Pindolol antagonizes the effects on hippocampal rhythmical slow activity of clonidine, baclofen and 8-OH-DPAT, but not chlordiazepoxide and sodium amylobarbitone.

Buspirone, benzodiazepines, barbiturates and ethanol all reliably reduce the frequency of reticular-elicited hippocampal rhythmical slow activity. In the present experiments we tested a number of drugs which are not usually used for treating generalized anxiety disorders but which have been reported to have some anxiolytic properties. Clonidine (0.3 mg/kg, i.p.), baclofen (6 mg/kg, i.p.) and 8-hydroxy-di-n-propylamino tetralin (8-OH-DPAT) (2.5 mg/kg, i.p.) all reduced the frequency of rhythmical slow activity. The effect of all three drugs was reduced by the 5-hydroxytryptamine 1a antagonist pindolol (2 mg/kg, i.p.). Pindolol had no effect on the reduction in rhythmical slow activity produced by sodium amylobarbitone, as has been previously reported for the benzodiazepine chlordiazepoxide. Flumazenil (10 mg/kg, i.p.), a benzodiazepine receptor antagonist, reduced the effects of chlordiazepoxide (5 mg/kg, i.p.), but not buspirone (10 mg/kg, i.p.). A combination of the selective beta 1 adrenergic receptor antagonist metoprolol (20 mg/kg, i.p.) and the beta 2 adrenergic receptor antagonist ICI 118,551 (4 mg/kg, i.p.) did not reduce the effects of either buspirone (10 mg/kg, i.p.) or diazepam (1 mg/kg, i.p.). These data show that there are at least two separate routes through which anxiolytic agents reduce the frequency of hippocampal rhythmical slow activity. Buspirone, clonidine, baclofen and 8-OH-DPAT act via a system dependent on 5-hydroxytryptamine 1a receptor activation. Benzodiazepines act via activation of the benzodiazepine receptor and probably share with barbiturates action at the GABA-benzodiazepine-chloride ionophore complex but do not produce their effects, directly or indirectly, by 5-hydroxytryptamine 1a receptor activation.

Neurochemically dissimilar anxiolytic drugs have common effects on hippocampal rhythmic slow activity.

Previous experiments have shown that anxiolytic drugs reduce the frequency of hippocampal rhythmic slow activity, induced by high frequency stimulation of the reticular formation and flatten the function relating threshold septal stimulation to the frequency of driven rhythmic slow activity. All of the drugs involved are known to augment GABAergic transmission. The present experiments investigated the effects of the novel anxiolytic compound buspirone which, unlike conventional anxiolytics, does not interact with GABA, yet is a clinically effective anxiolytic. Buspirone (0.156-40 mg/kg, i.p.) was found to reduce the frequency of reticular-elicited rhythmic slow activity, in a similar manner to chlordiazepoxide (0.019-20 mg/kg, i.p.). Buspirone did not change the linearity of the voltage-frequency function. Buspirone (10 mg/kg, i.p.) also altered the threshold for septal driving of rhythmic slow activity, in a similar manner to classical anxiolytics. The combination of chlordiazepoxide (5 mg/kg, i.p.) with corticosterone (0.2 mg, s.c.) removed the minor differences between buspirone and chlordiazepoxide in both the septal and reticular tests. These results show that buspirone altered the control of rhythmic slow activity in the hippocampus, in a manner which appeared functionally equivalent to other anxiolytics but which depends on mechanisms which are likely to be neurally and pharmacologically distinct from those of other anxiolytic drugs.

Buspirone affects hippocampal rhythmical slow activity through serotonin1A rather than dopamine D2 receptors.

Buspirone reduces anxiety clinically but, unlike classical anxiolytics, is not muscle relaxant, sedative, anticonvulsant or effective in increasing GABA function. The basis for its clinical action is not known, but action at both dopamine D2 and serotonin1A receptors has been suggested. Buspirone, like classical anxiolytics, produces a general reduction in the frequency of hippocampal rhythmical slow activity elicited by stimulation of the midbrain in the rat. Methysergide (3 mg/kg i.p.), GR38032F (0.3 mg/kg i.p.) and haloperidol (0.2 mg/kg and 2.0 mg/kg i.p.) failed to block this effect of buspirone (10 mg/kg i.p.). Apomorphine (0.3 mg/kg i.p.) had minor effects, but did not produce a general reduction in frequency. Pindolol (2 mg/kg i.p.) produced a small reduction in frequency itself. In the presence of pindolol, buspirone was without effect, while the effect of chlordiazepoxide (5 mg/kg i.p.) was potentiated. These results show that: (a) the similar effects of buspirone and classical anxiolytics such as chlordiazepoxide on reticular-elicited hippocampal rhythmical slow activity are achieved through different mechanisms; (b) the effects of buspirone in this particular test are more likely to depend on its interaction with serotonin1A receptors than its interaction with D2 receptors; and (c) that, as in other tests, buspirone does not act via serotonin2 or serotonin3 receptors.

Effects of GABAA and GABAB receptor agonists on reticular-elicited hippocampal rhythmical slow activity.

Hippocampal rhythmical slow activity (RSA) can be elicited by stimulation of the midbrain reticular formation. All classes of anxiolytic drug so far tested reduce the frequency of this RSA. Anxiolytic barbiturates and benzodiazepines, as opposed to compounds such as buspirone, are thought to act as receptor agonists of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In the present study muscimol (a GABAA receptor agonist) and baclofen (a GABAB receptor agonist) were injected into freely moving rats. Baclofen produced a dose-related decrease in frequency of RSA in the range 1 to 9 mg/kg i.p. and abolished RSA at 27 mg/kg. Muscimol produced an increase in RSA frequency with an inverted U-shaped dose response curve in the range 0.0001 to 1.0 mg/kg with maximal effect at 0.001 mg/kg. The effects of classical anxiolytic drugs in the present test resemble those of the GABAB receptor agonist baclofen more than they resemble those of the GABAA receptor agonist muscimol but it is possible that they are acting via GABA systems which employ low rather than high affinity GABAA receptors or through some transmitter system other than GABA.

Effects of ethanol and Ro 15-4513 in an electrophysiological model of anxiolytic action.

Previous research has implicated hippocampal rhythmical slow activity in the mechanisms of action of the anxiolytic drugs. In this study ethanol and a putative ethanol antagonist, Ro 15-4513, were investigated with reticular elicitation of rhythmical slow activity. Doses of ethanol between 0.6 and 3.1 g/kg were used. Ethanol reduced the frequency of reticular-elicited rhythmical slow activity in the same way as has been reported for anxiolytic barbiturates and benzodiazepines. This effect was linearly related to log dose of ethanol in the range of 1.7-3.1 g/kg. Ro 15-4513 at a dose of 2 mg/kg reduced the effect of ethanol (2.0 g/kg) but had no action itself. Ethanol also decreased the slope of the stimulation voltage-rhythmical slow activity frequency function but this effect was not reduced by Ro 15-4513. These results show that ethanol acts in a similar manner to conventional anxiolytic drugs but that only one component of this action can be reduced by Ro 15-4513.