Differential effect of quinpirole and 7-OH-DPAT on the spontaneous [(3)H]-dopamine efflux from rat striatal synaptosomes.

The effect of quinpirole and 7-OH-DAPT, two D(2)-like agonists, were examined using superfused rat striatal synaptosomes to study the autoregulation of spontaneous [(3)H]-dopamine ([(3)H]-DA) release. Basal [(3)H]-DA efflux was Ca(2+)-dependent by approximately 45% and was inhibited by cadmium 10 microM by 24%. Quinpirole (1 nM to 3 microM) inhibited spontaneous [(3)H]-DA efflux in a concentration-dependent manner (pEC(50) = 7.56 +/- 0.07 and E(max) = 26 +/- 0.09%) and this effect was competitively antagonized by haloperidol (0.3-1 nM) (apparent pA(2) = 9.61 +/- 0.08). In addition, activation of the D(2) DA autoreceptor by quinpirole only modulates the calcium-dependent component of [(3)H]-DA efflux. Low concentrations of a putative-selective D(3) DA agonist, (+/-)-7-OH-DPAT (0.03-0.1 microM), inhibited spontaneous [(3)H]-DA release by 13% (P < 0.05), but higher drug concentrations (> or =1 microM) increased basal [(3)H]-DA efflux in a concentration-dependent, nonsaturable, but reversible manner. Haloperidol (1-10 nM) reversed the (+/-)-7-OH-DPAT-induced inhibition, but not the increase in [(3)H]-DA outflow. The effect of (+/-)-7-OH-DPAT was mimicked by (+)-7-OH-DPAT. However, another putative D(3) DA agonist, PD 128,907 (1 nM to 3 microM), decreased spontaneous tritium efflux (maximal inhibition of 19 +/- 3.06% at 3 microM, P < 0.01). The effect of 7-OH-DPAT 10 microM was independent of the presence of extracellular Ca(2+), since its effect on basal [(3)H]-DA outflow was not significantly modified in a 200 nM free-Ca(2+) medium. In addition, the 7-OH-DPAT-induced enhancement of basal [(3)H]-DA efflux does not involve depolarization of nerve terminals or the reversal of the DA uptake system, as tetrodotoxin (1 microM) and nomifensine (1microM) did not modify the effect of 7-OH-DPAT 10 microM. The present data indicate that activation of D(2) DA autoreceptor subtype by quinpirole inhibits Ca(2+)-dependent spontaneous [(3)H]-DA efflux. 7-OH-DPAT activates the D(2) DA autoreceptor at low concentrations, whereas its action in releasing [(3)H]-DA effect is not receptor-mediated and could involve other mechanisms other than either conventional vesicular exocytosis or the DA uptake system.