In vivo modulation of excitatory amino acid receptors: microdialysis studies on N-methyl- d-aspartate-evoked striatal dopamine release and effects of antagonists

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Striatal dopamine (DA) release was measured following intrastriatal (i.s.) administration of N-methyl- d-aspartate (NMDA) to unanesthetized, freely-moving rats. One hour after insertion of a removable microdialysis probe and perfusion with normal Ringer's solution, a modified Ringer's solution containing 100 mM potassium (high-K + Ringer's) was used to standardize the preparation. DA release following i.s. administration of NMDA (12.5 mM in normal Ringer's) was dose-dependent. When NMDA (12.5 mM) was administered in high-K + Ringer's, DA release was greatly potentiated. Administration of the competitive NMDA receptor antagonist aminophosphonovalerate (APV) in normal Ringer's prior to treatment with NMDA in high-K + Ringer's resulted in a significant reduction of DA release compared to control animals. In contrast, administration of APV prior to treatment with NMDA in normal Ringer's resulted in a significantly increased release of DA compared to controls. Administration of the non-competitive NMDA antagonist, dextromethorphan (DXT) prior to treatment with NMDA in normal Ringer's or NMDA in high-K + Ringer's caused significant reductions of DA release compared to controls. Intrastriatal DXT also caused dose-dependent inhibition of high-K + Ringer's-induced DA release. Similarly, administration of the non-specific calcium channel blocker, cadmium, prior to treatment with NMDA resulted in a significant decrease when compared to control values. Results of this study indicate that dose-dependent NMDA-induced striatal DA release is greatly potentiated by potassium suggesting that under physiological conditions in vivo, striatal NMDA receptors are mostly inactivated. The inhibitory effect of cadmium on NMDA-induced DA release suggests that activation of calcium-dependent mechanisms is responsible in large part for the ability of NMDA to release DA. NMDA-induced release of DA in the presence of high-K + Ringer's is blocked by both APV and DXT suggesting specific involvement of NMDA receptors, although the ability of DXT to inhibit both high-K + Ringer's- and NMDA-induced striatal DA release supports the concept that DXT may act as a calcium channel antagonist. Whereas DXT effectively inhibited DA release following administration of NMDA in physiologic Ringer's, APV potentiated DA release suggesting that APV functions as a partial agonist at NMDA receptors or that APV relieves an inhibitory mechanism, mediated through interneurons, on dopaminergic function.