Neuropeptide Y (NPY) reduces excitatory synaptic transmission between stratum radiatum and CA1 pyramidal cells in rat hippocampal slice in vitro by a presynaptic action. To understand NPY's role in the control of excitability in hippocampus, its actions on excitatory and inhibitory synaptic transmission were examined, using intracellular, sharp microelectrode, and tight-seal, whole cell recordings from principal neurons in areas CA1, CA3, and dentate. Bath application of 1 microM NPY reversibly inhibited excitatory postsynaptic potentials (EPSPs) evoked in CA1 pyramidal cells from either stratum radiatum or stratum oriens by about 50%. Neuropeptide Y also inhibited EPSPs at mossy fiber-CA3, stratum oriens-CA3, and CA3-CA3 synapses by between 45% and 55%. As in CA1, the action of NPY was presynaptic. By contrast, NPY did not inhibit EPSPs evoked in dentate granule cells from either perforant path or commissural inputs. Neuropeptide Y did not alter postsynaptic membrane properties in any cell type. Although NPY attenuated the orthodromically evoked (stratum radiatum) inhibitory postsynaptic potentials in CA1 pyramidal cells by about the same amount as it inhibited the EPSPs, it did not affect the IPSPs evoked in the same cells by antidromic stimulation from alveus. Inhibitory postsynaptic potentials evoked in pharmacological isolation in CA1, CA3, or dentate were also not significantly affected by NPY. The evidence supports the hypothesis that NPY acts at feedforward excitatory synapses to presynaptically reduce the amplitude of excitation as it travels through hippocampal circuits. By contrast, synaptically mediated inhibition is not directly affected by NPY.(ABSTRACT TRUNCATED AT 250 WORDS)