Experiments with isolated bag cell neurons of Aplysia have produced evidence that changes in neuronal excitability may be brought about by the activation of calcium dependent enzymes such as calcium-dependent protein kinases. We have now examined the effects of agents which have been shown to inhibit several calcium-dependent enzymes on the properties of bag cell neurons in situ. In response to brief electrical stimulation the bag cell neurons of Aplysia generate an afterdischarge during which they release neuroactive peptides. We have found that the ability of stimulation to trigger an afterdischarge in the bag cell neurons is inhibited by trifluoperazine (TFP, 50-100 microM), N-(6-aminohexyl)-5-chloro-1-napthalenesulphonamide (W7) (25-50 microM) and calmidazolium (40-100 microM), each of which has previously been shown to inhibit calmodulin-dependent enzymes and the calcium-phospholipid-dependent protein kinase in the bag cell neurons. Further analysis of the effects of TFP showed that this inhibition occurs at concentrations which do not inhibit synaptic transmission or the endogenous bursting of another neurosecretory neuron, R15. Secretion of neuroactive peptides from the bag cell neurons was measured both electrophysiologically and biochemically. No attenuation of secretion could be observed at concentrations of TFP below those which inhibited the initiation of afterdischarge. Our results indicate that these agents inhibit secretion from these neurons primarily by inhibiting the onset of the afterdischarge and are consistent with the hypothesis that a calcium-dependent enzyme plays a role in triggering the stimulus-induced transformation in the electrical properties of these neurons.