Proglumide not only antagonizes the gastric secretion induced by histamine, tetragastrin and ligation of the pylorus, but also antagonizes the effects of cholecystokinin (CCK) on contraction of the gallbladder and stimulation of amylase secretion from the pancreas. Since CCK is a putative satiety peptide, it was hypothesized that administration of proglumide would increase food intake by inhibiting the satiety effect of CCK. Zucker obese (638±26 g) and lean (462±24 g) rats, trained to bar press for food pellets, were administered intragastrically 0.25, 0.42 or 0.59 g/kg proglumide 15 min before the end of a 3- or 6-hr fast. Feeding behavior was analyzed during the subsequent 18 hr using an automated data collection system. Food intakes, while not affected by proglumide treatment during the first meal (4.30 vs. 4.30 g) were increased 3 (5.60 vs. 4.92 g, p<0.02) and 18 (34.0 vs. 32.5 g. p<0.008) hr after treatment. In addition, water intake 18 hr after proglumide treatment was increased (46.8 vs. 41.5 ml, p<0.001) and food intake to water intake ratio was decreased (0.74 vs. 0.80 g/ml, p<0.004). These responses were not different in obese compared with lean rats or in 3-hrs vs. 6-hr fasted rats. Daily feeding patterns in 6-hr fasted obese rats treated with 0.59 g/kg proglumide were characterized by increased meal frequency (12.4±1.0 vs. 9.6±1.1, p<0.001) and decreased average meal size (3.1±0.2 vs. 3.6±0.3 g, p<0.03). In 3-hr fasted obese and lean rats serum concentrations of proglumide were 7.1±2.1 mg/dl 20 min and 6.6±1.5 mg/dl 120 min after administration of 0.59 g/kg proglumide, indicating levels remained significantly elevated after 120 min. Since proglumide has been shown previously to be an antagonist to the effects of CCK on gallbladder, gastric and pancreatic function, it is postulated that increased food intake in Zucker obese and lean rats after proglumide administration is a result of antagonism of the receptor for the effect of CCK on satiety.