Unlike in rodents, cholecystokinin (CCK) has not been established as a physiological regulator in avian exocrine pancreatic secretion. In the isolated duck pancreatic acini, CCK 1 nM was required for stimulation of amylase secretion, maximal effect being achieved at 10 nM; picomolar CCK was without effect. Vasoactive intestinal peptide (VIP) / pituitary adenylate cyclase activating peptide (PACAP) receptor (VPAC) agonists PACAP38 and PACAP27 (10^-12 - 10^-7 M) alone had no effect, but made picomolar CCK effective. VPAC agonist VIP 10^-10 - 10^-7 M stimulated amylase secretion marginally, but made CCK 10^-12 - 10^-10 M effective also. PACAP27 and VIP both shifted the maximal CCK concentration from 10^-8 to 10^-9 M. This sensitizing effect was mimicked by forskolin. CCK dose-dependently induced [Ca²⁺]_i oscillations. PACAP38 (1 nM), PACAP27 (1 nM), VIP (10 nM) or forskolin (10 µM) alone did not stimulate [Ca²⁺]_i increase, neither did they modulate CCK (1 nM)-induced oscillations; but when they were added to cells simultaneously exposed to sub-threshold CCK 10 pM, calcium spikes emerged. Amylase secretion induced by the simultaneous presence of CCK 10 pM and VPAC agonists was completely blocked by removing extracellular calcium, but the protein kinase C inhibitor staurosporine 1 µM was without effect. CCK (10 nM) induced secretion was inhibited by CCK₁ receptor antagonist FK480 (1 µM). Gastrin from 10^-12 - 10^-6 M did not stimulate amylase secretion, nor did it (100 nM) induce [Ca²⁺]_i increase. The above data suggest that duck pancreatic acini possess both CCK₁ and VPAC receptors, simultaneous activation of both is required for each to play a physiological role.