Although the adrenal cortex and medulla are both involved in the maintenance of homeostasis and stress response, the functional importance of intra-adrenal interactions remains unclear. When primary cocultures of frog (Rana pipiens) adrenocortical and chromaffin cells were used, selective chromaffin cell activation dramatically affected both chromaffin and adrenocortical cells. Depolarization with 50 µm veratridine enhanced chromaffin cell neuronal phenotype, contacts with adrenocortical cells, and secretion of norepinephrine, epinephrine, and serotonin. Time-lapse video microscopy recorded the rapid establishment of growth cones on the activated chromaffin cell neurites, neurite branching, and outgrowth toward adrenocortical cells. Simultaneously, adrenocortical cells migrated toward chromaffin cells. Following chromaffin cell activation, adrenocortical cell Fos protein expression and corticosteroid secretion were increased, indicating that chromaffin cell modulation of adrenocortical cells is at the transcriptional level. These results provide evidence that intra-adrenal interactions affect cellular differentiation and modulate steroidogenesis. Furthermore, this suggests that the activity-related plasticity of chromaffin and adrenocortical cells is developmentally and physiologically important.