Within the area tempestas (AT) in the anterior piriform cortex, unilateral microinfusions of
GABA receptor antagonists and
glutamate receptor agonists trigger brief episodic limbic
seizures. In the present study, we document a synergistic effect of coinfusing
bicuculline (GABAA receptor antagonist) with either
carbachol (
muscarinic receptor agonist) or
cyclothiazide (inhibitor of
AMPA receptor desensitization) but not with
glutamate receptor agonists (
AMPA,
NMDA or
kainate) in the rat AT. In particular, coadministration of
bicuculline (118 pmol) with either
carbachol (328 pmol) or
cyclothiazide (1.2 nmol) triggered continuous self-sustaining
seizures (
status epilepticus; SE).
Cyclothiazide alone did not evoke
seizures. Although blockade of
NMDA receptors with
AP-7 (100 or 500 pmol) prevented episodic
seizures evoked by
carbachol or
bicuculline alone, it was without effect on the continuous
seizures evoked by combined treatments.
NMDA-insensitive self-sustaining
seizures were also evoked by the combination of
AMPA and
cyclothiazide. Regardless of the mechanism by which SE was evoked, it was prevented only by an
AMPA receptor antagonist,
NBQX, thus reinforcing the crucial role of
AMPA receptors in the transition to SE. Further evidence for
AMPA receptor regulation of seizure severity came from the overexpression of the GluR1
AMPA receptor subunit in AT. This resulted in substantially increased severity of
bicuculline-evoked
seizures that was reversed by focal application of
NBQX. Thus, desensitization of
AMPA receptors appears to limit the duration and severity of seizure activity, and a failure of this mechanism, or an overabundance of slowly desensitizing
AMPA receptors, predisposes to severe and prolonged
seizures.