Neocortical epileptogenesis in vitro: studies with N-methyl-D-aspartate, phencyclidine, sigma and dextromethorphan receptor ligands.
Slices of rat neocortex have been used to study the role of N-methyl-D-aspartate (NMDA) receptors in the induction of epileptiform activity. The NMDA antagonist potency of a range of compounds with putative anticonvulsant activity has been compared with their ability to reduce epileptiform activity in this tissue. Epileptiform activity was induced by the omission of magnesium from the bathing medium. Competitive and noncompetitive phencyclidine-like NMDA antagonists reduced such spontaneous and stimulus-evoked epileptiform bursts and after potentials. Similar epileptiform activity induced by the addition of proconvulsant drugs, e.g. gamma-aminobutyric acidA antagonists, potassium channel blockers or carbachol was reduced by ketamine and/or D-2-amino-5-phosphonovaleric acid. In magnesium-free medium, the frequency of spontaneous bursts and the number of afterpotentials per burst were reduced in parallel. There was a good correlation (r greater than 0.9) between their potencies against NMDA depolarizations and against epileptiform bursts (MK-801 [(+)-5-methyl-10,11- dihydro-5H-dibenzvo[a,d]cyclohepten-5,10-imine] greater than thienylcyclohexylpiperidine phencyclidine greater than 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid greater than cyclazocine greater than D-2-amino-5-phosphonovaleric acid greater than dextrorphan greater than SKF10,047 (N-allylnormetazocine) greater than ketamine greater than dextromethorphan = or greater than pentazocine). Sigma and dextromethorphan receptor ligands (e.g. ditolyguanidine, carbetapentane and phenytoin), whereas inactive as NMDA antagonists, reduced epileptiform activity by decreasing the number of afterpotentials per burst with less effect on the burst frequency. The quisqualate/kainate antagonist, FG9041 (6,7-dinitro-quinoxaline-2,3-dione), only reduced spontaneous bursts at doses which also reduced NMDA. Our results imply a central role for NMDA receptors in epileptogenesis in neocortical slices.
Aram
J A
JA
Department of Veterinary Basic Sciences, Royal Veterinary College, London, United Kingdom.
Martin
D
D
Tomczyk
M
M
Zeman
S
S
Millar
J
J
Pohler
G
G
Lodge
D
D
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects*; D003915:Dextromethorphan / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy / Q000209:etiology*; D066298:In Vitro Techniques; D007981:Levorphanol / Q000031:analogs & derivatives*; D016202:N-Methylaspartate; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D011957:Receptors, Opioid / Q000187:drug effects*; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma
D015221:Potassium Channels; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D011957:Receptors, Opioid; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; D007981:Levorphanol; D001224:Aspartic Acid; D016202:N-Methylaspartate; D003915:Dextromethorphan; D002217:Carbachol