Blockade of neuropeptide Y2 receptors and suppression of NPY's anti‐epileptic actions in the rat hippocampal slice by BIIE0246

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Abstract
Neuropeptide Y (NPY) has been shown to suppress synaptic excitation in rat hippocampus by a presynaptic action. The Y2 (Y2R) and the Y5 (Y5R) receptors have both been implicated in this action. We used the non‐peptide, Y2R‐selective antagonist, BIIE0246, to test the hypothesis that the Y2R mediates both the presynaptic inhibitory and anti‐epileptic actions of NPY in rat hippocampus in vitro. NPY and the Y2R‐selective agonist, [ahx5‐24]NPY, both inhibited the population excitatory postsynaptic potential (pEPSP) evoked in area CA1 by stratum radiatum stimulation in a concentration‐dependent manner. BIIE0246 suppressed the inhibitory effects of both agonists, suppressing the maximal inhibition without causing a change in the agonist EC50, in a manner inconsistent with competitive antagonism. BIIE0246 washed out from hippocampal slices extremely slowly. Application of agonist at high concentrations (1–3 μM) for prolonged periods did not alter the rate of washout, but did partially overcome the antagonism, inconsistent with an insurmountable antagonism by BIIE0246. In the stimulus train‐induced bursting (STIB) model of ictal activity in hippocampal slices, both NPY and [ahx5‐24]NPY inhibited primary afterdischarge (1°AD) activity. BIIE0246 (100 nM) completely suppressed the actions of NPY and [ahx5‐24]NPY in this model. In contrast, the potent Y5R‐selective agonist, Ala31Aib32NPY, affected neither 1°AD activity in the presence of BIIE0246, nor, by itself, even the pEPSP in CA1. BIIE0246 potently suppresses NPY actions in rat hippocampus, suggesting a dominant role for Y2R there. The apparently insurmountable antagonism observed may result from the lipophilic nature of the antagonist. British Journal of Pharmacology (2002) 136, 502–509; doi:10.1038/sj.bjp.0704751