The anti-epileptic actions of neuropeptide Y in the hippocampus are mediated by Y2 and not Y5 receptors

Neuropeptide Y (NPY) potently inhibits glutamate release and seizure activity in rodent hippocampus in vitro and in vivo, but the nature of the receptor(s) mediating this action is controversial. In hippocampal slices from rats and several wild-type mice, a Y-2-preferring agonist mimicked, and the Y-2-specific antagonist BIIE0246 blocked, the NPY-mediated inhibition both of glutamatergic transmission and of epileptiform discharges in two different slice models of temporal lobe epilepsy, stimulus train-induced bursting (STIB) and 0-Mg2+ bursting. Whereas Y-5 receptor-preferring agonists had small but significant effects in vitro, they were blocked by BIIE0246, and a Y-5 receptor-specific antagonist did not affect responses to any agonist tested in any preparation. In slices from Y-2(-/-) mice, NPY was without effect on evoked potentials or in either of the two slice seizure models. In vivo, intrahippocampal injections of Y-2- or Y-5-preferring agonists inhibited seizures caused by intrahippocampal kainate, but again the Y-5 agonist effects were insensitive to a Y-5 antagonist. Neither Y-2- nor Y-5-preferring agonists affected kainate seizures in Y-2(-/-) mice. A Y-5-specific antagonist did not displace the binding of two different NPY ligands in WT or Y-2(-/-) mice, whereas all NPY binding was eliminated in the Y-2(-/-) mouse. Thus, we show that Y-2 receptors alone mediate all the anti-excitatory actions of NPY seen in the hippocampus, whereas our findings do not support a role for Y-5 receptors either in vitro or in vivo. The results suggest that agonists targeting the Y-2 receptor may be useful anticonvulsants.