Motility studies indicate that cholecystokinin (CCK) acts through a neural mechanism in the sphincter of Oddi (SO) after meals. To evaluate its actions in SO ganglia, CCK was applied by microejection (0.1 mM) or superfusion (0.1 to 300 nM) while recording was carried out intracellularly from intact SO neurons. In tonic cells, microejection and superfusion of CCK caused a prolonged depolarization accompanied by action potentials. In phasic cells, microejection of CCK caused brief and/or prolonged depolarizations, but superfusion caused only prolonged depolarizations. In afterhyperpolarized cells, CCK did not cause a detectable change in the resting membrane potential. In low-Na+ Krebs solution, the prolonged depolarizations in both tonic and phasic cells were significantly reduced. Unsulfated CCK (100 nM) had no effect. CCK-induced depolarization was significantly reduced by a CCK-A, but not a CCK-B, receptor antagonist. It is concluded that CCK can act on CCK-A receptors to depolarize SO neurons. However, it is unlikely that hormonal CCK could mediate such an action because of the discrepancy between the sensitivity of SO neurons for CCK and the peak concentrations of CCK in the serum after a meal.