Neuropeptide Y (NPY) has been shown to suppress synaptic excitation in rat hippocampus by a presynaptic action. The Y(2) (Y(2)R) and the Y(5) (Y(5)R) receptors have both been implicated in this action. We used the non-peptide, Y(2)R-selective antagonist, BIIE0246, to test the hypothesis that the Y(2)R mediates both the presynaptic inhibitory and anti-epileptic actions of NPY in rat hippocampus in vitro. NPY and the Y(2)R-selective agonist, [ahx(5-24)]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 EC(50), in a manner inconsistent with competitive antagonism. BIIE0246 washed out from hippocampal slices extremely slowly. Application of agonist at high concentrations (1 - 3 microM) 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 [ahx(5-24)]NPY inhibited primary afterdischarge (1 degrees AD) activity. BIIE0246 (100 nM) completely suppressed the actions of NPY and [ahx(5-24)]NPY in this model. In contrast, the potent Y(5)R-selective agonist, Ala(31)Aib(32)NPY, affected neither 1 degrees 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 Y(2)R there. The apparently insurmountable antagonism observed may result from the lipophilic nature of the antagonist.