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Differentiation of olfactory neurons is modulated by odor stimulation; exposure to stimulatory odorants induces acquisition of olfactory neuronal properties in cultured chick olfactory neurons. The mechanism by which odor-mediated neuronal differentiation remains unclear. It is known that cyclic adenosine monophosphate (cAMP) serves as a second messenger for odor signal transduction. To determine if stimulus-induced differentiation can occur in the absence of odorants, elements of the odor signal transduction cascade were directly stimulated using pharmacological agents. Cultured olfactory neurons from an E17 chick embryo were exposed to either an adenylyl cyclase activator (forskolin) or adenylyl cyclase inhibitors (MDL-12,330A or SQ 22,536) for 12-hour periods daily for five days. Neuron differentiation was determined using immunocytochemistry to stain for proteins characteristic of olfactory neurons. Cells were stained for olfactory marker protein (mature olfactory neurons only), Golf (functional olfactory neurons), and beta-tubulin III (neuron-specific tubulin; both mature and immature neurons). Data suggest that direct inhibition of adenylyl cyclase with MDL-12,330A increases the total number of neurons, while activation of the cyclase has no effect. Data also suggest that inhibition of adenylyl cyclase with SQ 22,536 decreases the percentage of functional mature neurons. Thus, MDL-12,330A increases neuronal proliferation and SQ 22,536 affects specific acquisition of olfactory neuronal properties, which suggests that adenylyl cyclase could play a role in stimulus-induced neuronal proliferation and differentiation.