Abstract

We showed previously, using in vitro microdialysis, that the activation of the soluble guanylate cyclase (sGC)/cyclic GMP pathway was the underlying mechanism of the extracellular Ca²⁺-dependent effects of exogenous NO on dopamine (DA) secretion from PC12 cells. In this study, the co-infusion of the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3] quinoxalin-1-one (ODQ) failed to affect the NO donor 3- morpholinosydnonimine (SIN-1, 5.0 mM)-induced DA increase (sevenfold baseline) in dialysates from the striatum of freely moving rats. Ca²⁺ omission from the perfusion fluid abolished baseline DA release but did not affect SIN-1-induced DA increases. The reintroduction of Ca2+ in the perfusion fluid restored the baseline dialysate DA; however, when Ca²⁺ reintroduction was associated with the infusion of either SIN-1 or the NO-donor S-nitrosoglutathione (SNOG), a sustained DA overflow was observed. DA overflow was selectively inhibited by the co-infusion of the store-operated channel blocker 2-aminoethoxydiphenyl borate. The chelation of intracellular Ca²⁺ by co-infusing 1,2-bis (o-amino-phenoxy)ethane-N,N,N’,N’-tetraacetic acid tetra (acetoxymethyl) ester (BAPTA-AM, 0.2 mM) greatly potentiated both SIN-1- and SNOG-induced increases in dialysate DA. BAPTA-AM-induced potentiation was inhibited by Ca²⁺ omission. We conclude that the sGC/ cyclic GMP pathway is not involved in the extracellular Ca²⁺-independent exogenous NO-induced striatal DA release; however, when intracellular Ca²⁺ is either depleted (by Ca²⁺ omission) or chelated (by BAPTA-AM co-infusion), exogenous NO does promote Ca²⁺ entry, most likely through store-operated channels, with a consequent further increase in DA release.

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