Age-dependent effects of gamma-aminobutyric acid agents on flurothyl seizures

Behavioral characteristics of seizures have age-dependent features, which suggests that effective treatment of seizures may be age-specific as well. In experiments that used the flurothyl seizure model, we examined the effects of several drugs that affect GABAergic neurotransmission in rats of various ages. Systemic administration of phenobarbital (PB, a drug that enhances GABAA receptor-mediated inhibition) was anticonvulsant in most age groups. In contrast, gamma-vinyl GABA (VGB, a drug that increases endogenous GABA levels and enhances both GABAA and GABAB receptor transmission) did not have anticonvulsant effects. Baclofen (a GABAB receptor agonist) was proconvulsant in 9-day-old rat pups, and anticonvulsant in 15-30-day-old rats and lost its anticonvulsant activity in 60-day-old rats. CGP 35348 (a GABAB receptor antagonist) was proconvulsant in developing rats but not in 60-day-old rats. A novel GABAB receptor antagonist, CGP 36742, was proconvulsant in 9- and 15-day-old rats but had no effects in 30- and 60-day-old rats. These results indicate that the effects of presumed GABAergic agents are not uniform across the age span. The differences may reflect age-dependent maturational changes of GABA receptor subtypes, differential action of the drugs on pre- and postsynaptic sites and possible non-GABAergic effects.