which were in the same direction. It is also suggested that cautious interpretation is necessary because these tests may measure different variables in male and female rats and they may not be valid tests of anxiety for female rats.

Animals↗
PubMed1991

Amnesia for dental procedures and mood change following treatment with nitrous oxide or midazolam.

Fifty-eight patients undergoing restorative dental treatment at Guy's Hospital had been previously allocated on the basis of clinical assessment, including that of their dental anxiety, to treatment under local anaesthetic alone or in combination with i.v. midazolam or inhalation nitrous oxide. They were tested before and after dental treatment to determine their memory of dental procedures and changes in mood and bodily symptoms. The patients allocated to the midazolam treatment had significantly higher pre-treatment scores on the Bond & Lader mood factors of "anxiety" and "discontent". All the groups showed significant pre- to post-treatment reductions in sweating, palpitations, restlessness, dry mouth, muscular tension, nausea, loss of appetite and upset stomach and the extent of these reductions were not different for the different treatments. Midazolam treatment resulted in significantly greater reductions in self-ratings of bodily symptoms of anxiety, shaking and trembling compared with the control (local anaesthetic) group. Nitrous oxide resulted in a significant reduction in irritability, compared with controls. Both midazolam and nitrous oxide significantly reduced the patients' memory of the dental procedures and the impairments in memory were independent of any changes in anxiety or sedation. Of the items remembered there were no differences between the groups in their ratings of how well explained, how pleasant or unpleasant, or how painful the procedures were.

Adult↗