Neuropeptide Y (NPY) and dynorphin elicit regionally selective presynaptic modulation in the hippocampal formation and the pars reticulata of the substantia nigra, respectively. We examined potential anatomical substrates for their presynaptic modulation by determining the distribution and size of large (80-120 nm) dense-core vesicles (DCVs), organelles previously shown to be immunoreactive for each peptide. Throughout the hippocampal formation, NPY-immunoreactive DCVs were located primarily in axon terminals and were more sparingly distributed in dendrites. In comparison with other portions of the hippocampal formation, NPY-labeled DCVs were most abundant in axons and terminals of the CA1 region. The DCVs in the CA1 region of the hippocampus also more frequently had larger mean cross-sectional diameters when located along portions of the terminal in contact with unlabeled axons. In both the CA1 region of the hippocampus and the dentate gyrus, NPY-labeled DCVs in contact with portions of the axonal membrane apposed to astrocytes also were larger than those located more centrally in the axon terminal. Dynorphin-immunoreactive DCVs in axon terminals of the substantia nigra were significantly larger when found near portions of the axonal membrane in contact not only with other axons and astrocytic processes, but also occasionally with postsynaptic dendrites. The parallels between diameters of DCVs and known selectivity of NPY for presynaptic modulation in the CA1 region of the hippocampus suggest a direct correlation between the size and distribution of immunoreactive DCVs and their sites of exocytotic release.(ABSTRACT TRUNCATED AT 250 WORDS)