title: Synchronous GABA-mediated potentials and epileptiform discharges in the rat limbic system in vitro.
abstract: Application of 4-aminopyridine (4AP, 50 microM) to combined slices of adult rat hippocampus-entorhinal cortex-induced ictal and interictal epileptiform discharges, as well as slow field potentials that were abolished by the mu-opioid agonist [D-Ala2,N-Me-Phe4,Gly-ol5] enkephalin (DAGO, 10 microM) or the GABAA receptor antagonist bicuculline methiodide (BMI, 10 microM); hence, they represented synchronous GABA-mediated potentials. Ictal discharges originated in the entorhinal cortex and propagated to the hippocampus, whereas interictal activity of CA3 origin was usually recorded in the hippocampus. The GABA-mediated potentials had no fixed site of origin or modality of propagation; they closely preceded (0.2-5 sec) and thus appeared to initiate ictal discharges. Only ictal discharges were blocked by the antagonist of the NMDA receptor 3,3-(2-carboxypiperazine-4-yl)propyl-1-phosphonate (CPP, 10 microM), whereas the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) abolished all epileptiform activities. The GABA-mediated potentials continued to occur synchronously in all regions even after concomitant application of CNQX and CPP. [K+]o elevations were recorded in the entorhinal cortex during the ictal discharge (peak values = 13.9 +/- 0.9 mM) and the synchronous GABA-mediated potentials (peak values = 4.2 +/- 0.1 mM); the latter increases were presumably attributable to postsynaptic GABAa-receptor activation because they were abolished by DAGO or BMI. Their role in initiating ictal activity was demonstrated by using DAGO, which abolished both GABA-mediated synchronous potentials and ictal discharges. These data indicate that NMDA-mediated ictal discharges induced by 4AP originate in the entorhinal cortex; such a conclusion is in line with clinical evidence obtained in temporal lobe epilepsy patients. 4AP also induces GABA-mediated potentials that spread within the limbic system when excitatory transmission is blocked and may play a role in initiating ictal discharge by increasing [K+]o.
authors.affiliation: Montreal Neurological Institute, McGill University, Quebec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Avoli
authors.forename: M
authors.initials: M
authors.lastname: Barbarosie
authors.forename: A
authors.initials: A
authors.lastname: Lücke
authors.forename: T
authors.initials: T
authors.lastname: Nagao
authors.forename: V
authors.initials: V
authors.lastname: Lopantsev
authors.forename: R
authors.initials: R
authors.lastname: Köhling
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004594:Electrophysiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D018728:Entorhinal Cortex / Q000737:chemistry / Q000503:physiopathology; D004827:Epilepsy / Q000503:physiopathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000503:physiopathology; D008032:Limbic System / Q000503:physiopathology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016202:N-Methylaspartate / Q000502:physiology; D009412:Nerve Fibers / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D011188:Potassium / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D000700:Analgesics; D004745:Enkephalins; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017366:Serotonin Receptor Agonists; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015761:4-Aminopyridine; C015068:1-(3-chlorophenyl)piperazine; D011188:Potassium