Amanda L. Johnston

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 (0ṁ25‐10 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 (0ṁ1875‐1ṁ5 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 (0ṁ0625‐0dependent manner in25 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 (β‐carboline‐3‐carboxylate methylamide) provided no clear evidence for a major role of 5‐HT pathways in the mediation of their anxiogenic effects.

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.

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.

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.

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.

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.

Measures of anxiety and stress in the rat following chronic treatment with yohimbine

Yohimbine (2.5 and 5 mg/kg) was investigated in two animal tests of anxiety and on baseline corticosterone plasma concentrations, following both acute and chronic administration. Acute treatment with yohimbine produced the following effects: a reduction in the percentage of total arm entries made onto the open arms and in the percentage of time spent on the open arms of an elevated plus-maze (indicating anxiogenic properties), an increase in baseline plasma corticosterone concentrations, and a reduction in locomotor activity (recorded in the social interaction test). No significant effects were observed on anxiety levels as measured by the social interaction test. Following chronic treatment, we saw no evidence for sensitization to the effects of yohimbine.

Kindling with the β-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.

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.

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.