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In vitro microdialysis was used to investigate the mechanism of nitric oxide (NO) donor-induced changes in dopamine (DA) secretion from PC12 cells. Infusion of the NO-donor S-nitrosoN-acetylpenicillamine (SNAP, 1.0 mM) induced a long-lasting increase in DA and 3-methoxytyramine (3-MT) dialysate concentrations. SNAP-induced increases were inhibited either by pre-infusion of the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4] oxadiazolo[4,3]quinoxalin-1-one (ODQ, 0.1 mM) or by Ca 2+ omission. Ca 2+ re-introduction restored SNAP effects. SNAP-induced increases in DA + 3-MT were unaffected by co-infusion of the L-type Ca 2+ channel inhibitor nifedipine. The NO-donor (+ / –)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro3-hexenamide (NOR-3, 1.0 mM) induced a short-lasting decrease in dialysate DA + 3-MT. Ascorbic acid (0.2 mM) co-infusion allowed NOR-3 to increase dialysate DA + 3-MT. ODQ pre-infusion inhibited NOR-3 + ascorbic acid-induced DA + 3-MT increases. Infusion of high K + (75 mM) induced a 2.5-fold increase in dialysate DA + 3-MT. The increase was abolished by NOR-3 co-infusion. Conversely, co-infusion of ascorbic acid (0.2 mM) with NOR-3 + high K + restored high K + effects. Co-infusion of nifedipine inhibited high K + -induced DA + 3-MT increases. These results suggest that activation of the NO / sGC / cyclic GMP pathway may be the underlying mechanism of extracellular Ca 2+ -dependent effects of exogenous NO on DA secretion from PC12 cells. Extracellular Ca 2+ entry may occur through nifedipine-insensitive channels.