Biphasic modulation of evoked [3H]D‐aspartate release by D‐2 dopamine receptors in rat striatal slices

Abstract

It has been hypothesized that dopamine (DA) inhibits glutamate release from corticostriatal fibers via presynaptically located D-2 DA receptors although the evidence presented in the literature has not been conclusive. In the present experiments, the effect of D-2 receptor ligands on K⁺-stimulated tritium release from rat striatal slices preloaded with the nonmetabolizable glutamate analog [³H]D-aspartate ([³H]ASP) was measured. The D-2 receptor antagonist S-sulpiride increased stimulated [³H]ASP release by 75% (EC₅₀ value = 240 nM) and the biologically less-active isomer R-sulpiride, although equally effective, was tenfold less potent. The D-2 receptor agonists pergolide and (+)-4-propyl-9-hydroxynapthoxazine (+PHNO) inhibited [³H]ASP release at nM concentrations; however, this effect was small (20%). This low efficacy of the exogenous agonists was apparently due to competition by high concentrations of endogenous DA since the effect of pergolide was increased in rats whose striatal DA levels were decreased by 97%. These data support the hypothesis that D-2 DA receptors modulate [³H]ASP release in an inhibitory fashion. However, when the agonists were tested at lower concentrations, [³H]ASP release was increased significantly by 20% in control rats and 60% in DA-depleted rats. Both the facilitory and inhibitory effects of pergolide were blocked by 10 μM S-sulpiride, suggesting D-2 receptor mediation. In addition, the facilitory effect of pergolide was blocked by tetrodotoxin (TTX) and by the GABA_A antagonist bicuculline, implying mediation of this D-2 effect by an inhibitory GABAergic interneuron. The inhibitory effect of pergolide was decreased by the muscarinic antagonist atropine. These data are consistent with the hypothesis that receptors mediating both facilitory and inhibitory D-2 modulation of [³H]ASP release are located on interneurons rather than directly on the corticostriatal afferents.