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OtherNEUROPHARMACOLOGY

Protein Kinase C Inhibitors Block Amphetamine-Mediated Dopamine Release in Rat Striatal Slices

L. Kantor and M. E. Gnegy
Journal of Pharmacology and Experimental Therapeutics February 1998, 284 (2) 592-598;
L. Kantor
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M. E. Gnegy
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Abstract

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.

Footnotes

  • Send reprint requests to: Dr. Margaret E. Gnegy, 2220E MSRB III, Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, MI 48109-0632. E-mail: pgnegy{at}umich.edu

  • ↵1 This work was supported by Grant DA-05066 from the National Institutes for Drug Abuse and NIDA Interdisciplinary Training Grant DA-07267 at the University of Michigan Substance Abuse Research Center (L.K.).

  • Abbreviations:
    AMPH
    amphetamine
    DA
    dopamine
    DMSO
    dimethylsulfoxide
    GAP-43
    growth-associated protein
    HPLC
    high-performance liquid chromatography
    KRB
    Krebs-Ringer buffer
    PKC
    protein kinase C
    TPA
    12-O-tetradecanoylphorbol-13-acetate
    ANOVA
    analysis of variance
    • Received June 10, 1997.
    • Accepted October 16, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 2
1 Feb 1998
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OtherNEUROPHARMACOLOGY

Protein Kinase C Inhibitors Block Amphetamine-Mediated Dopamine Release in Rat Striatal Slices

L. Kantor and M. E. Gnegy
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 592-598;

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OtherNEUROPHARMACOLOGY

Protein Kinase C Inhibitors Block Amphetamine-Mediated Dopamine Release in Rat Striatal Slices

L. Kantor and M. E. Gnegy
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 592-598;
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