CL 218,872 a triazolopyridazine with a selective affinity for the benzodiazepine BZ1 receptor subtype, retards the development and expression of amygdaloid-kindled seizures: effects of flumazenil.

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.