We have previously reported a transient and remarkable increase in dopamine (DA) release in the rat striatum during application of 2 mM sodium cyanide (NaCN) through a brain microdialysis membrane. In the present study we examined the involvement of extracellular Ca2+ in this response. Rats were divided into 4 groups. In the NaCN group a microdialysis probe inserted into the striatum was perfused with Ringer's solution containing 2 mM NaCN for 60 min. The Ca2+ free + NaCN group was subjected to perfusion with NaCN dissolved in Ca2+ free Ringer's solution, and the CdCl2 + NaCN group with the same plus 0.3 mM CdCl2 (a non-specific Ca2+ channel blocker). In the NaCN and Ca2+ free + NaCN groups DA levels in the dialysates increased to 36- and 44-fold of the control level, respectively, while this was suppressed to only a 16-fold increase in the CdCl2 + NaCN group. In response to a 100 mM KCl perfusion given 3 hr later DA levels were increased (22-fold) in the control group. On the other hand this response was inhibited in the NaCN group (3-fold), but not in the other two groups. An in vitro study with striatal slices showed a gradual increase in intracellular Ca2+ during incubation with 2 mM NaCN. These results suggest that excessive influx of extracellular Ca2+ during NaCN perfusion may contribute partly to the increase in the extracellular DA level in the striatum, and also to the suppression of a DA increase in response to high K+ stimulation observed 3 hr later.