Effects of felbamate on muscarinic and metabotropic-glutamate agonist-mediated responses and magnesium-free or 4-aminopyridine-induced epileptiform activity in guinea pig olfactory cortex neurons in vitro.
The effects of the anticonvulsant agent felbamate (FBM) were examined on muscarinic and metabotropic-glutamate receptor agonist-induced responses and chemically induced epilepti-form activity, in guinea pig olfactory cortex slices in vitro. FBM (100-500 microM) had little effect on neuronal membrane properties and on postsynaptic potentials evoked by electrical stimulation of lateral olfactory tract terminals, whereas it reduced the duration of presumed Ca++ spikes induced by intracellular Cs+ loading. In contrast, the muscarinic receptor agonist oxotremorine-M (10 microM) or the metabotropic glutamate receptor agonist 1-aminocyclopentane-1S-3R-dicarboxylic acid (10 microM) induced a sustained membrane depolarization with repetitive firing, an increase in input resistance and the appearance of a slow poststimulus afterdepolarizing potential. These effects were reversibly reduced in the presence of FBM (100-500 microM). After preincubation of slices with Mg+(+)-free solution or 200 microM 4-aminopyridine, neurons exhibited spontaneous and stimulus-evoked epileptiform potentials that were suppressed by FBM (1 mM). We conclude that FBM can interfere with muscarinic and metabotropic-glutamate response generation and slow after-depolarization induction in olfactory cortical neurons, most likely by blocking Ca++ influx through voltage-sensitive Ca++ channels. A possible interaction of FBM with other voltage-insensitive Ca++ conductances is also considered. We also suggest that FBM can suppress epileptiform activity induced by Mg+(+)-free or 4-aminopyridine exposure primarily through inhibition of N-methyl-D-aspartate-gated ion channels, although additional actions on non-N-methyl-D-aspartate receptor sites and/or presynaptic transmitter release mechanisms cannot be excluded.
Libri
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V
Department of Pharmacology, School of Pharmacy, London, UK.
Constanti
A
A
Zibetti
M
M
Nisticó
S
S
D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000078328:Felbamate; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009830:Olfactory Bulb / Q000187:drug effects*; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000494:pharmacology*; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects
D000927:Anticonvulsants; D048448:Phenylcarbamates; D011409:Propylene Glycols; D018094:Receptors, Metabotropic Glutamate; D011976:Receptors, Muscarinic; D015761:4-Aminopyridine; D000078328:Felbamate