Biomedical subjects

S E File

Publications and source records attributed to S E File.

At least 181 records · Page 10Linked to original sources

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↗

PubMed1986

Intrinsic actions of the benzodiazepine receptor antagonist Ro 15-1788.

The imidazodiazepine Ro 15-1788 is a benzodiazepine receptor antagonist that was initially reported to be lacking in intrinsic activity in a variety of test situations in which benzodiazepine-like effects can be identified. However, many recent studies have shown that this compound does indeed have intrinsic activity in a variety of behavioural, neurological, electrophysiological and biochemical preparations in both animals and man. The purpose of the present review is firstly to describe these intrinsic actions, and secondly to consider to what extent these intrinsic actions of Ro 15-1788 have implications for current concepts of the functioning of the benzodiazepine receptor.

Aggression↗

PubMed1986

Actions of the beta-carboline ZK 93426 in an animal test of anxiety and the holeboard: interactions with Ro 15-1788.

The effects of the beta-carboline ZK 93426, a putative benzodiazepine receptor antagonist, were investigated in the social interaction test of anxiety and in the holeboard. Like the receptor antagonist Ro 15-1788, ZK 93426 (2.5-10 mg/kg) caused a specific reduction in social interaction (interpreted as an anxiogenic effect) and caused a significant elevation in exploratory head-dipping (5 mg/kg). When low (ineffective) doses of both compounds (1 mg/kg ZK 93426; 4 mg/kg Ro 15-1788) were administered together they significantly reduced social interaction. No further reductions in social interaction were observed when effective doses of both compounds (5 mg/kg ZK 93426; 10 mg/kg Ro 15-1788) were tested in combination; it is likely that this is due to almost total benzodiazepine receptor occupancy at effective doses of either compound. When doses of each compound (5 mg/kg ZK 93426; 10 mg/kg Ro 15-1788) that resulted in stimulation of head-dipping were examined in combination, the elevation in exploration was no longer observed. Since at higher doses of both compounds there is an attenuation of the elevation in head-dipping, it is again likely that the effects of the two compounds are additive.

Animals↗

PubMed1986

Effect on hypothalamic self-stimulation of the novel beta-carbolines ZK 93 426 (a benzodiazepine receptor antagonist) and ZK 91 296 (a putative partial agonist).

Low doses (300 micrograms/kg-1.0 mg/kg) of the novel beta-carboline, ZK 91 296, a putative agonist at the benzodiazepine receptor, produced a significant increase in the rate of variable-interval self-stimulation responding, similar to that found with typical benzodiazepines. This effect was blocked by simultaneous administration of the specific benzodiazepine-receptor antagonists Ro 15-1788 (2.0 mg/kg), and ZK 93 426 (10 mg/kg). Neither antagonist, ZK 93 426 (100 micrograms/kg-10 mg/kg) or Ro 15-1788 (2.0 mg/kg), had any effect on self-stimulation when given alone. Unlike all benzodiazepine-receptor agonists previously tested, higher doses of ZK 91 296 did not depress self-stimulation response rates, even at a dose-level 100 times greater than the maximally stimulant dose. It is uncertain why ZK 91 296 lacks depressant effects: available evidence does not conclusively favour any single current explanation, but is consistent with it acting as a "partial" agonist.

Animals↗

PubMed1986

The effects of yohimbine on exploratory and locomotor behaviour are attributable to its effects at noradrenaline and not at benzodiazepine receptors.

A recent study has shown that the alpha 2-adrenoceptor antagonist, yohimbine, has an additional action, in micromolar concentrations, to inhibit the binding of [3H]benzodiazepines to their receptors in the CNS. An important question raised by this finding is to what extent the behavioural effects of yohimbine can be attributed to this action. Yohimbine (1.25-2.5 mg/kg) produced a dose-related decrease in exploratory head-dipping and locomotor activity in the holeboard test. The alpha 2-adrenoceptor agonist clonidine, in small doses (0.01-0.025 mg/kg), antagonized the reduction in exploratory head-dipping and locomotor activity produced by yohimbine (2.5 mg/kg). The benzodiazepine chlordiazepoxide (5-10 mg/kg), which reduces the activity of noradrenergic neurones, antagonized the effects of yohimbine less effectively. The inability of flumazepil (10-20 mg/kg; Ro 15-1788, a benzodiazepine receptor antagonist) to reverse the effects of yohimbine suggested that the low-affinity effect of yohimbine to displace the binding of benzodiazepines from their receptors, is not important in its behavioural effects in the holeboard, but that these effects are attributable to the alpha 2-antagonist action of yohimbine. These conclusions are consistent with previous results in an animal test of anxiety.

Adrenergic alpha-Antagonists↗

PubMed1986

The effects of benzodiazepines in newborn rats suggest a function for type 2 receptors.

In day 4 female rats lorazepam, diazepam and clonazepam produced dose-related increases in forward walking and loss of righting and diazepam produced a dose-related increase in paddling. Lorazepam and diazepam increased jerks of the fore- and hind-limbs and the whole body, and clonazepam increased the latter two; these increases were not dose-related. Some doses of lorazepam and the lowest dose of diazepam increased tonic-clonic movements. Thus the benzodiazepines were observed to have two kinds of stimulant effect in day 4 rats. One is to cause hyperactivity and this effect is dose-related. The other is to cause a type of seizure-like behavior, although this action is not dose-related and the responses can be distinguished from those caused by convulsant compounds. The effects of the benzodiazepine antagonist Ro 15-1788 resembled those of the benzodiazepines. It increased hind-limb and whole body jerks, forward walking, paddling, loss of righting and tonic-clonic movements. CL 218,872, which is selective for type 1 benzodiazepine receptors, was devoid of significant effects. This suggests that the behavioral changes observed with the other compounds were mediated by the type 2 receptors.

Animals↗

PubMed1986

5-HT and anxiety: promises and pitfalls.

This review examines the evidence implicating serotonergic systems in the control of anxiety. The effects of manipulations of 5-HT, including 5-HT lesions, pharmacological reduction and enhancement of serotonergic function in animal tests of anxiety are reviewed. Biochemical and behavioral evidence implicating serotonergic pathways in the anxiolytic action of benzodiazepines is presented. In each section the promises of a serotonergic involvement, as indicated by positive findings, and the pitfalls, evidenced by inconsistent and conflicting results, are discussed. Finally the dangers of a superficial interpretation of the behavioral and biochemical findings is stressed.

Animals↗

PubMed1986

Antagonism of the effects of the atypical benzodiazepine, Ro 5-4864 on intracranial self-stimulation in the rat.

The effects of Ro 5-4864 (chlordiazepam) were examined on responding for self-stimulation of the mid-lateral hypothalamus. Rewarding stimuli were delivered according to a 10-sec variable interval schedule of reinforcement. Ro 5-4864 (10-30 mg/kg, subconsulsive doses in these rats) decreased responding. This effect was antagonized by chlordiazepoxide (5-10 mg/kg) and phenobarbitone (35 mg/kg) but not by the benzodiazepine receptor antagonist Ro 15-1788 (10-20 mg/kg), the ligand for peripheral benzodiazepine receptors PK 11195 (60 mg/kg) or phenytoin (60 mg/kg). The pattern of interactions of Ro 5-4864 with these compounds differs from the pattern obtained with other procedures, and suggests that Ro 5-4864 has effects on systems unrelated to anxiety, convulsive activity or sedation.

Animals↗

PubMed1986

Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat.

The current studies further investigated the effects, in animal models of anxiety, of novel putative anxiolytic and anxiogenic compounds believed to induce their effects by actions at the GABA-benzodiazepine receptor complex. It was expected that the results would also provide further validation for a novel test of anxiety based on the ratio of open to closed arm entries in an elevated plus maze in the rat. The novel putative anxiolytics CL 218,872 (10-20 mg/kg) and tracazolate (5 mg/kg) significantly elevated the percentage of time spent on the open arms of an elevated plus-maze, consistent with their anxiolytic activity in several other animal tests. Also consistent with results from other animal tests, no anxiolytic activity was observed for the phenylquinoline PK 8165 (10-25 mg/kg), the 3,4-benzodiazepine tofisopam (25-50 mg/kg), or buspirone (0.5-20 mg/kg). The benzodiazepine receptor inverse agonists FG 7142 (1-5 mg/kg) and CGS 8216 (3-10 mg/kg) had anxiogenic activity in this test, as did the atypical benzodiazepine Ro 5-4864 (1-5 mg/kg). Interestingly, however, the benzodiazepine receptor antagonists Ro 15-1788 (10-20 mg/kg) and ZK 93426 (5-10 mg/kg) had no anxiogenic activity in this test.

Animals↗

PubMed1986

The effects of tricyclic and 'atypical' antidepressants on spontaneous locomotor activity in rodents.

With the exception of amineptin, buproprion and nomifensine all tricyclic and 'atypical' antidepressants have been reported to reduce spontaneous motor activity in rodents, after both acute and chronic administration. However, with the diversity of chemical actions of these drugs it is unlikely that a single neurochemical mechanism is underlying this one behavioral effect. These widespread sedative effects have implications for interpreting behavioral changes in other test situations, since sedation generally occurs at doses that fall within the dose-range effective in other tests. We also review the effects on spontaneous motor activity of withdrawal from chronic antidepressant treatment.

Animals↗