CL 218,872 A TRIAZOLOPYRIDAZINE WITH A SELECTIVE AFFINITY FOR THE BENZODIAZEPINE BZ(1) RECEPTOR SUBTYPE, RETARDS THE DEVELOPMENT AND EXPRESSION OF AMYGDALOID-KINDLED SEIZURES - EFFECTS OF FLUMAZENIL

To clarify the role of benzodiazepine receptors in kindling, the prese nt experiment assessed the effects of CL 218,872 (1, 5, 10, and 20 mg/ kg), a triazolopyridazine with a selective affinity for the putative b enzodiazepine 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 antag onist, on kindling and the expression of kindled seizures alone or con comitantly with CL 218,872 (20 mg/kg). CL 218,872 retarded the develop ment of kindled seizures in a linear dose-dependent manner; rats treat ed 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 seizur es than controls. Flumazenil also retarded kindling and failed to atte nuate the prophylactic effect of CL 218,872. In a cross-over procedure rats that did not develop generalized seizures after 30 ADs while und er drug were rekindled under vehicle and rats kindled under vehicle we re subsequently tested under drug. Rats crossed over to vehicle rekind led at a faster rate than did controls during initial kindling, sugges ting that some kindling had occurred under the drug. CL 218,872 also d ose-dependently depressed kindled seizures and this was attenuated by flumazenil, which had little effect on kindled seizures by itself. Tog ether, 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.