Role of excitatory amino acid and GABAB receptors in the generation of epileptiform activity in disinhibited hippocampal slice cultures.
Selective excitatory amino acid- and GABAB-receptor antagonists were used to examine the role these receptors play in epileptiform burst discharge elicited by blocking GABAA receptor-mediated inhibition in hippocampal slice cultures of the rat. Application of bicuculline caused a single ictal burst followed by interictal bursting. The N-methyl-D-aspartate receptor antagonist, D-2-amino-5-phosphonovalerate, reduced the depolarizing envelope underlying interictal discharge, and accentuated the appearance of concomitant slow oscillatory potentials, which occurred synchronously in all CA3 cells. The non-N-methyl-D-aspartate receptor antagonists, 6-nitro-7sulphamoyl-benzo(F) quinoxaline and 6-cyano-7-nitro-quinoxaline-2,3-dione, blocked interictal bursting at high concentrations, and low concentrations of 6-cyano-7-nitro-quinoxaline-2,3-dione selectively eliminated the slow oscillations in an all-or-none manner, leaving the depolarizing envelope. No effects of either metabotropic glutamate receptor antagonists or of dihydropyridine Ca2+ channel agonists or antagonists on evoked interictal discharge were observed. 6-Cyano-7-nitro-quinoxaline-2,3-dione-resistant interictal-like discharge could be obtained in the presence of bicuculline when the external Mg2+ concentration was reduced from 1.5-0.5 mM. The GABAB receptor antagonist CGP 35348 prolonged individual evoked interictal bursts, and caused the appearance of spontaneous ictal-like discharges. The implications of these results are discussed with regard to the mechanisms of epileptogenesis and to potential therapeutic intervention.
Brain Research Institute, University of Zurich, Switzerland.
M
M
Scanziani
D
D
Debanne
M
M
Müller
B H
BH
Gähwiler
S M
SM
Thompson
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D004594:Electrophysiology; D004827:Epilepsy / Q000503:physiopathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D058788:GABA-B Receptor Antagonists; D006624:Hippocampus / Q000503:physiopathology*; D017403:In Situ Hybridization; D009924:Organ Culture Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018080:Receptors, GABA-B / Q000502:physiology*; D017470:Receptors, Glutamate / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018691:Excitatory Amino Acid Antagonists; D058788:GABA-B Receptor Antagonists; D018080:Receptors, GABA-B; D017470:Receptors, Glutamate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D001640:Bicuculline