Supraspinal convulsions induced by inverse benzodiazepine agonists in rabbits

The electroencephalographic (EEG) effects of inverse benzodiazepine (BDZ) agonists have been studied in rabbits after i.v. administration. A dose-dependent progression of three different stages of EEG changes have been observed with inverse BDZ agonists. At first, trains of slow waves in the occipital cortex occur, followed by trains of spike-and-wave complexes in the sensorimotor cortex. These two stages are superimposed on a desynchronized cortical activity, accompanied by an enhancement of the hippocampal theta rhythm. These EEG changes parallel a state of alertness. The third stage is characterized by generalized grand-mal seizures made up of high voltage spikes in the cortical and subcortical brain areas accompanied by generalized tonico-clonic convulsions. No modification of electrical activity is observed at the level of the spinal cord. Methyl-beta-carboline-3-carboxylate (beta-CCM) (at doses higher than 0.2 mg/kg) and 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (at doses higher than 0.4 mg/kg) elicit all three stages, whereas ethyl-beta-carboline-3-carboxylate (beta-CCE) (0.2-2 mg/kg) and N-methyl-beta-carboline-3-carboxamide (2-20 mg/kg) only elicit the first two, and finally CGS 8216 only the first. The extent of the EEG progression by inverse BDZ agonists may therefore be used as an index of the efficacy of each compound. The BDZ antagonists Ro 15-1788 and Ro 15-3505 (0.3 mg/kg or higher), which do not change the EEG pattern, block the effects of the convulsant and subconvulsant doses of the inverse BDZ agonists, giving rise to a desynchronized EEG pattern.(ABSTRACT TRUNCATED AT 250 WORDS)