Feeding rats a diet containing high levels of protein (as casein) increases the secretion and biosynthesis of pancreatic serine proteases. Cholecystokinin (CCK) presumably plays a role in this process although other GI peptides such as the gastrin-releasing peptide (GRP) may be involved. In this article, we describe the kinetics of pancreatic adaptation to a diet containing 45% protein as soybean and fish. Then we report the effect of treatment with either a cholecystokinin-receptor antagonist (MK-329) or a gastrin-releasing peptide-receptor antagonist ([D-F-5 Phe(6), D-Ala(11)]-Bn(6-13)OMe, or BIM 26226) on pancreatic adaptation to this diet. Prior to experiments, adult male Fischer rats received a diet containing 22% protein for 1 week. In the first experiment, 48 rats were fed a diet containing 45% protein; they were killed after 0-7 days. In the second experiment, 53 rats were fed the 22- or 45%-protein diet and received three daily injections of either the vehicle alone, MK-329, or BIM 26226 for 7 days before they were killed. T When the protein-rich diet was fed for 0-7 days, amylase, in vitro biosynthesis, and mRNA levels were gradually decreased while serine protease biosynthesis was increased, reflecting the general enhancement of chymotrypsinogen, trypsinogen, and elastase mRNA levels. For all these parameters, adaptation leveled off after a 5-day feeding. When the protein diets were fed for 7 days, MK-329 significantly inhibited the adaptation of trypsin (specific activity and mRNA) and elastase (mRNAs) to the 45%-protein diet. BIM 26226 had no effect on pancreatic adaptation to the protein-rich diet. CCK plasma levels were not affected by the content of dietary protein and by MK-329 treatment, but BIM 26226 increased this parameter in rats fed the 45%-protein diet. In conclusion, during the first week of adaptation to a diet enriched with fish and soybean protein, CCK is responsible for the increase of some serine protease although it is not the only peptide involved in this phenomenon.