Electroencephalographic investigation in rabbits of drugs acting at GABA- benzodiazepine-barbiturate/picrotoxin receptors complex

Abstract

This paper describes the EEG profiles, observed in rabbits, of drugs which affect GABA synaptic activity by acting at GBB complex. Drugs which enhance GABA synaptic activity induce sedation associated with EEG synchronization. However, muscimol, THIP, GHB and baclofen induce signs of CNS stimulation (light tremors of the forelimbs, chewing, light nystagmus and hyperpnea) associated with EEG spikes. Signs of light stimulation (chewing and jerks of the head) also occur after BDZs and barbiturates, and are associated with the presence of 12–24 and 20–25 Hz waves, respectively. Drugs which reduce GABA synaptic activity (bicuculline, inverse BDZ agonists, PTZ, picrotoxin and Ro 5-3663) induce three dose-dependent stages of EEG changes: trains of slow waves, trains of spike-and-wave complexes and paroxysmal activity in the rostral encephalic structures without apparent changes of the electrical activity in the spinal cord. The first two stages are associated with a behavioral state of alert and the third stage with tonico-clonic convulsions. Among the inverse BDZ agonists, DMCM and β-CCM elicit all three stages, whereas FG 7142 and β-CCE induce only the first two and CGS 8216 only the first. The BDZ antagonists Ro 15-1788 and Ro 15-3505 (0.2–30 mg/kg IV) do not significantly affect the EEG pattern. However, they selectively inhibit the effects of diazepam and of the inverse BDZ agonists. In both cases, the inhibition is observed with doses as low as 0.2 mg/kg IV and leads to an EEG desynchronization. The possible involvement of the modifications of GABA synaptic activity in the etiology of both petit mal and grand mal epilepsies is discussed.