Somatostatin and its synthetic analogue, octreotide, inhibit gallbladder emptying and cause gallstones. Whether octreotide-induced alterations in sphincter of Oddi motility contribute to this process is unknown. We, therefore, examined the effect of octreotide on fasting and protein-stimulated sphincter of Oddi motility. In 25 anesthetized prairie dogs, sphincter of Oddi motility and gallbladder pressure were monitored during the intravenous administration of octreotide, cholecystokinin (CCK) octapeptide, atropine, the intraduodenal administration of casein, and combinations of these agents. Intravenous octreotide decreased fasting sphincter of Oddi motility index both with (59 +/- 19 vs. 84 +/- 28, P less than 0.05) and without (137 +/- 31 vs. 227 +/- 42, P less than 0.05) prior cholinergic blockade with atropine. Octreotide also prevented the increases in sphincter of Oddi motility and gallbladder pressure seen with intraduodenal casein. Exogenous CCK increased sphincter of Oddi motility index and gallbladder pressure despite the simultaneous administration of octreotide alone (357 +/- 109 vs. 137 +/- 31, P less than 0.07, and 11.2 +/- 1.0 mmHg vs. 9.6 +/- 0.6 mmHg, P less than 0.05) or the combination of octreotide and atropine (317 +/- 69 vs. 59 +/- 19, P less than 0.05, and 10.1 +/- 1.6 mmHg vs. 8.5 +/- 1.4 mmHg, P less than 0.05). We conclude that both a cholinergic and an octreotide-sensitive noncholinergic pathway stimulate fasting sphincter of Oddi motility in the prairie dog.