Behavioral consequences of antidepressant treatment in rodents.

This review discusses the effects of antidepressant drugs on behaviors that are changed during the clinical treatment of depression. We first consider whether there is a similar subjective state produced by antidepressant drugs that might be akin to the mood changes caused clinically by these drugs. We thus review the evidence that antidepressant drugs can produce a distinctive enough subjective state to serve as a discriminative stimulus, and then discuss the nature of the cue produced.

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.

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.

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.

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).

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.

Amnesic and anxiolytic effects of intravenous diazepam in dental anxiety.

The effects of intravenous administration of diazepam (average 20 mg) on learning, performance and mood were assessed in dental patients. These patients required sedation due to excessive anxiety in a dental situation, or because they were to undergo stressful surgery. On a verbal learning task, subjects recalled and recognized significantly fewer words from a list presented after drug administration than from a list presented prior to drug administration, when tested at the end of the treatment period.

Is tofisopam an atypical anxiolytic?

This review describes the behavioural and biochemical profile of tofisopam, a 3,4-benzodiazepine that differs considerably in its effects and mechanisms of action from classical 1,4-benzodiazepines. In man tofisopam appears to possess anxiolytic activity without appreciable sedative and muscle relaxant side effects; in animals, however, tofisopam totally lacks anxiolytic and anticonvulsant properties in tests sensitive to the effects of 1,4-benzodiazepines. Tofisopam also has mixed dopamine agonist and antagonist-like properties in several in vivo and in vitro tests in animals.

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.

The effects of PK 11195, a ligand for benzodiazepine binding sites, in animal tests of anxiety and stress.

PK 11195 (1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3-isoquinolinecarboxami de, a potent ligand for peripheral benzodiazepine binding sites, was unable to reverse the anxiogenic effects of Ro 5-4864 (chlorodiazepam) in the social interaction test or in the punished drinking test. However, at 90 mg/kg PK 11195 also reduced social interaction, indicating an anxiogenic effect. Both PK 11195 (30-120 mg/kg) and Ro 5-4864 (20-60 mg/kg) significantly increased the plasma corticosterone concentrations of rats left in their home cages after injection, and in those placed in novel apparatus.

The effects of triazolobenzodiazepines in two animal tests of anxiety and in the holeboard.

In addition to possessing anti-anxiety activity in man, triazolobenzodiazepines have been reported to have antidepressant and antipanic properties. In this they differ from classical 1,4-benzodiazepines that have only anti-anxiety activity. The purpose of the present study was to examine the effects of the triazolobenzodiazepines in two animal tests of anxiety and in the holeboard, to see whether clear differences could be observed between them and the 1,4-benzodiazepines.

Triazolobenzodiazepines antagonize the effects of anxiogenic drugs mediated at three different central nervous system sites.

The ability of the triazolobenzodiazepines to antagonize the anxiogenic effects of three different compounds in the social interaction test was investigated. The compounds were selected for their different sites of action in the central nervous system: FG 7142, acting at the beta-carboline site on the gamma-aminobutyric acid-benzodiazepine receptor complex; pentylenetetrazole, acting at the picrotoxin site on this complex, and yohimbine, an alpha 2-adrenoceptor antagonist. Adinazolam (5 mg/kg) and U-43,465 (32 mg/kg) were able to antagonize the anxiogenic effects of all three compounds, unlike classical 1,4-benzodiazepines, that are not able to antagonize the effects of yohimbine.

Anticonvulsant effects of chronic treatment with phenytoin against pentylenetetrazole-induced seizures in the mouse.

Acute administration of phenytoin (40 and 75 mg/kg) was unable to counteract seizures induced by pentylenetetrazole and even prolonged them in some cases. These prolonged seizures remained with chronic (10 days) treatment but an anticonvulsant effect of phenytoin (40 and 75 mg/kg) also emerged, shown by a decrease in the incidence of seizures. This latter effect could be detected even 24 hr after the last dose.

The effects of putative anxiogenic compounds (FG 7142, CGS 8216 and Ro 15-1788) on the rat corticosterone response.

The effects of FG 7142, CGS 8216 and Ro 15-1788, three compounds that are believed to produce anxiety by an action at benzodiazepine receptors in the CNS, are investigated on the plasma corticosterone concentrations in the rat both in the home cage and after exposure to novelty stress. FG 7142 (5 mg/kg) and CGS 8216 (10 mg/kg), but not Ro 15-1788 (4 or 10 mg/kg) increased basal corticosterone levels in the home cage, and all three compounds potentiated the increase in corticosterone concentrations observed after exposure to a novel environment. The relationship between the effects of drugs on corticosterone concentrations and on anxiety is considered in the light of these results.

The effects of putative anxiolytic compounds (PK 8165, PK 9084 and tracazolate) on the rat corticosterone response.

The effects were investigated of three putative anxiolytics, thought to act at the GABA-benzodiazepine receptor complex, on basal corticosterone and novelty-induced rise in plasma corticosterone concentrations. The two phenylquinolines, PK 8165 and PK 9084, increased basal concentrations, but reduced the novelty-induced rise in corticosterone; these actions resemble those found with high doses of benzodiazepines. Tracazolate, a pyrazolopyridazine that enhances the binding of benzodiazepines to their receptors, was without significant effect in either situation.

Does the benzodiazepine antagonist Ro 15-1788 reverse the actions of picrotoxin and pentylenetetrazole on social and exploratory behaviour?

The effects of the benzodiazepine receptor antagonist, Ro 15-1788, were examined in combination with those of picrotoxin and pentylenetetrazole on social and exploratory behaviour in the rat. Both Ro 15-1788 (10 mg/kg) and picrotoxin (2 mg/kg) reduced social interaction, but there was no additive effect of these drugs together. Ro 15-1788 (10 and 20 mg/kg, which had no intrinsic effects in the holeboard alone) antagonized the reductions in exploratory head-dipping and motor activity produced by low (2 mg/kg), but not by high (4 mg/kg), doses of picrotoxin.

No cross-tolerance between the stimulatory and depressant actions of benzodiazepines in mice.

Doses of the benzodiazepines chlordiazepoxide and diazepam were selected that elevate, or that depress, exploratory and locomotor behaviour in the holeboard in mice, and the development of tolerance to these effects was investigated. Tolerance did not develop to the stimulant effects of low doses of these compounds after 10 or 20 days pretreatment with either a low (stimulant) dose or a high (depressant) dose of each. When animals were pretreated with a high (depressant) dose of the benzodiazepines, tolerance developed to the depressant effects of a high test dose, and in fact, after 20 days a stimulatory effect on head-dipping had developed with this dose.

Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat.

A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated + -maze consisting of two open arms and two enclosed arms. The use of this test for detecting such drug effects was validated behaviourally, physiologically, and pharmacologically. Rats made significantly fewer entries into the open arms than into the closed arms, and spent significantly less time in open arms.

Pro- and anti-convulsant drug effects in combination with the convulsant benzodiazepine Ro 5-4864.

The effects of several compounds believed to act at the GABA-benzodiazepine receptor complex and which have anticonvulsant or proconvulsant properties when administered in combination with picrotoxin and pentetrazol (leptazol, pentylenetetrazole) were investigated in combination with the convulsant benzodiazepine Ro 5-4864. Tracazolate (25-100 mg kg-1) failed to affect convulsions induced by Ro 5-4864; however, they were prevented by treatment with CL 218,872 (20 mg kg-1). Compounds having proconvulsant activity in combination with a subthreshold dose of Ro 5-4864 were: CL 218,872 (5 mg kg-1), and CGS 8216 (20 mg kg-1) and FG 7142 (40 mg kg-1), two compounds characterized as 'inverse agonists' at benzodiazepine receptors.

Chlordiazepoxide enhances the anxiogenic action of CGS 8216 in the social interaction test: evidence for benzodiazepine withdrawal?

The benzodiazepine receptor 'inverse agonist' CGS 8216 has a specific anxiogenic action in the social interaction test that cannot be reversed by other compounds acting at the benzodiazepine site: Ro 15-1788, FG 7142 or beta-CCE. We tried to reverse the anxiogenic effect with chlordiazepoxide, which is able to antagonise the anxiogenic effects of several other compounds acting at benzodiazepine or related sites. Chlordiazepoxide given acutely (10-20 mg/kg) was unable to antagonise the anxiogenic action of CGS 8216 (5-10 mg/kg); instead there was a tendency to enhance its effects.

Effects of the beta-carboline, FG 7142, in the social interaction test of anxiety and the holeboard: correlations between behaviour and plasma concentrations.

The behavioural effects of the beta-carboline FG 7142 were investigated in the social interaction test of anxiety and the holeboard test of exploration and locomotor activity. FG 7142 (5-20 mg/kg) produced a significant decrease in the time spent in social interaction by pairs of rats, without an accompanying decrease in motor activity. This anxiogenic effect was highly correlated with the plasma concentrations of FG 7142 for the rats receiving 5 and 10 mg/kg doses, but not for those receiving the 20 mg/kg dose.

A comparison of the effects of lorazepam with those of propranolol on experimentally-induced anxiety and performance.

In a double-blind cross-over study the effects of propranolol (80 mg) and of lorazepam (1 or 2.5 mg) were assessed in normal student volunteers using a number of performance tests and mood-rating and bodily symptom questionnaires. Drug effects on experimentally-induced anxiety were also studied.

Effects of acute and chronic treatment on the pro- and anti-convulsant actions of CL 218, 872, PK 8165 and PK 9084, putative ligands for the benzodiazepine receptor.

CL 218,872 is a triazolopyridazine that acts at the benzodiazepine binding site. At low doses (0.5-7.