Pharmacology of the Inhibitory Systems in Primary Generalized Epilepsy of “Petit Mal” Type

Abstract

That the neurochemical substrate of bilaterally synchronous spikes-and-wave (SW) discharges differs substantially from the one of focal epilepsy appeared evident to us about 10 years ago while we were studying the effect of homotaurine (3-aminopropanesulfonic acid, 3APS), a highly specific GABA agonist, on various seizure models, in view of its potential use as an antiepileptic agent. An intravenous injection of 3APS in cats with an acute neocor-tical focus induced by topical application of penicillin provoked a transient suppression of all focal epileptiform discharges associated with systemic phenomena such as bradycardia, hypertension, and dyspnea (Fariello, 1979). When a pattern of bilaterally synchronous SW discharges was induced by systemic penicillin injection, however intravenous 3APS at the dose capable of suppressing focal spikes induced a remarkable potentiation of the SW complexes, which lasted several minutes and was accompanied by the same systemic effects (Fariello et al., 1981). In view of the fact that in the same animal species two epileptiform phenomena induced by the same epileptogenic agent showed diametrically opposite responses to the same Gaba agonist administered at the same dose through the same route and causing the same systemic phenomena, it appeared reasonable to ascribe the discrepancy of the two responses to a different role played by GABA-mediated inhibition in the two seizure models. Review of the available literature confirmed that several other models of bilaterally synchronous SW discharges were enhanced by the administration of direct or indirect GABA agonists. The bilaterally synchronous SW discharge elicited by photic stimulation in the baboon Papio papio is potentiated by administration of muscimol, a powerful direct GABAA agonist (Pedley et al., 1979). Other partial or indirect agonists, such as gammahydroxybutyrate and imidazole-4-acetic acid, potentiate models of SW epileptiform activity (Marcus et al., 1971; King, 1979; Snead, 1978). Also, in rats, agents that block GABA transaminase, which presumably increases GABA availability in the synaptic cleft, markedly potentiate metrazol-induced SW discharges (Myslobodsky et al., 1979). In the following years, several studies further confirmed this seizure-enhancing effect of GABA agonists on bilaterally synchronous SW. In rodents, the gamma hydroxybutirate-induced model of petit mal is remarkably facilitated by the administration of several GABA-mimetics (Snead, 1984). Furthermore, administration of such direct GABA agonists as 4,5,6,7 tetrahydroxyisoxasolo (4,5-c) pyridine 3-ol (THIP) and muscimol induced in several animal species de novo epileptiform abnormalities. In particular, in rats, three stages of EEG epileptiform phenomena are seen after incremental doses of these two direct GABAA agonists: Isolated spikes are first seen, then bilaterally synchronous SW discharges, and eventually, with the higher doses, a burst-suppression pattern appears (Golden and Fariello, 1984). Actually the administration of THIP to Sprague-Dawley albino or Long Ev-ans hooded rats at doses between 5 to 10 mg/kg induces a sustained pattern of 5- to 7-Hz SW discharges that are remarkably similar to the one observed spontaneously in several rodent species (Fariello and Golden, 1987). This spontaneous high voltage spindle-like (HSV) activity is now being accepted as a model of petit mal epilepsy, in spite of a continuing controversy about whether it is epileptic or nonepileptic in nature (Kaplan, 1985). In recent studies, HSVs were enhanced by direct GABA agonists, by GABA transaminase antagonists, and GABA uptake inhibitors (Marescaux et al., in press).