There is a spontaneous induction of vasoactive intestinal polypeptide (VIP) expression in adult rat dorsal root ganglion sensory neurons when grown in culture. The mechanism of this induction may be the same as that responsible for the increased VIP expression in sensory neurons following peripheral axotomy in vivo. This study investigates the effects of depolarization and cyclic AMP on VIP expression (measured by radioimmunoassay) in cultures of newborn and adult rat sensory neurons. Unlike adult neurons, newborn rat sensory neurons, supported in culture with nerve growth factor, did not spontaneously express VIP. However, potassium-evoked depolarization and drugs that increase intracellular cyclic AMP concentrations (forskolin, 8-bromo cyclic AMP, isobutylmethylxanthine) interacted synergistically to stimulate high levels of VIP expression in newborn rat neurons. The contribution of depolarization to this effect could be mimicked by the L-type calcium channel agonist Bay K 8644 and blocked by the channel antagonist nifedipine, implying the involvement of calcium influx through L-type channels. While depolarization and forskolin individually had small effects on VIP content of adult rat sensory neuron cultures, there was no synergism of the kind seen in newborn rat cultures. Immunostaining showed that VIP was localized within approximately 30% of both newborn and adult rat sensory neurons. Thus, a subpopulation of newborn rat sensory neurons exhibit marked plasticity of VIP expression in an integrated response to activation of cyclic AMP- and calcium-dependent signalling pathways. This property is no longer present in mature neurons, however, where VIP expression is regulated by as yet undetermined factors.