Excitatory amino acid blockers differentially affect bursting of in vitro hippocampal neurons in two pharmacological models of epilepsy.
The role of excitatory amino acid neurotransmitters in generating two distinct types of epileptiform discharge in the CA3 region of hippocampal slices was examined in the guinea-pig using a variety of different excitatory amino acid blockers. In magnesium-free medium the N-methyl-D-aspartate receptor antagonist, DL-aminophosphonovaleric acid, and the putative N-methyl-D-aspartate channel blockers phencyclidine and ketamine, reduced the amplitude and duration of spontaneous bursts and blocked their afterdischarges. In marked contrast none of these compounds significantly depressed spontaneous bursts recorded in the presence of 2 mM Mg2+ and penicillin. This was confirmed for individual slices where Mg2+-free bursts had previously been suppressed by the same concentration of blocker. Therefore, the N-methyl-D-aspartate receptor mechanism does not contribute significantly to the generation of this type of epileptiform discharge. The channel blockers lost their effect on Mg2+-free bursts in the presence of penicillin; however, the receptor blockers did not. This is probably due to the unique mechanisms of action of the channel blockers. This implies that different types of N-methyl-D-aspartate blockers might be effective anticonvulsants only in specific conditions. While the non-specific excitatory amino acid blocker, kynurenic acid, was effective against both burst types it appeared to suppress them by different mechanisms. Kynurenic acid depressed the amplitude and duration of Mg2+-free bursts but its only effect on penicillin bursts was to reduce their frequency. This suggests that neither N-methyl-D-aspartate nor non-N-methyl-D-aspartate receptors play a major role in the production of the paroxysmal depolarizing shift resulting from the block of GABA-mediated inhibition by penicillin. However, these receptors may be involved in generating the spontaneous activity which triggers the bursts.
Schneiderman
J H
JH
Department of Medicine, Wellesley Hospital, Toronto, Ontario, Canada.
MacDonald
J F
JF
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004827:Epilepsy / Q000503:physiopathology*; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D007649:Ketamine / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000494:pharmacology*; D010622:Phencyclidine / Q000494:pharmacology*; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*
D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; D007649:Ketamine; D015763:2-Amino-5-phosphonovalerate; D007736:Kynurenic Acid; D010622:Phencyclidine