We examined in male Sprague-Dawley rats the effects of nicotine at doses of 50 (0.31 mM) and 200 mg/L (1.23 mM) given for a period of 16 weeks on body weight gain, food and fluid intake, plasma CCK, glucose and insulin levels, amylase secretory responses of isolated pancreatic acinar cells to CCK-8 and carbachol, and histopathology (gross and light microscopy) of stomach and pancreas. These parameters were re-examined further in animals treated with nicotine at doses of 200 mg/L (1.23 mM) for 12 weeks and given tap water for an additional 4 weeks to evaluate the effects of nicotine withdrawal. Metabolic data suggest that decreases in body weight gain, food and fluid intake, and plasma levels of glucose and insulin by nicotine are dose dependent. Endocrinological studies showed that the plasma levels of CCK were significantly increased with nicotine but the amylase secretory response of pancreatic acinar cells was inhibited in response to CCK-8 and carbachol. Histopathologic data revealed that treatment of animals with a high dose of nicotine enhanced the appearance of numerous vacuoles in the pancreatic acinar cell cytoplasm. When the pancreatic acinar cell morphology was closely examined, it showed evidence of pyknotic nuclei and fusion of vacuoles. Prominent loss of gastric mucosal surface was found in nicotine-treated animals with gross microscopic evidence of bleeding ulcers. All of the metabolic parameters except body weight gain were reversed upon nicotine withdrawal. In addition, plasma CCK levels and pancreatic enzyme secretion were reversed upon nicotine withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)