Epileptiform synchronization and GABA(B) receptor antagonism in the juvenile rat hippocampus.
The GABA(B) receptor agonist baclofen enhances the epileptiform activity induced by 4-aminopyridine (4AP) in juvenile rat hippocampal slices. In this study, we used a similar experimental approach (i.e., field potential, intracellular, and [K+]o recordings in the CA3 area of slices obtained from 15-23-day-old rats) to establish whether antagonizing GABA(B) receptors could exert opposite (presumably anticonvulsant) effects. Bath application of 4AP (50 microM) induced spontaneous interictal and ictal discharges along with synchronous GABA receptor-mediated potentials. All types of 4AP-induced synchronous activity occurred more frequently during application of the GABA(B) receptor antagonist p3-amino-propyl,p-diethoxymethylphosphonic acid (CGP 35348) (0.1-1 mM; EC50 = 0.25 mM). Moreover, CGP 35348 augmented the frequency and, to a lesser extent, the duration of the asynchronous synaptic activity recorded intracellularly from CA3 pyramids (n = 19). In medium containing 4AP + ionotropic glutamatergic antagonists (which abolished interictal and ictal activity), CGP 35348 prolonged both GABA-receptor-mediated field potentials and the accompanying intracellular long-lasting depolarizations without modifying their rate (n = 12). The transient elevations in [K+]o associated with GABA receptor-mediated potentials in 4AP-containing medium (n = 7 slices) became larger during CGP 35348 application. Similar findings were obtained when CGP 35348 was applied to medium containing 4AP + ionotropic glutamatergic antagonists (n = 6). Thus, the effect of CGP 35348 on 4AP-induced epileptiform activity is not anticonvulsant and to some extent similar to what was reported in this model during GABA(B) receptor activation. We propose that the facilitation of ictal activity by CGP 35348 is mainly caused by the blockade of presynaptic GABA(B) receptor, leading to an increase in GABA release and subsequent larger [K+]o elevations.
Motalli
Rita
R
Montreal Neurological Institute and Department of Neurology, McGill University, Montreal, Quebec, Canada.
D'Antuono
Margherita
M
Louvel
Jacques
J
Kurcewicz
Irene
I
D'Arcangelo
Giovanna
G
Tancredi
Virginia
V
Manfredi
Mario
M
Pumain
René
R
Avoli
Massimo
M
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D004827:Epilepsy / Q000378:metabolism / Q000503:physiopathology*; D058788:GABA-B Receptor Antagonists; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D009943:Organophosphorus Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000502:physiology
D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; C066430:CGP 35348