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Publications and source records attributed to S E File.

At least 73 records · Page 4Linked to original sources
PubMed1989

Effects of a single or repeated administration of the benzodiazepine inverse agonist FG7142 on behaviour and cortical adrenoceptor binding in the rat.

We have reported previously an increase in the number of beta-adrenoceptors in mouse cerebral cortex 7 days after kindling of seizures by repeated once-daily administration of the benzodiazepine receptor inverse agonist, FG7142. In subsequent experiments, an even larger increase in beta-adrenoceptor number was found 7 days after a single injection of this compound. The present experiments investigated whether FG7142-induced changes in adrenoceptor binding are also found in the rat and whether the effects of a single and repeated injections of this drug differ quantitatively. In view of the anxiogenic effects of FG7142, we have also tested for parallel changes in behaviours associated with anxiety and exploration. Nine days after a single injection of FG7142, the number of beta-adrenoceptors in the cerebral cortex was greater than that found after repeated administration of this compound; this difference was statistically significant. There was no difference in beta-adrenoceptor binding to tissues from chronically FG7142-treated and vehicle-injected animals and there were no changes in alpha 2-adrenoceptor binding or noradrenaline levels after either a single or repeated FG7142 treatment. Neither single nor repeated FG7142 treatment modified spontaneous behaviour in either the elevated plus-maze test of anxiety or the holeboard test of exploration. The behavioural effects of yohimbine and clenbuterol in these tests were also unaffected by FG7142. We discuss the possibility that the difference in the effects of a single and repeated administration of FG7142 on beta-adrenoceptor binding is related to the expression of kindled seizures.

Animals↗
PubMed1989

Sodium phenobarbitone reverses the anxiogenic effects of compounds acting at three different central sites.

Sodium phenobarbitone was tested for its ability to antagonise the anxiogenic effects of compounds acting at three different central sites. These compounds were: FG 7142, a beta-carboline which acts at the benzodiazepine binding site on the GABA-benzodiazepine receptor complex; pentylenetetrazole, which acts at the picrotoxinin site on the GABA-benzodiazepine receptor complex; and yohimbine which is an antagonist at the alpha 2-adrenoceptor. The experiments were carried out in two tests of anxiety using rats. In the social interaction test (the test arena was familiar and dimly lit), FG 7142 (5 mg/kg) and pentylenetetrazole (15 mg/kg) reduced the time spent in social interaction (indicating anxiogenic activity); these effects were reversed by sodium phenobarbitone (35 mg/kg). Sodium phenobarbitone (35 mg/kg) alone decreased locomotor activity as measured in the social interaction test, which was reversed by pentylenetetrazole (15 mg/kg). In the elevated plus-maze, FG 7142 (6.7 mg/kg) pentylenetetrazole (20 mg/kg) and yohimbine (4 mg/kg) reduced the percentage of open-arm entries and the percentage of time spent on the open arms (indicating anxiogenic activity); these effects were reversed by sodium phenobarbitone (35 mg/kg). Sodium phenobarbitone (35 mg/kg) alone significantly increased the percentage of open-arm entries and the percentage of time spent on the open arms (indicating anxiolytic activity). This study, together with previous studies using other clinically-effective anxiolytic drugs, suggests that the ability of a compound to antagonise the effects of anxiogenic agents may be a useful indirect means of predicting anxiolytic activity.

Animals↗
PubMed1989

Diazepam reverses the effects of pentylenetetrazole in rat pups by acting at type 2 benzodiazepine receptors.

Pentylenetetrazole (75 mg/kg) induced a characteristic coarse body tremor (accompanied by limb extension) and hyperactivity in 4-day-old rat pups. These effects were reversed by diazepam (0.5 and 2 mg/kg) but not by CL 218,872 (10 and 20 mg/kg) which is selective for type 1 benzodiazepine receptors. Diazepam did not affect the brain concentrations of pentylenetrazole, indicating that the reversal was not based on a pharmacokinetic interaction. Neither diazepam nor CL 218,872 had significant effects on the behavior of the rat pups, although diazepam (2 mg/kg) tended to increase locomotor activity. The results suggest that diazepam displays an anticonvulsant effect in the neonatal rat which is mediated by type 2 receptors.

Animals↗
PubMed1989

Yohimbine's anxiogenic action: evidence for noradrenergic and dopaminergic sites.

Yohimbine (2.5 or 4 mg/kg) reduced the percentage of open arm entries and the percentage of time spent on the open arms displayed by rats on an elevated plus-maze indicating anxiogenic activity. These effects were reversed by the alpha 2-adrenoceptor agonist clonidine (0.01 mg/kg) and by the dopamine receptor agonist apomorphine (0.57 mg/kg). The following failed to reverse the effects of yohimbine: the selective alpha 2-adrenoceptor agonists, guanfacine (0.25 and 1 mg/kg), B-HT920 (0.025 and 0.1 mg/kg), B-HT933 (1 and 10 mg/kg); the beta-blocker propranolol (2.5 and 10 mg/kg); the alpha 1-adrenoceptor agonist phenylephrine; the D1 agonist SK&F 38393 (5 and 10 mg/kg) and the D2 agonist LY 171555 (0.5 and 1 mg/kg). Therefore, it is unlikely that activity at only the alpha 1, alpha 2, beta, D1 or D2 sites can entirely account for the anxiogenic actions of yohimbine in the elevated plus-maze. Evidence that clonidine affects the dopaminergic system and that apomorphine affects the noradrenergic system suggest that yohimbine may produce its anxiogenic response by activity on both the noradrenergic and dopaminergic systems.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Caffeine-induced anxiogenesis: the role of adenosine, benzodiazepine and noradrenergic receptors.

The purpose of this study was to determine the mechanism by which caffeine increases anxiety. Rats were tested in the social interaction test of anxiety after administration of caffeine (20 or 40 mg/kg) alone or in combination with various compounds. In order to investigate the role of adenosine receptors, caffeine was given in combination with 2-chloroadenosine (0.1 and 1 mg/kg). To investigate the role of benzodiazepine receptors, chlordiazepoxide (5 mg/kg), a benzodiazepine antagonist, flumazenil (RO 15-1788, 1 and 10 mg/kg) and a triazolobenzodiazepine U-43,465 (32 mg/kg) were used. Finally, an alpha 2-receptor agonist, clonidine (0.1 and 0.025 mg/kg) and a beta-adrenoceptor antagonist, DL-propranolol (5 mg/kg), were used to study the role of noradrenergic systems in the effects of caffeine. Caffeine (20 and 40 mg/kg) reduced the time spent in social interaction and this effect was antagonized by chlordiazepoxide, U-43,465 and DL-propranolol, but not by flumazenil, 2-chloroadenosine or clonidine. It was therefore concluded that the anxiogenic effect of caffeine was unlikely to be due to its effects at adenosine or benzodiazepine receptors. It is suggested that the reversal of caffeine's effects by chordiazepoxide may have been "functional," i.e., merely a cancellation of two opposite effects. It is discussed whether the reversal of caffeine's effects by propranolol and U-43,465 are functional, or reflect a noradrenergic site of action.

2-Chloroadenosine↗
PubMed1989

Evidence that the increased anxiety detected in the elevated plus-maze during chlordiazepoxide withdrawal is not due to enhanced noradrenergic activity.

Rats displayed a reduction in the percentage of time spent on the open arms of the elevated plus-maze 24-30 hours after withdrawal from chronic chlordiazepoxide treatment (10 mg/kg/day IP for 4 weeks). This indicated an anxiogenic response in this test. This anxiogenic response was not significantly reversed by DL-propranolol (5 and 10 mg/kg IP) or clonidine (0.02 and 0.04 mg/kg IP). These results provide no evidence to suggest that the anxiogenic effects of chlordiazepoxide withdrawal are mediated by an increase in noradrenergic activity. The possible involvement of multiple transmitter systems in benzodiazepine withdrawal symptomology is discussed.

Animals↗
PubMed1988

Low and high doses of benzodiazepine receptor inverse agonists respectively improve and impair performance in passive avoidance but do not affect habituation.

The benzodiazepine receptor inverse agonists, methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) and N-methyl-beta-carboline-3-carboxamide (FG 7142), were given to rats at various stages of a passive avoidance task. When the drugs were given before trial 1, low doses enhanced, and high doses impaired, performance as assessed 24 h later. A group given drugs on both trials showed that the impairment was not due to state-dependent effects. When the drugs were given immediately after trial 1, or before trial 2, they were without effect, except for the low dose of DMCM which impaired consolidation. It is discussed whether the changes in passive avoidance performance are due to direct or indirect effects. Between-trial habituation of exploratory head-dipping was measured in a holeboard. When FG 7142 was given before trial 1, the high dose impaired between-trial response decrement; but this was because it decreased the level of head-dipping on trial 1. When FG 7142 was given immediately after trial 1, or before trial 2, it was without effect on between-trial habituation.

Animals↗
PubMed1988

Sodium valproate decreases exploratory behaviour in mice: development of tolerance and cross-tolerance with chlordiazepoxide.

Sodium valproate (400 mg/kg) significantly reduced exploratory head-dipping in mice, without significant reductions in locomotor activity or rearing. After 5 daily injections of sodium valproate (50 or 400 mg/kg) there was tolerance to the effects of a test dose of 400 mg/kg. Pretreatment for 5 days with chlordiazepoxide (5 mg/kg) did not change the effects of sodium valproate (400 mg/kg), but 5 days pretreatment with chlordiazepoxide (20 mg/kg) did produce cross-tolerance. Sodium valproate (50 mg/kg) was without significant effect acutely, or after 5 days of pretreatment with sodium valproate (50 or 400 mg/kg) or chlordiazepoxide (5 or 20 mg/kg). Daily injections of the benzodiazepine antagonist, flumazenil (10 mg/kg), immediately after the daily injection of sodium valproate (400 mg/kg) or chlordiazepoxide (20 mg/kg) did not prevent the development of tolerance or cross-tolerance. This suggests that benzodiazepine receptors may not mediate these phenomena; possible roles of GABA and 5-HT are also discussed.

Animals↗
PubMed1988

Does the behavioural activation detected after a single dose of a benzodiazepine reflect a withdrawal response?

The effects, in mice, of a single dose of lorazepam or oxazepam were determined, in the holeboard, 24, 48 and 72 hours after treatment. Lorazepam produced significant increases in both spontaneous locomotor activity and in rearing 48 hours after treatment and oxazepam produced a significant overall increase in rearing over the three time points. There was no detectable in vivo receptor occupancy for either drug at the 48 hour time point, so that these effects were not due to residual concentrations of drug in the brain. We therefore suggest that we were detecting a spontaneous withdrawal response to a single dose of benzodiazepine. The increases in both locomotor activity and rearing, detected 48 hours after lorazepam, could be reversed by treating simultaneously with Ro 15-1788 (a benzodiazepine antagonist). When Ro 15-1788 was injected 20 minutes prior to testing, the mice that had been treated 48 hours previously with lorazepam still showed increased locomotor activity and rearing. We conclude that the hyperactivity was not caused by any change in the levels of endogenous substances acting at the benzodiazepine receptor.

Animals↗
PubMed1988

Behavioral effects of acute and chronic administration of caffeine in the rat.

This study investigated the effects of acute and chronic caffeine treatment on behavior in the social interaction, holeboard and home-cage aggression tests and on proconvulsant actions with pentylenetetrazol. Acutely-treated rats received an IP injection of caffeine (20 or 40 mg/kg). Chronically-treated rats received caffeine in their drinking water for 21 days (50 or 100 mg/kg/day) followed by an injection of caffeine on the test day (20 or 40 mg/kg respectively). Acutely, the higher dose of caffeine (40 mg/kg) decreased levels of social interaction. In the holeboard test, 20 mg/kg of acute caffeine increased motor activity whilst 40 mg/kg reduced head-dipping behavior. In the home-cage aggression test, acute caffeine (40 mg/kg) reduced offensive aggressive behaviors. After chronic treatment with caffeine none of these behaviors differed significantly from controls. After both acute and chronic treatment, caffeine (20 and 40 mg/kg) was proconvulsant with pentylenetetrazol.

Aggression↗
PubMed1988

Withdrawal, tolerance and sensitization after a single dose of lorazepam.

Forty-eight hours after a single dose of lorazepam (0.25 mg/kg), there was tolerance to the lorazepam-induced reduction of locomotor activity in the holeboard; but no tolerance to the reductions in exploratory head-dipping or rearing. Mice tested undrugged at this time showed significant hyperactivity and increased rearing, indicating withdrawal responses, but no change in head-dipping. In the elevated plus-maze, no tolerance could be detected to the effects of lorazepam (0.25 mg/kg) when the mice were tested 48 hr after an initial dose; in fact, there was a trend towards enhanced effects in this group. When mice were tested undrugged 24, 48 or 72 hr after a single dose of lorazepam there was an increase in the % time spent on the open arms, compared with controls, that reached significance for the 24 hr group. This indicates a sensitization to the anxiolytic effects of lorazepam, as assessed in the plus-maze. These results demonstrate long-lasting effects of even a single dose of lorazepam.

Animals↗
PubMed1988

Profiles of the antipanic compounds, triazolobenzodiazepines and phenelzine, in two animal tests of anxiety.

Two animal tests of anxiety (the elevated plus-maze and the social interaction test) were used to investigate the effects of several antipanic agents. In the elevated plus-maze, the triazolobenzodiazepines adinazolam (2 and 5 mg/kg) and alprazolam (1 mg/kg), tested after 5 days of pretreatment, demonstrated significant anxiolytic effects, while phenelzine (9 mg/kg), after 21 days of pretreatment, demonstrated nonsignificant anxiolytic effects. In the social interaction test, the triazolobenzodiazepines generally did not produce an anxiolytic profile, and phenelzine even revealed significant anxiogenic activity. The antipanic agents therefore distinguish between the two tests of anxiety. The lack of a strong anxiolytic profile with these agents in both tests lends support to the distinction between generalized anxiety and panic disorder.

Administration, Oral↗
PubMed1988

Reversal of increased anxiety during benzodiazepine withdrawal: evidence for an anxiogenic endogenous ligand for the benzodiazepine receptor.

Rats were injected daily for 21 days with water or with chlordiazepoxide hydrochloride (10 mg/kg) and then tested in the elevated plus-maze 24-30 hr after the last of their chronic injections. At this time, rats withdrawn from chlordiazepoxide showed a significant decrease in the % of time spent on the open arms, compared with controls, thus indicating enhanced anxiety. The benzodiazepine antagonist, flumazenil (Ro 15-1788, 4 mg/kg, IP 20 min before test) significantly (p less than 0.01) reversed this withdrawal anxiety, and was without effect in the control group. The partial inverse agonist, FG 7142 (5 mg/kg IP 30 min before test) had no significant effect on the withdrawal anxiety. Possible mechanisms underlying the enhanced anxiety displayed by rats in withdrawal from chlordiazepoxide are discussed. It is concluded that a likely explanation is that chronic benzodiazepine treatment leads to an increased production and release of an endogenous ligand for the benzodiazepine receptor, with inverse agonist properties.

Animals↗
PubMed1988

Myoclonic seizures in the mouse induced by alphaxalone and related steroid anaesthetics.

The anaesthetic steroids alphaxalone. 5 beta-alphaxalone and pregnanolone each caused myoclonic jerks in mice in a dose-related manner between 4 and 16 mg kg-1 i.v. There was no loss of righting reflex at these doses. The veterinary product Saffan, which contains alphaxalone and alphadalone, also caused myoclonic jerks at 2 mg kg-1 i.v., and a loss of righting reflex at doses of 4 mg kg-1 and above. These effects appear to be unrelated to the wide spectrum of potencies at the GABAA receptor complex of the three individual steroids as potentiators of muscimol, or as attenuators of picrotoxin.

Anesthetics↗
PubMed1988

Evidence for simultaneous anxiolytic and aversive effects several hours after administration of sodium phenobarbitone to the rat.

Using a place conditioning paradigm, it was shown that the state experienced by rats 8 h after a 50-mg/kg dose of sodium phenobarbitone had aversive properties. However, at this same time, rats showed an increase in the percentage of time spent on the open arms of an elevated plus-maze, and an increase in the number of punished licks in a conflict test. These two effects are indicative of an anxiolytic action. It was therefore possible to demonstrate, simultaneously, an anxiolytic effect of sodium phenobarbitone and that it induced an aversive state. Conditioned place aversion could also be demonstrated 1 h after a 20-mg/kg dose of sodium phenobarbitone, but this dose was ineffective in the elevated plus-maze test of anxiety. These results provide further evidence that drugs that reduce anxiety do not necessarily have secondary positive reinforcing properties.

Animals↗
PubMed1988

Kindling with the beta-carboline FG7142 suggests separation between changes in seizure threshold and anxiety-related behaviour.

The aim of this paper was to determine whether the prolonged decrease in seizure threshold produced by chemical kindling was accompanied by behavioural changes in tests of anxiety and aggression. The responses of rats in five tests were examined after chronic treatment with the benzodiazepine inverse agonist FG7142. This treatment caused chemical kindling, so that the originally proconvulsant drug caused full seizures. This effect is very long-lasting, and our previous work with mice had suggested that it might be accompanied by an increase in anxiety-related behavior. In the present work no significant differences were found between the behaviour of FG7142-kindled rats and vehicle-treated controls in social interaction test, elevated plus maze, or the Vogel conflict test of anxiety or in tests of home cage aggression or startle responses. The results therefore show that prolonged changes in seizure threshold can occur without alterations in the apparent level of anxiety.

Aggression↗