PT  - JOURNAL ARTICLE
AU  - Kantor, L.
AU  - Gnegy, M. E.
TI  - Protein Kinase C Inhibitors Block Amphetamine-Mediated Dopamine Release in Rat Striatal Slices
DP  - 1998 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 592--598
VI  - 284
IP  - 2
4099  - http://jpet.aspetjournals.org/content/284/2/592.short
4100  - http://jpet.aspetjournals.org/content/284/2/592.full
SO  - J Pharmacol Exp Ther1998 Feb 01; 284
AB  - The stimulant drug amphetamine is postulated to enhance dopamine release through the plasmalemmal dopamine transporter by an exchange diffusion with synaptosomal dopamine. Because protein kinase C has been shown to have an effect on dopamine transporter activity, we examined the effect of protein kinase C inhibitors on endogenous dopamine release stimulated by amphetamine in perfused rat striatal slices. At concentrations of 1 μM, the selective protein kinase C inhibitors chelerythrine, Ro31–8220 and calphostin C nearly completely inhibited endogenous dopamine release elicited by 1 μM amphetamine. The inactive analog bisindoylmaleimide V had no effect. Extracellular Ca++ was not required for the effect of the inhibitors. The importance of vesicular dopamine release was examined by determining inhibitor activity in reserpine-treated rats. Dopamine release elicited by 1 μM amphetamine was not significantly altered in reserpine-treated rats compared with control animals. Ro31–8220 at 1 μM completely blocked amphetamine-induced dopamine release in reserpine-treated rats. Activation of protein kinase C with 250 nM of the phorbol ester 12-O-tetradecanoylphorbol 13-acetate increased dopamine release, and the release was not additive with 1 μM amphetamine. Both chelerythrine and Ro31–8220 at 1 μM increased [3H]dopamine uptake by 17% and 30%, respectively, whereas a brief exposure to 12-O-tetradecanoylphorbol 13-acetate slightly inhibited [3H]dopamine uptake. Our results suggest that amphetamine-mediated dopamine release through the plasmalemmal transporter is highly dependent on protein kinase C activity. The American Society for Pharmacology and Experimental Therapeutics