European Journal of Pharmacology, 192 (1991) 103-108 © 1991 Elsevier Science Publishers B.V. (Biomedical Division) 0014-2999/91/$03.50 ADONIS 001429999100074G 103 EJP 51660 Effects of GABA A and GABA B receptor agonists on reticular-elicited hippocampal rhythmical slow activity Colleen F. Coop, Neff McNaughton and Ian Lambie Department of Psychology and Centrefor Neuroscience, University of Otago, P.O.B. 56, Dunedin, New Zealand Received 14 June 1990, revised MS received 3 October 1990, accepted 16 October 1990 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 "r-aminobutyric acid (GABA). In the present study muscimol (a GABA n receptor agonist) and baclofen (a GABA B 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 0.00001 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 GABA B receptor agonist baclofen more than they resemble those of the GABA A receptor agonist muscimol but it is possible that they are acting via GABA systems which employ low rather than high affinity GABA A receptors or through some transmitter system other than GABA. GABA (-/-aminobutyric acid); Muscimol; Baclofen; Hippocampus; Hippocampal rhythmical slow activity; Anxiolytics; (Rat) I. Introduction Drugs used clinically to treat anxiety in the past (classical anxiolytics) include barbiturates, meproba- mate and benzodiazepines. They are all thought to act by increasing, directly or indirectly, neurotransmission of -y-aminobutyric acid (GABA; Sepinwall, 1983). By contrast, buspirone, which has been found to be clini- cally as potent as the benzodiazepine diazepam, does not interact with GABA receptors. Nor does it produce the muscle relaxant, sedative or anticonvulsant effects of the classical anxiolytics (Goa and Ward, 1986). The basis of its clinical action is at present unknown but both dopamine (McMillen et al., 1983) and serotonin (Traber and Glaser, 1987) have been suggested as candidate neurotransmitter systems. Stimulation of the midbrain reticular formation elicits rhythmical slow activity in the hippocampus (RSA). All anxiolytic drugs so far tested, including buspirone, re- duce the frequency of such RSA (McNaughton and Sedgwick, 1978; McNaughton et al., 1986; 1988). Inter- estingly, the effect of buspirone in this test can be blocked by the 5-HT1A receptor antagonist pindolol, Correspondence to: N. McNaughton, Department of Psychology, University of Otago, P.O.B. 56, Dunedin, New Zealand. whereas the effect of the benzodiazepine chlordiazepo- xide is potentiated (Coop and McNaughton, in press). Similarly, the effect of chlordiazepoxide on reticular- elicited RSA can be blocked by Ro 15-1788 (a benzodi- azepine receptor antagonist) whereas the effect of buspirone cannot. Reduction of reticular-induced hip- pocampal RSA represents, therefore, a final common path for the actions of classical and novel anxiolytics which have primary actions on quite distinct systems. The available data are consistent with the view that classical anxiolytics (as opposed to buspirone) are af- fecting RSA through action at the 'GABA-benzodi- azepine-chloride ionophore' macromolecular complex. This has at least five functional binding sites; the GABA receptor itself; the benzodiazepine recognition site; the chloride ionophore; the picrotoxin site; and a de- pressant site (Mazzari et al., 1981; Barnard, 1988; Teicher, 1988). The different classes of classical anxio- lytic site achieve their common GABA agonism by interacting with different components of this complex. The GABA receptor which forms part of the macro- molecular complex is believed to be of the GABA A rather than GABA B type. GABA A receptors are activated by GABA and muscimol and antagonised by bicuculline. Muscimol is a potent inhibitor of GABA binding at postsynaptic GABA A receptors (Beaumont et al., 1978). GABA A receptors are not activated by