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At least 127 records · Page 7Linked to original sources
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↗
PubMed1987

Effects of beta-carbolines in animal models of anxiety.

Animal models of anxiety can be classified into three main groups: those based on conflict or conditioned fear; those exploiting the anxiety produced by novelty; those in which anxiety or aversion is chemically induced. This review briefly describes the existing tests and, where available, the results obtained with beta-carbolines. Many of the beta-carbolines are anxiogenic in the tests, however ZK 91296 and ZK 93423 appear to have anxiolytic properties, and ZK 93426 has a similar profile to that of the benzodiazepine receptor antagonist RO 15-1788. By the results across the spectrum of tests, the reliability and sensitivity of the tests is assessed. The evidence that the anxiogenic and anxiolytic actions of the beta-carbolines are mediated by the BDZ binding sites is also discussed.

Animals↗
PubMed1987

Selective agonists and antagonists for 5-hydroxytryptamine receptor subtypes, and interactions with yohimbine and FG 7142 using the elevated plus-maze test in the rat.

The effects of some 5-HT receptor ligands were investigated on measures of anxiety in an elevated plus-maze test in the rat. Quipazine (2 and 4 mg kg-1), a non-specific 5-HT agonist and ritanserin (0.25-10 mg kg-1), a 5-HT2 receptor antagonist displayed anxiogenic profiles by reducing both of the measures of anxiety used in this test. Two 5-HT1A receptor ligands, buspirone (4 and 8 mg kg-1) and ipsapirone (2.5-10 mg kg-1) and the 5-HT1 agonist, RU 24969 (0.1875-1.5 mg kg-1) significantly reduced only the percentage of time spent on the open arms. (-)-Propranolol (5 and 10 mg kg-1), a 5-HT1 receptor antagonist significantly reduced only the percentage of entries made onto the open arms. Metergoline (4 mg kg-1), a non-specific 5-HT antagonist displayed anxiolytic effects in this test by increasing both measures of anxiety. The 5-HT1A receptor agonist, 8-OH-DPAT (0.0625-0.25 mg kg-1) had no effect on either of the measures of anxiety. The results from the non-specific ligands (quipazine and metergoline) are consistent with the theory that a reduction in 5-HT function reduces anxiety. However, in spite of their more selective effects on 5-HT receptors the results in this test from the more specific ligands are not consistent with a strong involvement of any single receptor subtype. The interaction studies with yohimbine and FG 7142 (beta-carboline-3-carboxylate methylamide) provided no clear evidence for a major role of 5-HT pathways in the mediation of their anxiogenic effects.

Animals↗
PubMed1987

Can anti-panic drugs antagonise the anxiety produced in the rat by drugs acting at the GABA-benzodiazepine receptor complex?

The beta-carboline FG 7142 and pentylenetetrazole, believed to act at different sites on the GABA-benzodiazepine receptor complex, have anxiogenic activity in the social interaction test in the rat. Two compounds that have anti-panic activity in man, the tricyclic antidepressant imipramine and the alpha 2-adrenoceptor agonist clonidine, were used to try to antagonise the anxiogenic effects of the 2 drugs. Imipramine (5 and 15 mg/kg) was tested after 0 or 15 days pretreatment. In neither case was it able to reverse the anxiogenic effect of pentylenetetrazole (15 mg/kg). However, after chronic treatment the effects of FG 7142 were reversed. Imipramine itself had an anxiogenic action that was significant after acute treatment, and its effects were not additive with those of FG 7142 or pentylenetetrazole, suggestive of some mutual antagonism between acute imipramine and the 2 drugs. Similar mutual antagonism was obtained after acute treatment with clonidine (0.01 and 0.025 mg/kg).

Animals↗
PubMed1987

Chronic treatment with imipramine does not reverse the effects of 3 anxiogenic compounds in a test of anxiety in the rat.

The ability of chronic treatment with imipramine (an antidepressant with anti-panic activity) to antagonise the anxiogenic effects of 3 different compounds was investigated in the elevated plus-maze. The compounds chosen are likely to produce anxiety by activity at different sites in the central nervous system: yohimbine, by blocking the alpha 2-adrenoceptor; FG 7142, by action at the beta-carboline site on the GABA-benzodiazepine receptor complex and pentylenetetrazole, by acting at the picrotoxinin site on this complex. Administration of imipramine following 21 days pre-treatment did not produce a significant consistent anxiolytic effect alone and was unable to reverse the anxiety produced by any of the 3 anxiogenic compounds. Our results are discussed in terms of the nature of the anxiety produced by the anxiogenic drugs and the sensitivity of tests of anxiety to anti-panic agents.

Animals↗
PubMed1986

Evidence that the beta-carboline, ZK 91296, can reduce anxiety in animals at doses well below those causing sedation.

The effects of ZK 91296, a beta-carboline derivative that potently displaces [3H]benzodiazepines from their CNS binding sites, were examined in two extensively validated animal tests of anxiety and in the holeboard in rats. In the social interaction test of anxiety. ZK 91296 (5 mg/kg) had an anxiolytic effect that was no longer apparent at a higher dose (15 mg/kg). In a test using exploratory activity on an elevated plus-maze as a measure of anxiety, the effects of ZK 91296 (5-15 mg/kg) did not reach significance. In the holeboard. ZK 91296 did not significantly reduce exploratory head-dipping, locomotor activity or rearing until doses of 40 mg/kg. These data suggest that ZK 91296 can reduce anxiety as assessed by animal tests at doses at which it does not induce sedation.

Animals↗
PubMed1986

Chronic treatment with Ro 15-1788 distinguishes between its benzodiazepine antagonist, agonist and inverse agonist properties.

Ro 15-1788 (flumazepil) is an imidazodiazepine that is able to antagonise most of the behavioural actions of the benzodiazepines, as well as having some intrinsic effects. Acute administration of Ro 15-1788 (10 mg/kg) decreases social interaction between male rats and elevates exploratory head-dipping. After 5 days of pretreatment there was tolerance to the former effect, although Ro 15-1788 retained its ability to antagonise the effects on social interaction of the beta-carboline, FG 7142. Ro 15-1788 also retained its ability to elevate head-dipping: additionally, the chronically-treated rats had elevated motor activity and rearing scores. The acute effects of lorazepam in the holeboard were unchanged by chronic pretreatment with Ro-15-1788. The plasma and brain concentrations after acute administration of lorazepam were unchanged following chronic administration of Ro 15-1788. After chronic treatment the brain concentrations of Ro 15-1788 were unchanged. It is unlikely that pharmacokinetic factors could underlie the different behavioural changes following chronic treatment.

Animals↗
PubMed1986

A late-appearing benzodiazepine-induced hypoactivity that is not reversed by a receptor antagonist.

The activity of rats in a holeboard test is reduced 30, 90, and 240 min after treatment with a single dose of lorazepam. The administration of a benzodiazepine antagonist (RO 15-1788) 20 min before the holeboard test (i.e., 10, 70, or 220 min after lorazepam administration) reverses the hypoactivity of animals tested 30 min after treatment with lorazepam, partially reverses the hypoactivity of animals tested 90 min after receiving lorazepam, but is without effect on the hypoactivity observed 240 min after treatment with the benzodiazepine. If, however, RO 15-1788 is given at the same time as lorazepam then it reverses the hypoactivity seen 4 h later. The results of these experiments demonstrate that a benzodiazepine can exert a behavioral effect at a time when it no longer appears to be acting at central benzodiazepine receptors.

Animals↗