To clarify the role of
benzodiazepine receptors in kindling, the present experiment assessed the effects of
CL 218,872 (1, 5, 10, and 20 mg/kg), a triazolopyridazine with a selective affinity for the putative
benzodiazepine BZ1 receptor subtype, on the development and expression of amygdaloid-kindled
seizures. Additionally, we assessed the effects of
flumazenil (10 mg/kg), a non-specific
benzodiazepine receptor antagonist, on kindling and the expression of kindled
seizures alone or concomitantly with
CL 218,872 (20 mg/kg).
CL 218,872 retarded the development of kindled
seizures in a linear dose-dependent manner; rats treated with 5, 10, and 20 mg/kg, but not 1 mg/kg, of
CL 218,872 required a greater number of afterdischarges (ADs) to develop
generalized seizures than controls.
Flumazenil also retarded kindling and failed to attenuate the prophylactic effect of
CL 218,872. In a cross-over procedure rats that did not develop
generalized seizures after 30 ADs while under
drug were rekindled under vehicle and rats kindled under vehicle were subsequently tested under
drug. Rats crossed over to vehicle rekindled at a faster rate than did controls during initial kindling, suggesting that some kindling had occurred under the
drug.
CL 218,872 also dose-dependently depressed kindled
seizures and this was attenuated by
flumazenil, which had little effect on kindled
seizures by itself. Together, these data suggest that
CL 218,872 is a potent
anticonvulsant, implicating the BZ1 receptor subtype in seizure development and in the expression of kindled
seizures.