Biomedical subjects

S E File

Publications and source records attributed to S E File.

At least 91 records · Page 5Linked to original sources

PubMed1994

Noise stress and the development of benzodiazepine dependence in the rat.

Rats housed in conditions of noise stress were given daily injections of diazepam (4 mg/kg). Significant tolerance developed to the sedative effects within 5 days of treatment, as measured by head dipping and motor activity in the holeboard and by the number of closed arm entries in the plus-maze. These results are in agreement with other reports of rapid tolerance to sedative effects. However, in contrast to the usual finding of tolerance to anxiolytic actions after 2-3 weeks of treatment, in this study no tolerance developed after 23 days of treatment to diazepam's anxiolytic effects in the plus-maze. On withdrawal from the 23 days of diazepam treatment, there was no anxiogenic response in the plus-maze. Therefore, it seems that when chronic administration of diazepam is accompanied by chronic stress, tolerance does not occur to the anxiolytic effects, although it does develop to the sedative effects.

Animals↗

PubMed1994

Raised corticosterone in the rat after exposure to the elevated plus-maze.

Rats given one or two 5-min trials in the elevated plus-maze had plasma corticosterone concentrations significantly higher than the home cage control group and there was no sign of habituation in the group given two trials. In rats given two plus-maze trials the corticosterone responses were significantly higher in the group given 10-min rather than 5-min trials. A previous experience of cat odour (1 week earlier) has no effect on the plasma corticosterone response, but did have an anxiogenic effect that could be detected by a decrease in the percentage of time spent on the open arms of the plus-maze. The results are discussed with reference to the nature of anxiety generated by trials 1 and 2 and by the trial duration in the plus-maze, and with respect to dissociation between behavioural and endocrinological measures.

Animals↗

PubMed1994

Chronic exposure to noise modifies the anxiogenic response, but not the hypoactivity, detected on withdrawal from chronic ethanol treatment.

Two groups of rats received chronic ethanol treatment in quiet or noisy housing conditions. Animals from both housing conditions were then withdrawn from ethanol for 12 h prior to testing in the social interaction and elevated plus-maze tests of anxiety. Both ethanol withdrawal groups showed marked hypoactivity (decreased motor activity and decreased closed arm entries in the plus-maze), but they differed in their anxiogenic response (decreased social interaction and percentage of time spent on the open arms), with only the group treated in quiet conditions showing a significant response. A similar pattern of results was found in rats tested 18 h after withdrawal and thus it is unlikely that the anxiogenic response was simply delayed in time. It therefore seemed that chronic exposure to noise during the chronic ethanol treatment modifies dependence, but only as assessed by measures reflecting anxiety. This implies that the adaptive changes are suppressed only in the neural pathways mediating anxiety; possible mediating factors are discussed.

Animals↗

PubMed1994

Regional differences in rat benzodiazepine binding in response to novelty and cat odour.

Laboratory rats exhibit innate behavioural and corticosterone responses when exposed to cat odour. However, not all are responsive and differences in benzodiazepine receptor binding between responders and non-responders were explored. Rats were exposed to cat odour for 5 min and based on time spent sheltering were divided into responders (n = 21; mean +/- SEM = 244 +/- 8.2 sec) or non-responders (n = 20; 43.9 +/- 4.8 sec). Four days later, both groups were randomly allocated among 3 experimental conditions: home-cage, neutral or cat odour, and killed 30 min after exposure. [3H]flunitrazepam binding was performed at two ligand concentrations (2 and 10 nM); where significant differences in single point binding were found, Scatchard analysis was performed on pooled samples. In hippocampus and frontal cortex responders had significantly lower binding than non-responders. In hippocampus this was most apparent when the rats were exposed to the novel test situation, i.e. neutral odour and was due to a reduction in affinity (Kd = 0.4 and 1.2 nM non-responders and responders). In frontal cortex, differences were significant only following exposure to cat odour (Bmax = 2663 and 1501 fmol/mg protein in non-responders and responders). The changes in amygdala were not significant.

Amygdala↗

PubMed1994

Handling alters habituation and response to stimulus change in the holeboard.

The responses of rats that had been extensively handled for 18 days were compared in the holeboard with those of rats that had received handling for only 4 days before the test. The extensively handled group showed slower between-day habituation of exploratory head-dipping. They did not differ in the number of head-dips, but spent longer head-dipping, at holes with objects than at those without. The less-handled group did not differ in the time spent head-dipping, but made more head-dips at empty holes. Both groups reacted similarly to the removal of the objects on day 4. However, the extensively handled rats showed a greater response of increased head-dipping when a novel object was introduced on day 5. The groups did not differ in their locomotor activity, but the extensively handled group made more rears. The results are discussed with respect to the neurochemical changes that have been found after repeated handling.

Animals↗

PubMed1994

Receptor binding in Japanese quail selected for long or short tonic immobility.

Japanese quail, selectively bred for long (LTI) and short (STI) tonic immobility (TI) responses, are thought to represent high and low fear groups, respectively. To study the neurochemical mechanisms underlying the behavioral distinctions, binding parameters were determined at the benzodiazepine, 5-HT1A, 5-HT3, alpha 2, and opioid receptor sites in the forebrains of the two lines. No differences were found in 5-HT1A, 5-HT3, alpha 2, mu- or kappa-opioid receptor binding between the lines. The KD for the binding of [3H]-flunitrazepam at the benzodiazepine receptor was significantly greater in the LTI than in the STI birds, indicating lower affinity for benzodiazepine ligands. The lines did not differ in benzodiazepine receptor number. Using [3H]-naltrindole, the LTI line was found to have fewer delta-opioid receptors than the STI line; the birds did not vary with respect to the affinity of these receptors. Thus, the selective breeding of the two lines has resulted in differences in benzodiazepine and delta-opioid binding, and these could produce differences in activity levels, fear, and pain responses, all of which could contribute to the tonic immobility response.

Animals↗

PubMed1994

Dizocilpine prevents the development of tolerance to the sedative effects of diazepam in rats.

Acute treatment with diazepam (2 mg/kg) decreased locomotor activity, rearing, and the number of head dips made in a holeboard. After 3 days of diazepam treatment, tolerance developed to the decreases in locomotor activity and the number of head dips, and there was an emergence of an increased time spent head dipping, compared with controls. Two days of concomitant treatment with the noncompetitive NMDA receptor antagonist, dizocilpine (0.25 mg/kg) blocked the development of tolerance and the increased time spent head dipping. In some respects, the effects of dizocilpine resembled those of holeboard experience. Thus, the rats tested daily in the holeboard after diazepam treatment showed significantly less tolerance to the decrease in locomotor activity and did not show enhanced time spent head dipping after 3 days of treatment. Possible similarities between changes induced by experience and those occurring during the development of tolerance are discussed.

Animals↗

PubMed1994

Diazepam withdrawal increases [3H]-5-HT release from rat amygdaloid slices.

The release of [3H]-5-HT and [14C]-GABA from hippocampal and amygdaloid slices was studied in a group of rats in which an anxiogenic response had been found on withdrawal of chronic diazepam treatment (2 mg/kg/day for 21 days). Basal release and uptake of [3H]-5-HT and [14C]-GABA and K(+)-evoked release of [14C]-GABA were not significantly changed in either brain region following diazepam withdrawal. However, there was a significant increase in K(+)-evoked [3H]-5-HT release from the amygdala, but not from the hippocampal, slices. These results demonstrate that increased 5-HT release from the hippocampus is not necessary to mediate the anxiogenic withdrawal response, and that raised 5-HT release in the amygdala may be sufficient to mediate this response. The results are discussed with respect to conditions, such as noise during diazepam treatment, that might produce regionally specific changes in 5-HT tone and hence modify the pattern of changes found during diazepam withdrawal.

Amygdala↗

PubMed1994

Responders and nonresponders to cat odor do not differ in other tests of anxiety.

Laboratory-bred rats can be divided into those showing clear innate behavioral responses to the odor of a predator (a cat) and those showing no response. However, these two groups did not differ in their responses to a neutral odor, or in the social interaction or elevated plus-maze tests of anxiety. This suggests a distinction between phobic anxiety (generated by cat odor) and a generalized anxiety state (generated by novelty in the other tests). Trial 2 in the plus-maze generates a state of fear that is distinct from that generated on trial 1, and one suggested to reflect phobic anxiety. Although the groups of cat responders and nonresponders did not differ in their scores on trial 2 in the plus-maze, two clear groups of responders and nonresponders could be identified on this trial (but not on trial 1 or in the social interaction test). This suggests that it is possible to identify bimodal populations of rats in tests of both innate and acquired simple phobias.

Animals↗

PubMed1994

F 2692: flumazenil-reversible anxiolytic effects but inactive on [3H]-Ro 15-4513 binding.

F 2692, a pyridazine derivative, has little affinity for benzodiazepine receptors, yet in two animal tests its anxiolytic effects have been reported to be reversed by benzodiazepine antagonists. In the rat social interaction test, after 5 days of IP treatment, F 2692 (3, 10, or 30 mg/kg) produced greater increases in social interaction than diazepam (0.3, 1, or 3 mg/kg). A comparison of acute and 5 day administration of F 2692 showed rapidly developing tolerance at all doses. The acute anxiolytic effects of F 2692 (1 mg/kg) were reversed by the benzodiazepine antagonists flumazenil (4 mg/kg) and ZK 93426 (4 mg/kg). We, therefore, examined whether F 2692 was active at a benzodiazepine binding site (the diazepam-insensitive portion of [3H]-Ro 15-4513) to which flumazenil but not flunitrazepam binds. However, F 2692 (10(-9) to 10(-4) M) was without effect on this binding. Thus, F 2692 has anxiolytic actions in the social interaction test, that are greater than those of diazepam, and which can be reversed by benzodiazepine antagonists. However, the site of action of the compound remains unknown.

Affinity Labels↗

PubMed1994

Habituation and generalization of phobic responses to cat odor.

Rats exposed to a cloth impregnated with the odor of a cat made fewer contacts with the cloth and spent more time sheltering under the food and water hopper than did rats exposed to a neutral odor. In two experiments there was little evidence of between-trial habituation of these responses to cat odor. The pattern of within-session changes depended on the trial duration (15 or 60 min) and the initial level of the avoidance responses. In order to test for conditioned generalization of the avoidance responses to the test situation, rats with two previous exposures to cat odor were given a third trial in which they were exposed to a neural odor. Experiment 1 showed that those previously exposed to cat odor for two 15 min trials spent more time sheltering when exposed to the neutral odor cloth than those previously exposed to the neutral odor. Experiment 2 confirmed this effect and found that the increase in sheltering was even more marked for a group exposed to cat odor for 60 min on trial 1. The number of contacts with the neutral odor cloth on trial 3 was reduced only in the group of high avoiders (defined as making no contacts with the cat odor cloth in the first 5 min of trial 1). Thus, both the duration of exposure to cat odor and the initial response level were important in determining the conditioned generalization of the responses to a phobic stimulus.

Animals↗

PubMed1993

The interplay of learning and anxiety in the elevated plus-maze.

In naive rats benzodiazepines have clear anxiolytic effects in the elevated plus-maze, but in rats with previous plus-maze experience benzodiazepines are ineffective. This phenomenon does not depend on the drug state on trial 1 or on the inter-trial interval and generalises across mazes of different material; it is dependent on experience of the open arm. The phenomenon of "one-trial tolerance" to the anxiolytic effect of benzodiazepines is not seen in other animal tests; and there is no equivalent phenomenon of "one-trial withdrawal" or of tolerance to anxiogenic effects in the plus-maze. The phenomenon is not seen in unhandled rats, in rats given longer trials in the plus-maze, or in those given an amnesic treatment on trial 1. It is suggested that during the first 5 min in the elevated plus-maze the rats are acquiring a fear of heights and it is this phobic anxiety state that is measured during the second 5-min trial. Thus the nature of the anxiety generated by the maze is different on trials 1 and 2. The results of a factor analysis study confirm this conclusion.

Animals↗

PubMed1993

Enhanced anxiolytic effect of zacopride enantiomers in diazepam-withdrawn rats.

The effects of a low (0.001 mg/kg) and a high (0.1 mg/kg) dose of the R(+) and S(-) enantiomers of zacopride were investigated in the elevated plus-maze in control-treated and diazepam-withdrawn rats. The rats withdrawn from diazepam were tested 36 h after the last of 28 days of treatment (2 mg/kg per day). The rats withdrawn from diazepam had a significant anxiogenic response, shown by decreases in the percentage of open arm entries and the percentage of time spent on the open arms. The low dose of S(-)-zacopride and both doses of R(+)-zacopride significantly reversed this anxiogenic response. In contrast, in the control-treated rats there were no significant effects on any measure of either isomer at doses of 0.001, 0.1 or 1 mg/kg.

Animals↗

PubMed1993

Handling history of rats modifies behavioural effects of drugs in the elevated plus-maze test of anxiety.

In rats naive to handling, but not in handling-habituated animals, baclofen (1 mg/kg) and (R,S) zacopride (1 microgram/kg) had significant anxiolytic effects, shown by an increased percentage of time spent on the open arms of the elevated plus-maze. The effects of buspirone were also modified by the animals' handling history and 200 micrograms/kg was significantly anxiogenic only in handling-habituated animals. The pattern of results is discussed in relation to biochemical differences already reported between handling-naive and handling-habituated animals, with particular respect to changes in the 5-HT system.

Animals↗

PubMed1993

Benzodiazepines increase preprocholecystokinin messenger RNA levels in rat brain.

Using in situ hybridisation, the effects of acute and chronic diazepam administration and diazepam withdrawal on preprocholecystokinin (CCK) mRNA levels in discrete regions of rat brain were determined. In cerebral cortex and a subpopulation of hippocampal neurones, CCK mRNA levels were increased after a single injection of diazepam and 24 h after withdrawal from chronic diazepam treatment, but not after chronic diazepam treatment. These results show that, in some neuronal groups, CCK mRNA expression is regulated by benzodiazepines, although there is no clear link between CCK mRNA levels and anxiety state.

Animals↗

PubMed1993

"One-trial tolerance" to the anxiolytic actions of benzodiazepines in the elevated plus-maze, or the development of a phobic state?

Diazepam (5 mg/kg) increased the number of shocks accepted by rats on two successive trials in the punished drinking test. Thus, the phenomenon of "one trial tolerance" to the anxiolytic effects of benzodiazepines in the elevated plus-maze does not generalise to this other animal test of anxiety. FG 7142 (20 mg/kg) and prior exposure to the odour of a cat had significant anxiogenic effects on two successive trials in the plus-maze. Thus the phenomenon of "one trial tolerance" does not generalise to these anxiogenic effects in the plus-maze. Furthermore, chlordiazepoxide retained its ability to counteract the anxiogenic effects in the plus-maze of prior exposure to cat odour, over successive trials. On the basis of these and previous experiments it is suggested that the state of anxiety generated on trial 2 in the plus-maze is close to a phobic state, against which benzodiazepines are relatively ineffective. Chlordiazepoxide (5 and 10 mg/kg) was also ineffective against the behavioural responses of rats during exposure to cat odour, another possible animal test of phobia. This contrasted with its efficacy against the anxiogenic effects of cat odour that subsequently generalised to and could be detected in the plus-maze.

Animals↗

PubMed1993

Increased 5-HT release mediates the anxiogenic response during benzodiazepine withdrawal: a review of supporting neurochemical and behavioural evidence.

This paper reviews the biochemical and behavioural evidence that the increased anxiety that occurs during benzodiazepine withdrawal is caused by increased 5-HT activity. In hippocampal slices taken from rats withdrawn for 24 h from chronic diazepam treatment (2 mg/kg/day for 21 days) there was a significant increase in K(+)-evoked release of [3H]5-HT and in 45Ca2+ uptake and both of these changes were reversed by the GABAB agonist, baclofen. Baclofen also reversed the anxiogenic response that is detected on withdrawal from chronic diazepam treatment. Other drugs that reduce 5-HT function (tianeptine which increases 5-HT uptake; buspirone, a 5-HT1A receptor agonist/partial agonist; zacopride, a 5-HT3 receptor antagonist) also reversed this anxiogenic response. Finally, we present data from a group of rats that did not develop tolerance to the anxiolytic effects of diazepam (2 mg/kg), even after 5 weeks treatment. This group failed to show an anxiogenic response on withdrawal from diazepam, nor was there an increase in hippocampal 5-HT release. We discuss the extent to which increased hippocampal 5-HT release can be causally linked to the increased anxiety during benzodiazepine withdrawal.

Animals↗

PubMed1993

Trial 2 in the elevated plus-maze: a different form of fear?

A factor analysis of the scores from rats given two trials in the elevated plus-maze showed that four independent factors emerged. Measures of anxiolytic activity on trial 1 (number of open arm entries and time spent on open arms) loaded on factor 1, measures of anxiolytic activity on trial 2 loaded on factor 2, the measure of general activity (number of closed arm entries) on both trials loaded on factor 3, and a measure of decision time (time spent in central square) for both trials loaded on factor 4. The independence of trials 1 and 2 anxiety measures raises the possibility that the state of anxiety/fear on the second trial in the plus-maze is qualitatively different from that on trial 1. This difference is reflected in the loss of anxiolytic action of diazepam (2 mg/kg) on trial 2. However, this occurs only when the trials are short (5 min); when they are longer (10 min) diazepam retains anxiolytic efficacy. It is concluded that during a brief (5 min) trial in the plus-maze rats acquire a specific phobic anxiety, which is relatively resistant to benzodiazepines. With a longer exposure to the plus-maze this form of fear extinguishes.

Animals↗