Abstracts

Rationale: Inhibition mediated by postsynaptic GABA-B receptors is stronger and lasts longer than that mediated by GABA-A receptors. Due to GABA-B receptors localized presynaptically GABA-B receptor agonists exhibit mixed anti- and proconvulsant action. Therefore we started to study effects of a positive modulator of GABA-B receptors CGP7930 with the aim to know if this drug may be able to differentiate anti- and proconvulsant effects. Study was focused on immature animals because of marked role of GABA-B system in immature brain. Methods: Effects of CGP7930 (Tocris, UK) against pentetrazol(PTZ)-induced motor seizures were studied in 7-, 12-, 18-, 25-day-old and adult rats. Animals pretreated with CGP7930 (1-40 mg/kg ip) were injected 30 min later with PTZ (100 mg/kg sc) and observed in isolation for 30 min. Seizure patterns and latencies were evaluated. In the second series of experiments various intervals between GP7930 and PTZ injections were used in 12- and 25-day-old rats to know time profile of anticonvulsant action. Effects against cortical epileptic afterdischarges were recorded in 12-, 18- and 25-day-old rats with implanted stimulation and registration epidural electrodes. First stimulation (8-Hz for 15 s) was a control one, then CGP7930 was injected (20 or 40 mg/kg ip) and the stimulation was repeated five more times with 20-min intervals. Pattern and duration of EEG seizures as well as intensity of movements elicited by stimulation and clonic seizures accompanying EEG afterdischarges were evaluated. Results: CGP7930 specifically suppressed tonic phase of generalized tonic-clonic seizures in 7-, 12- and 18-day-old rats; the highest dose was able to abolish generalized seizures completely. The two older groups exhibited dose-dependent suppression of the whole pattern of generalized seizures without any specificity against the tonic phase. Minimal clonic seizures induced by PTZ in 18-, 25-day old and adult animals were influenced by the highest dose of CGP; their suppression was significant only in 25-day-old rats. Latencies of both types of seizures tended to be longer, level of statisticl significance was reached only exceptionally. Duration of action of CGP7930 was longer in 12- than in 25-day-old animals. Neither cortical epileptic afterdischarges nor motor phenomena registered could be significantly influenced by CGP7930 in any age group. Conclusions: Positive modulator GABA-B receptors CGP7930 exhibits an anticonvulsant action in only one of the two models used in our study. Its age-specific anticonvulsant action against PTZ-induced seizures was significant only if high doses were used. In contrast to GABA-B receptor agonists baclofen and SKF97541 no proconvulsant action was recorded. This study was supported by grant No.305/05/2581 of the Grant Agency of Czech Republic and by Research Projects No. LC-554 and AV0Z 50110509.