The ventral tegmental area (VTA) receives extensive afferent input from neurons containing the opioid peptide enkephalin (Enk) and/or GABA. We examined the ultrastructural basis for known functional interactions between these inhibitory neuromodulators using a combined immunoperoxidase and immunogold-silver technique. As visualized with either marker in single sections, Enk-immunolabeled terminals contained numerous small clear vesicles and one or more intensely immunoreactive dense-cored vesicles. Enk-labeled terminals formed either symmetric or asymmetric synapses on small or large unlabeled dendrites. The immunoreactive dense-cored vesicles were usually detected away from these sites of synaptic contact. Terminals singly immunoreactive for GABA, or dually labeled for Enk and GABA, showed similar morphological features but formed primarily symmetric axo-dendritic synapses. In many instances, GABA- and/or Enk-immunolabeled terminals were in direct apposition to each other and formed synapses on immediately adjacent parts of a common dendrite. Close appositions were also noted between GABA- and Enk-immunoreactive axons and varicosities that did not form synapses with either common or divergent dendrites in single sections. Immunoreactive dense-cored vesicles were frequently detected at the apposed plasmalemmal surfaces between these axon terminals. The findings suggest that Enk and GABA are released from the same or convergent terminals and co-regulate the activity of common target neurons within the rat VTA. The results are also consistent with potential presynaptic interactions between these transmitters.