Intracellular methods were used to record the electrical behavior of myenteric neurons from guinea-pig ileum in vitro. Cholecystokinin-octapeptide (CCK-8) at 1 to 100 microM in the ejection pipettes were applied to the neurons by pressure microejection. CCK-8 (0.01 to 1 microM) and caerulein (0.01 to 0.1 microM) were applied also in the superfusion solution. CCK-8, applied by either method, evoked a long-lasting depolarization of the cell membranes that was associated with an increase in the input resistance, suppression of hyperpolarizing afterpotentials and enhanced excitability. The enhanced excitability was reflected by increased probability of action potential discharge during membrane depolarization by intracellularly injected current. Caerulein evoked the same excitatory responses as CCK-8. The actions of both agents simulated slow synaptic excitation in the neurons. In another group of AH/type 2 neurons, CCK-8 evoked a long-lasting membrane hyperpolarization and decreased input resistance that mimicked stimulus-evoked slow inhibitory postsynaptic potentials. Hyperpolarizing responses were never evoked by caerulein. About 25% of tested neurons failed to respond to CCK-8 and 70% did not respond to caerulein. Pentagastrin (1 microM in the superfusion solution) did not affect the electrical behavior of the neurons. The results are consistent with a neurotransmitter role for cholecystokinin that could be either excitatory of inhibitory in the enteric nervous system.