The purpose of this investigation was to determine if alpha 1-adrenergic receptor activation would potentiate the vasoactive intestinal peptide (VIP)-stimulated increase in cAMP accumulation in the rat pinealocyte. Treatment with VIP alone increased cAMP accumulation less than 5-fold, and treatment with phenylephrine increased cAMP accumulation less than 2-fold. However, combined treatment with VIP and phenylephrine increased cAMP accumulation more than 20-fold. This is the first report that alpha 1-adrenergic and VIP receptors can interact to regulate cAMP in a cell of neural tube origin. The demonstration of such an integrated mechanism in pinealocytes is of special interest because VIP innervation of the pineal gland is of central origin, and adrenergic innervation is of peripheral origin. The magnitude of response makes the pinealocyte an attractive model for the study of such dual receptor regulation.