ANTICONVULSANT PROPERTIES OF BIBP3226, A NONPEPTIDE SELECTIVE ANTAGONIST AT NEUROPEPTIDE-Y Y-1 RECEPTORS

Several lines of evidence indicate that neuropeptide Y (NPY)-mediated neurotransmission in the hippocampus is altered by limbic seizures. Th e functional consequences of this change are still unresolved and clea rly depend on the type of NPY receptors involved. We have investigated the role of NPY Y-1 receptor subtypes, which are enriched in the dent ate area of the hippocampus, on EEG seizures induced by a local inject ion of 0.04 mu g kainic acid in rats. Intrahippocampal administration of 10 mu g BIBP3226 lacetyl)-N-[(4-hydroxyphenyl)methyl]D-arginamide), a non-peptide selective antagonist at the NPY Y-1 receptors, increase d threefold on average (P < 0.01) the time to onset of seizures and re duced the number of seizures and the total time in seizures three-and fourfold, respectively (P < 0.01). Its inactive S-enantiomer BIBP3435 was ineffective on seizure activity. One microgram [Leu(31),pro(34)]NP Y, agonist at Y-1 receptors, did not modify per se the EEG sequelae in duced by kainic acid but it antagonized the anticonvulsant effect of B IBP3226. These results indicate that NPY Y-1 receptors in the hippocam pus are involved in epileptic phenomena and suggest that selective Y-1 receptor antagonists may be of value for attenuating limbic seizures.