Differential antagonism by the selective A1 adenosine receptor agonist CCPA of seizures induced by NMDA, kainic acid, and domoic acid

Abstract

10.1002/(SICI)1520-6769(199601)18:1<9::AID-NRC135>3.3.CO;2-0The ability of 2-chloro-N6-cyclopentyladenosine (CCPA), a selective agonist for A1 adenosine receptors, to antagonize convulsions induced by the activation of different excitatory amino acid receptor subtypes was evaluated in rats. CCPA (0.5 to 3 mg/kg, i.p.) antagonized in a dose-dependent manner seizures induced by intracerebroventricular infusion of N-methyl-D-aspartate (NMDA). At a dose of 1 mg/kg, CCPA induced a marked delay (∼15 min) in the onset of seizures and reduced by 60% the number of animals showing seizures in rats treated with 5 μg of NMDA, whereas at 3 mg/kg the adenosine analog completely prevented convulsions. A similar, but less pronounced, effect of CCPA was apparent in animals injected with 15 μg of NMDA. Previous administration of a specific A1 receptor antagonist abolished the antagonistic action of CCPA on NMDA-induced seizures, suggesting that the effect of CCPA is mediated by a direct activation of A1 receptors. In contrast, CCPA (1 or 3 mg/kg, i.p.) had no effect on seizures induced by kainic acid (12 mg/kg, i.p.) or by the intracerebroventricular injection of domoic acid (1 to 5 μg), a selective and high-affinity ligand for kainate-sensitive glutamate receptors. These results indicate that the anticonvulsant action of CCPA is specific for seizures induced by activation of NMDA-sensitive glutamate receptors.