Neuronally differentiated PC12 cells have been used as a model for habituation. These cells secrete norepinephrine in response to extracellular ATP, as well as other stimulants, and the response is diminished with repetitive stimulation. This loss of neurosecretory responsiveness displays characteristics commonly associated with habituative learning. These include an increase in both the rate and the relative degree of response loss with either increasing stimulation frequency or decreasing stimulus intensity, and selective generalization of the decreased responsiveness to heterologous stimuli. In PC12 cells, the loss of neurosecretory responsiveness appears to be entirely caused by stimulation-dependent inactivation of the ATP-gated cation channel. Several unusual properties of this channel apparently allow its regulation to produce the behaviors associated with short- term habituation. Recovery of the ATP-gated channel requires several minutes, allowing habituation of responses to repetitive stimuli given at intervals of several minutes. Inactivation of the ATP-gated channel may be proportionately faster in response to lower ligand concentrations, allowing habituation to be more rapid in response to stimuli of weaker intensity.