Age‐Dependent Effects of γ‐Aminobutyric Acid Agents on Flurothyl Seizures

Abstract

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.

Progressive NKCC1-Dependent Neuronal Chloride Accumulation during Neonatal Seizures

“…In addition, the ictal time course of changes in neuronal Cl − are important experimental variables. In vivo models of neonatal seizures, primarily induced by GABA antagonists, demonstrate efficacy of GABAergic anticonvulsants administered before or coincident with convulsants (Velisek et al, 1995;Haugvicova et al, 1999;Isaev et al, 2007). As demonstrated in Figures 1–4, administration of phenobarbital prior to or just after the first seizure, when [Cl − ] i is relatively low and the net effect of GABA is still inhibitory, may prevent or reduce the positive feedback cycle of seizure-dependent disinhibition and subsequent disinhibition-induced seizures that limit the subsequent efficacy of GABAergic anticonvulsants.…”

GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations

“…Intrahippocampal injection of epileptogenic agents (high K ϩ and low Mg 2ϩ ) in vivo induced in P8 -P12 rat hippocampal generated electrographic seizures that were facilitated by coinfusions of the GABA A receptor antagonist and blocked by coinfusions of isoguvacine or diazepam, suggesting anticonvulsants effects of GABA (282). Although barbiturates and benzodiazepines suppressed seizures in neonatal rats in various models of ictogenesis (357,358,572,636), hippocampal seizures induced by systemic injection of kainate were suppressed by bumetanide, phenobarbital, and bicuculline, suggesting that depolarizing GABA facilitates seizures in the developing brain (173).…”

The effects of seizures on the connectivity and circuitry of the developing brain

“…Indeed, the convulsant properties of GABA A receptor antagonists suggest that starting at the end of the first postnatal week, GABA systems act to prevent the genesis of seizures. Moreover, it is commonly observed that drugs that enhance GABA-mediated synaptic transmission are anticonvulsant in both immature animals and human neonates and infants [Kubova and Mares, 1991;Kubova et al, 1999;Velisek et al, 1995;Mizrahi, 1997;Camfield et al, 1997]. In contrast, it is commonly observed that glutamate receptor antagonists readily block electrographic seizures induced by GABA A receptor antagonists [Gomez-DiCesare et al, 1997;Lee and Hablitz, 1991].…”