Protein kinase C and dopamine release—II: Effect of dopamine acting drugs in vivo

The hypothesis that protein kinase C (PKC) plays a role in the release of dopamine (DA) in the nigrostriatal pathway was examined. It was found that injections of apomorphine, SKF 38393 (D1 agonist), LY 171555 (D2 agonist) or γ-butyrolactone (GBL) (which decreases impulse-induced release of DA) resulted in a decrease in particulate, and an increase in soluble, PKC activity. Injections of fluphenazine, haloperidol, SCH 23390 (D1 antagonist), sulpiride (D2 antagonist) or picrotoxin (γ-aminobutyric acid antagonist which increases DA release transneuronally) had the opposite effect of increasing particulate and decreasing soluble PKC activity. The total activity was not changed. These effects were receptor mediated since the effect of each agonist could be reversed by its specific antagonist. These drugs influenced PKC in the striatum in a dose-dependent manner. In contrast, no effects were seen in the cerebellum, a region with sparse dopaminergic innervations. The change in PKC activity was mediated via a change in the K m for calcium, while the V max was unchanged. The phosphorylation of endogenous substrate proteins by PKC was also altered by injections of these drugs. Besides affecting PKC, these DA acting drugs also affected the calmodulin-dependent protein kinase activity, but the direction of change was opposite to that for PKC. In a synaptosomal preparation, PKC acting drugs also affected the depolarization-induced release of DA. Adriamycin and melittin decreased the potassium-induced release of DA, whereas tetradecanoyl-phorbol-13-acetate (TPA) enhanced this release. These results showed that there was a good correlation between the ability of drugs to alter the impulseinduced release of DA in vivo and their ability to affect changes in particulate and soluble PKC activity. They lend support to the hypothesis that PKC, together with calmodulin, plays a key role in the release of DA in the nigrostriatal pathway.