MODULATION OF DOPAMINE RELEASE FROM RAT STRIATUM BY PROTEIN-KINASE-C - INTERACTION WITH PRESYNAPTIC D-2-DOPAMINE-AUTORECEPTORS

1 Interactions between dopamine receptors and protein kinase C (PKC) h ave been proposed from biochemical studies. The aim of the present stu dy was to investigate the hypothesis that there is an interaction betw een protein kinase C and inhibitory D-2-dopamine receptors in the modu lation of stimulation-induced (S-I) dopamine release from rat striatal slices incubated with [H-3]-dopamine. Dopamine release can be modulat ed by protein kinase C and inhibitory presynaptic D-2 receptors since phorbol dibutyrate (PDB) and (-)-sulpiride, respectively, elevated S-I dopamine release. 2 The protein kinase C inhibitors polymyxin B (21 m u M) and chelerythrine (3 mu M) had no effect on stimulation-induced ( S-I) dopamine release. However, when presynaptic dopamine D-2 receptor s were blocked by sulpiride (1 mu M), an inhibitory effect of both PKC inhibitors on S-I dopamine release was revealed. Thus, sulpiride unma sks an endogenous PKC effect on dopamine release which suggests that p resynaptic D-2 receptors normally suppress endogenous PKC activity. Th is is supported by results in striatal slices which were pretreated wi th PDB to down-regulate PKC. In this case the facilitatory effect of s ulpiride was completely abolished. 3 The inhibitory effect of the dopa mine D-2/D-3 agonist quinpirole on S-I dopamine release was partially attenuated by PKC down-regulation. Since the effect of sulpiride was c ompletely abolished under the same conditions, this suggests that exog enous agonists may target a PKC-dependent as well as a PKC-independent pathway. The inhibitory effect of apomorphine was not affected by eit her polymyxin B or PKC down-regulation, suggesting that it operated ex clusively through a PKC-independent mechanism. 4 These results suggest that there are at least two pathways involved in the inhibition of do pamine release through dopamine receptors. One pathway involves dopami ne receptor suppression of protein kinase C activity, perhaps through inhibition of phospholipase C activity and this is preferentially util ized by neuronally-released dopamine. The other pathway which seems to be utilized by exogenous agonists does not involve PKC.