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S E File

Publications and source records attributed to S E File.

At least 73 records · Page 4Linked to original sources
PubMed1997

Evidence that the median raphé nucleus--dorsal hippocampal pathway mediates diazepam withdrawal-induced anxiety.

On the basis of our previous series of experiments we had postulated that the increased anxiety that occurred during diazepam withdrawal was mediated by increased 5-HT release in the hippocampus. The present series of experiments provide evidence for a major role of the median raphé nucleus (MRN) dorsal hippocampal pathway. Rats were treated once daily for 21 days with diazepam (2 mg/kg IP) and then tested after 24 h withdrawal in the social interaction test of anxiety. Relative to chronically vehicle treated animals, those withdrawn from diazepam were significantly more anxious and had significantly greater K(+)-evoked release of [3H]-5-hydroxytryptamine (5-HT) from slices of dorsal and of ventral regions of the hippocampus. Estimation of extracellular concentrations of 5-HT within the dorsal hippocampus, using in-vivo microdialysis, showed doubling in the levels of 5-HT in the rats withdrawn from chronic diazepam treatment. This just failed to reach significance, but 33% of the rats showed dramatic increases (650%). It was not possible to test these animals in the social interaction test, but it is proposed that only the diazepam-withdrawn rats with raised extracellular levels of 5-HT would have displayed increased anxiety. 5-HT1A receptor agonists injected into the MRN decrease the MRN firing rate, and hence the release of 5-HT in the dorsal hippocampus. As a further test of our hypothesis, we examined the effects of MRN injection of the 5-HT1A receptor agonist, 8-OH DPAT, on animals withdrawn from diazepam and tested in the low light familiar condition of the social interaction test. 8-OH DPAT (50-200 ng) dose-dependently reversed the anxiogenic effect of diazepam withdrawal, while having no effects in chronic vehicle-treated animals. These results provide clear evidence that the MRN-dorsal hippocampal 5-HT pathway is at least one of the pathways playing an important role in mediating diazepam withdrawal-induced anxiety.

Animals↗
PubMed1997

Changes in tonic immobility and the GABA-benzodiazepine system in response to handling in the chick.

Changes in the GABA-benzodiazepine system were investigated following regular handling of male chicks. Compared with handling-naive chicks, those exposed to 10 days of gentle handling required a larger number of inductions and had a lower duration of tonic immobility. Corresponding biochemical changes occurred, with handling-habituated chicks having a significantly lower basal [14C]GABA release from archistriatal slices and a reduction in the Bmax of [3H]muscimol binding in the forebrain. Benzodiazepine binding in the archistriatum was investigated using in vitro quantitative receptor autoradiography. Binding was localised in the anterior, mediale, dorsalis, and ventralis intermedium nuclei of the archistriatum, and there was significantly more binding in the anterior and ventralis intermedium/mediale archistriatum nuclei than in the dorsalis intermedium archistriatum nuclei. Benzodiazepine binding was not altered after handling in any of the investigated nuclei of the archistriatum. The results suggest that whereas several days of gentle handling in chicks leads to a decrease in forebrain GABAA receptors and a decrease in GABA release from the archistriatum, there are no accompanying changes in benzodiazepine receptors. Regular handling exerts a specific effect on chicks: it reduces their fear or human beings but not that of novel places or objects. It is possible that the pattern of biochemical changes observed in the present study may be specifically associated with this particular behavioural modification rather than with a change in general fearfulness.

Animals↗
PubMed1997

Anxiolytic action of a neurokinin1 receptor antagonist in the social interaction test.

CGP 49823, a substance P antagonist acting at NK1 receptors, had significant anxiolytic effects at 3, 10 and 30 mg/kg orally in the high-light unfamiliar and low-light unfamiliar conditions of the social interaction test but was without effect in the low-light familiar condition. The effects were less marked after 3 and 6 weeks of treatment (10 mg/kg/day), indicating that some tolerance had developed, but a significant anxiolytic effect still remained. After 3 weeks of diazepam treatment (2 mg/kg/day, intraperitoneally), tolerance developed to the anxiolytic effects, and there was an anxiogenic response 24 h after withdrawal. In contrast, there were no anxiogenic withdrawal effects 24 h after 3 weeks or 24, 48 or 72 h after 6 weeks treatment with CGP 49823 (10 mg/kg/day). These results suggest that the compound may prove to be a useful anxiolytic and that substance P may play a role in mediating states of anxiety.

Animals↗
PubMed1997

Decreased 5-HT1A and increased 5-HT2A receptor binding after chronic corticosterone associated with a behavioural indication of depression but not anxiety.

The effects of chronic corticosterone treatment (100 mg pellet implanted for 1 week) were assessed in animal tests of anxiety, exploration and motor activity, and changes in binding to 5-HT1A and 5-HT2A receptors, and the 5-HT transporter, were measured. At the end of the week's treatment, the corticosterone concentration was significantly elevated and there were significant decreases in adrenal, thymus and body weights. However, there were no changes in the measures of anxiety in the social interaction test or on trials 1 and 2 of the elevated plus-maze. Also supporting a dissociation between anxiety and elevated corticosterone concentrations are previous findings that benzodiazepine withdrawal causes increased anxiety but no change in corticosteroid concentrations. Therefore these two situations provide a double dissociation between anxiety and elevated corticosteroids. Decreased 5-HT1A receptor binding in the dentate gyrus and increased 5-HT2A receptor binding in the parietal cortex was found following chronic corticosterone treatment. This reciprocal relationship between 5-HT1A and 5-HT2A receptors has been proposed to be important in mediating depression. The significant decreases in motor activity observed in all the test situations would be compatible with this proposal. Thus the constellation of behavioural and biochemical changes detected after chronic corticosterone treatment is more pertinent to depression than anxiety. One week after removal of the pellets, the behavioural and neurochemical changes had disappeared and the only differences to remain were decreased adrenal, thymus and body weights in the animals that had been treated chronically with corticosterone.

Animals↗
PubMed1996

Sex differences in benzodiazepine binding in the frontal cortex and amygdala of the rat 24 hours after restraint stress.

Marked sex differences have been reported in behavioural responses of rats 24 h after exposure to a brief period of restraint (RT) stress. In the present study, differences in benzodiazepine (BZ) binding between male and female rat litter-mates randomly allocated to control or RT groups were investigated 24 h after RT. Scatchard analysis, using [3H] flunitrazepam, was carried out on the the frontal cortex and amygdala. In the frontal cortex, females had a significantly lower affinity and a greater number of BZ receptors than males; males, but not females, showed increased affinity after RT. In the amygdala, there was a tendency towards a greater number of BZ receptors in females, with no effect of RT on receptor number or affinity. These results provide evidence of sex differences in BZ binding both under basal conditions and 24 h after RT, which could contribute to the behavioural sex differences already reported.

Amygdala↗
PubMed1996

Evidence against oppositional and pharmacokinetic mechanisms of tolerance to diazepam's sedative effects.

Acute administration of diazepam (2 mg/kg i.p.) to rats decreased the number of head-dips, locomotor activity and the number of rears made in the holeboard apparatus, indicating sedative effects. After daily treatment for 7 days with diazepam (2 mg/kg) tolerance developed to all these behavioural effects, despite serum concentrations of diazepam and N-desmethyldiazepam significantly higher than those following acute treatment. After 7 drug-free recovery days the rats were quite unresponsive to a probe dose of diazepam (2 mg/kg) and although there was a gradual recovery of responsiveness to diazepam, the reduction in rears still did not reach the level of the acute group even after 21 drug-free days. There was evidence for pharmacokinetic changes when probe doses of diazepam were given after 7, 14 or 21 recovery days. Lower levels of diazepam and higher levels of N-desmethyldiazepam than following an acute dose to the drug-naïve group were detected, indicating that the chronic treatment had resulted in a persistently enhanced rate of N-demethylation. It is argued that these changes do not fully account for the reduced responsiveness to the probe doses, and nor can they account for the gradual return of response over the 3-week recovery period. There were no detectable scrum concentrations of either compound 24 h after the end of the chronic treatment. However, no rebound increases in behavioural responses were detected at any time-point in withdrawal. Thus, the mechanism underlying this behavioural tolerance was not oppositional in nature. It is suggested that a situation-independent learned behavioural strategy is the most likely mechanism for the observed tolerance.

Animals↗
PubMed1996

5-HT1A and benzodiazepine receptors in the basolateral amygdala modulate anxiety in the social interaction test, but not in the elevated plus-maze.

In order to investigate the role of the 5-HT1A receptors of the amygdala in modulating anxiety, rats were implanted with bilateral cannulae aimed at the basolateral nucleus of the amygdala complex and infused with either artificial cerebrospinal fluid (aCSF) or the selective 5-HT1A receptor agonist 8-OH-DPAT (50-200 ng) and tested in two animal models of anxiety. In the elevated plus-maze test, no significant effects were detected in this dose range. In contrast, 8-OH-DPAT caused an overall reduction in levels of social investigation, thus indicating anxiogenic actions in the social interaction test. At 50 ng, 8-OH-DPAT had a selective action on anxiety, while at 200 ng there was a concomitant reduction in locomotor activity and, in some animals, signs of the 5-HT1A syndrome. Evidence that the anxiogenic effect of 8-OH-DPAT (50 ng) was due to activation of 5-HT1A receptors came from the finding that (-)-tertatolol, a 5-HT1A receptor antagonist, reversed this effect at a dose (1.5 micrograms) which was silent when given alone. The benzodiazepine receptor agonist, midazolam (1 and 2 micrograms) was bilaterally administered into the basolateral nucleus of the amygdala and evoked clear-cut anxiolytic effects in the social interaction test. These data indicate that the agonist activation of post-synaptic 5-HT1A receptors in the basolateral nucleus of the amygdala may produce anxiogenic effects, while agonist activation of BDZ receptors in the same areas evokes anxiolytic effects. Our results from the social interaction test are similar to those previously reported from tests of anxiety using punished paradigms, but contrast with those found in the elevated plus-maze. Thus, it is concluded that either the two tests have different sensitivities to midazolam and 8-OH-DPAT or more intriguingly, the tests are evoking fundamentally different states of anxiety, with that evoked by the plus-maze being mediated via brain areas or receptors different from those studied here.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Comparative study of pre- and postsynaptic 5-HT1A receptor modulation of anxiety in two ethological animal tests.

The purpose of this study was to determine the roles of the presynaptic 5-hydroxtryptamine1A (5-HT1A) receptors in the median raphé nucleus (MRN) and of the postsynaptic 5-HT1A receptors in its projection area of the dorsal hippocampus in the social interaction and elevated plus-maze tests of anxiety. Direct administration of the 5-HT1A receptor agonist (+/-)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT, 200 ng) into the MRN had significant anxiolytic effects in all three test situations examined (social interaction, plus-maze trails 1 and 2). These anxiolytic effects were antagonized by a silent dose (200 ng) of the 5-HT1A receptor antagonist WAY 100635, confirming that they were mediated by 5-HT1A receptors. In contrast, after bilateral administration to the dorsal hippocampus, 8-0H-DPAT (100 ng) had significant anxiogenic effects in the social interaction test and in plus-maze trial 2. These anxiogenic effects were antagonized by silent doses of 5-HT1A receptor antagonists [(+)WAY 100135, 10 mg/kg s.c., and intrahippocampal (+/-)tertatolol, 3 microg, respectively], confirming mediation by 5-HT1A receptors. In rats naive to the plus-maze, neither 8-OH-DPAT (50, 100, or 200 ng) nor the 5-HT1A receptor antagonist (+/-)tertatolol (3 microgram) had any significant effect when administered to the dorsal hippocampus. This demonstrates that previous experience of a rat in the plus-maze has a major effect on the sensitivity of dorsal hippocampal 5-HT1A receptors, as we have demonstrated previously for the 5-HT1A receptors in the dorsal raphé nucleus. Overall, our results provide evidence that stimulation of the presynaptic 5-HT1A receptors in the MRN results in an anxiolytic action, whereas stimulation of the post-synaptic 5-HT1A receptors in its projection area results in an anxiogenic effect. These results are consistent with an overall reduction in 5-HT neurotransmission in the dorsal hippocampus having an anxiolytic effect, and they explain the relatively weak anxiolytic profile detected when 5-HT1A receptor agonists are given systemically.

Animals↗
PubMed1996

Short-term rebound anxiolytic effects and long-term changes in platelet benzodiazepine binding after pentylenetetrazole-kindling in two strains of rat.

Although there were no differences in response to an acute injection of pentylenetetrazole (PTZ), there were strain differences in the development of kindled seizures to repeated injections (PTZ; 30 mg/kg 3 times weekly for 13 injections), with Wistar rats reaching stage 4 or 5 of clonic-tonic seizures, but hooded Lister rats reaching only stage 2 or 3 of convulsive waves axially through the body. The strains also reacted differently to a test dose of PTZ (20 mg/kg) one week after the end of kindling, with the Wistar strain showing stage 3 and the Lister strain stage 2 seizures. When the rats were tested 24 h after the end of the kindling injections there was an anxiolytic effect in the social interaction test, in both the low light, familiar and the low light, unfamiliar test conditions that reached significance in the Wistar strain. The Wistar kindled rats showed an anxiolytic effect in the elevated plus-maze test of anxiety when they were tested 24 h after the end of kindling. The anxiolytic effects found 24 h after kindling could not be due to the seizure 24 h earlier, since no changes were found in rats tested 24 h after a single seizure from PTZ (60 mg/kg). When the rats were tested 1 week after the end of kindling there were no changes, compared with vehicle-injected controls, in either test of anxiety. There was no change in benzodiazepine binding in platelets of the kindled Lister rats but there was a significant increase in the kindled Wistar rats 1 week after the end of kindling and also 24 h after a single PTZ seizure. The pattern of increased platelet benzodiazepine binding did not correspond with the time course of rebound anxiolytic effects. However, after kindling it seems that there are long-lasting changes in benzodiazepine binding that are similar to the short-term increases that are found following a single seizure.

Animals↗
PubMed1996

Anxiolytic effects in the plus-maze of 5-HT1A-receptor ligands in dorsal raphé and ventral hippocampus.

The response of rats naive to, or experienced with, the elevated plus-maze test of anxiety was observed following direct administration of the 5-HT1A-receptor agonist (+/-)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) (50, 100, or 200 ng) or antagonist tertatolol (3 micrograms) into the dorsal raphé nucleus or bilaterally into the ventral hippocampus. In rats naive to the plus-maze, neither drug had a significant effect when microinjected into the dorsal raphé nucleus. However, in rats experienced with the plus-maze, 8-OH-DPAT (100 and 200 ng) had significant anxiolytic effects when administered to the dorsal raphé nucleus, which were antagonised by tertatolol (3 micrograms); this suggests they were mediated by 5-HT1A receptors. Hyperactivity (increased number of closed-arm entries) was found following bilateral injection of 8-OH-DPAT (100 ng) into the ventral hippocampus of rats naive to the plus-maze. This was not completely antagonised by tertatolol (3 micrograms). Interestingly, tertatolol (3 micrograms) itself had an anxiolytic effect which was not antagonised by 8-OH-DPAT (100 ng), suggesting the effect was not mediated by 5-HT1A receptors, and indeed other actions of tertatolol, such as those on 5-HT1B or beta-adrenergic receptors could have been involved. In rats experienced with the plus-maze, tertatolol (3 micrograms) again had a significant anxiolytic effect when administered bilaterally to the ventral hippocampus, and again, this was not antagonised by 8-OH-DPAT (100 ng). These results demonstrate that both the intracerebral location of the injection and test experience profoundly influence the effects of 5-HT1A ligands on behaviour of rats in the elevated plus-maze test of anxiety.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Differences in benzodiazepine binding in quail selectively bred for differences in tonic immobility.

We have previously found that quail selectively bred to exhibit long (LTI) or short (STI) tonic immobility responses to manual restraint differed with respect to the affinity of binding at the diazepam-sensitive benzodiazepine binding site. In the current study, binding at other components of the GABAA-benzodiazepine receptor complex was investigated. Whereas the lines did not differ in either number or affinity of GABAA receptors, we found that GABA caused significantly greater enhancement of [3H]flunitrazepam binding in the forebrains of LTI than in STI birds. There was also significantly higher binding to the diazepam-insensitive component (alcohol binding site) of the GABAA-benzodiazepine complex in the forebrain of the LTI line. It is not known, however, whether this difference in the lines is due to differences in number or affinity of these sites. It is discussed whether these manifold differences between the lines in binding at the forebrain sites of the GABAA-benzodiazepine complex could be founded on subunit differences, and whether differences in benzodiazepine binding could underlie the genetically determined behavioural differences in tonic immobility.

Animals↗
PubMed1996

Behavioural and neurochemical responses of male and female chicks to cat odour.

In the first experiment male chicks were exposed to neutral and cat odours at days 4, 7, or 10 after hatching. Of the chicks tested at day 4, few made contact with either odour cloth, but those tested at day 7 made fewer contacts with the cat odour cloth, compared with the neutral odour, spent less time in contact with it, and spent more time in the zone furthest from the cloth. These clear differences were not seen in the group tested at day 10. In a second experiment, the behaviour of day 7 male chicks was compared in the presence of neutral, disinfectant, chick blood or cat odours, and the most extreme differences were between neutral and cat odours. In a third experiment, both male and female chicks were exposed to cat odour at day 7 and both showed similar avoidance. After exposure to cat odour both sexes showed significantly reduced GABA enhancement of benzodiazepine binding; which is a change associated with increased fear. However, after exposure to cat odour, they also showed significant decreases in 5-HT availability evidenced by lower basal and K(+)-evoked [3H]-5-HT release and, in the male chicks only, by an increased [3H]-5-HT uptake from archistriatal slices. These changes in 5-HT function are in the direction associated with reduced fear and would, therefore, seem to be adaptive and compensatory in function. Neither male nor female chicks showed any differences in [14C]-GABA release or uptake as a result of exposure to cat odour. Although the pattern of response to cat odour was the same in both male and female chicks at day 7, there were significant sex differences in 5-HT and GABA tone and benzodiazepine binding; these sex differences were also found in day 10 chicks. The importance of these for sex differences in trait anxiety is discussed.

Animals↗
PubMed1996

The influence of open arm ledges and maze experience in the elevated plus-maze.

In Experiment 1, rats were tested in a plus-maze, with or without small ledges on the open arms, after injection with vehicle or chlordiazepoxide (7.5 mg/kg). They were scored either on their first or second exposure to the maze; those scored on trail 2 had received a 5-min undrugged exposure to the maze 24 h earlier. This dose of chlordiazepoxide had a significant anxiolytic effect on trial 1 only in the maze without ledges, and on trial 2 only in the maze with ledges; thus, the presence of ledges differentially affected anxiolytic sensitivity on trials 1 and 2. The results of a factor analysis study (Experiment 2) confirmed that ledges had a differential effect when rats were repeatedly exposed to the maze. Thus, in the maze without ledges, the scores reflecting anxiolytic activity on trial 1 loaded on one factor, whereas the scores from trials 2 and 3 loaded on another independent factor. In the maze with ledges, the scores reflecting anxiolytic activity on trials 1, 2, and 3 loaded on three independent factors. Considering the published evidence and the results of the present study, we suggest that both types of plus-maze may be measuring the same type of anxiety with different sensitivities on trial 1 (e.g., generalised anxiety or fear of open spaces); different types of anxiety on trial 2 (without ledges--phobia/fear of heights; with ledges--not known), and trial 3 in the maze with ledges, yet another type of anxiety. The factor analysis results are also presented for ethological measures on the plus-maze, and for activity and exploration in the holeboard. Based on the factor loadings, a composite measure of anxiety on trial 1 is presented which will increase the sensitivity of the plus-maze to anxiolytic treatments. The measures of motor activity in the plus-maze load on a different factor from those derived from the holeboard, thus cautioning against considering all measures of motor activity as interchangeable.

Animals↗
PubMed1996

Recent developments in anxiety, stress, and depression.

Recent research in the development, analysis, and pharmacology of animal tests of state anxiety is discussed, including the use of responses to predator odours, the role of learning in modifying the anxiety measured in the plus-maze, and the roles of cholinergic, NMDA, and dopaminergic systems. Developmental and genetic factors are considered with particular reference to the development of tests of trait anxiety. The roles of 5-HT1A receptors in anxiety, depression, impulsivitity, and agonistic behaviours are discussed. Recent studies on the impacts of stress on neurotransmitter, endocrine, and immune systems and the interactions between these systems are discussed, with particular emphasis on their contributions to the development of pathologic states relevant to anxiety and depression.

Animals↗
PubMed1996

Methodological considerations in neurobehavioral teratology.

Neurobehavioral teratology is a rapidly expanding field benefitting from recent advances in neurobiology and behavior and from the increasing availability of compounds with specific pharmacological actions. There is evidence that data derived from animal studies are clinically pertinent and hence animal studies are useful in extending clinical findings, in anticipating consequences of early drug exposure and, by determining the underlying neural mechanisms, in developing therapeutic approaches. However, the usefulness of animal studies crucially depends on the reliability and sensitivity of the methods used. We highlight the importance of appropriate selection of the route, dose, frequency, duration and timing of drug administration. We also emphasize the importance of not confounding treatment with litter effects and suggest that either the litter be used as the unit of analysis, or that each litter contribute only one pup to each test condition. We discuss the question of the time of testing and of testing, not only under baseline conditions, but also in conditions in which the offspring are exposed to stressful, pharmacological or cognitive challenges. We hope that future studies will benefit from these considerations and avoid the methodological weaknesses that beset some of the early studies in this field.

Animals↗
PubMed1996

Cognitive impairments of alcoholic cirrhotic patients: correlation with endogenous benzodiazepine receptor ligands and increased affinity of platelet receptors.

OBJECTIVES: To determine whether differences in cognitive function between alcoholic and non-alcoholic cirrhotic patients relate to differences in endogenous ligands for the benzodiazepine receptor and/or benzodiazepine binding. METHODS: Seventeen grade-I hepatic encephalopathic patients (nine alcoholic, eight non-alcoholic) were compared with 10 matched controls on plasma concentrations of endogenous ligands for the neuronal benzodiazepine receptor, benzodiazepine binding in platelets, and performance on tests of cognitive function. RESULTS: Both groups of patients were impaired on verbal recall and on reaction time tasks compared with controls; alcoholic patients were also impaired on Reitan's trails test and digit cancellation. Four of the 17 patients had detectable concentrations of endogenous benzodiazepine ligands and they were more impaired than other patients on trails and cancellation tests. The groups did not differ in the density of benzodiazepine platelet receptors, but receptor affinity was higher in alcoholic patients than in controls; furthermore, receptor affinity correlated with the time to complete the cancellation task and with reaction time. CONCLUSION: Alcoholic cirrhotic patients may have enhanced concentrations of ligands for neuronal and peripheral benzodiazepine receptors and these may contribute to cognitive impairments in these patients.

Adult↗
PubMed1994

5-HT1A receptors in the median raphe nucleus and dorsal hippocampus may mediate anxiolytic and anxiogenic behaviours respectively.

The behavioural response of rats in the high light unfamiliar condition of the social interaction test of anxiety was observed following direct administration of the 5-HT1A receptor agonist, (+/-)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT, 50, 100 or 200 ng) or antagonist tertatolol (3 micrograms) into the median raphe nucleus or dorsal hippocampus. In the median raphe nucleus, 8-OH-DPAT (200 ng) significantly increased social interaction without changing locomotor activity; lower doses were inactive. In the dorsal hippocampus, bilateral injection of 8-OH-DPAT (100 ng) significantly decreased social interaction, without effect on locomotor activity; both 50 and 100 ng significantly changed grooming. Tertatolol had no effect on social interaction following administration to the median raphe nucleus, but significantly increased locomotor activity. Bilateral injection of tertatolol into the dorsal hippocampus decreased social interaction and changed grooming. These effects are similar to those of 8-OH-DPAT suggesting tertatolol may have 5-HT1A receptor agonist properties. In conclusion, the findings of this study demonstrate that 5-HT1A somatodendritic autoreceptors and post-synaptic receptors mediate anxiolytic and anxiogenic effects, respectively, in the social interaction test.

8-Hydroxy-2-(di-n-propylamino)tetralin↗