SY07-2 * ROLE OF OXIDATIVE STRESS IN METHAMPHETAMINE-INDUCED DOPAMINERGIC TOXICITY MEDIATED BY PROTEIN KINASE C

Abstract

This study examined the role of protein kinase C (PKC) isozymes in methamphetamine (MA)-induced dopaminergic toxicity. Multiple-dose administration of MA did not significantly alter PKCα, PKCβI, PKCβII, or PKCζ expression in the striatum, but did significantly increase PKCδexpression. Go6976 (a co-inhibitor of PKCα and -β), hispidin (PKCβ inhibitor), and PKCζ pseudosubstrate inhibitor (PKCζ inhibitor) did not significantly alter MA-induced behavioral impairments. However, rottlerin (PKCδ inhibitor) significantly attenuated behavioral impairments in a dose-dependent manner. In addition, MA-induced behavioral impairments were not apparent in PKCδknockout (−/−) mice. MA-induced oxidative stress was significantly attenuated in rottlerin-treated mice and was not apparent in PKCδ(−/−) mice. Consistent with this, MA-induced apoptosis (i.e., terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells) was significantly attenuated in rottlerin-treated mice. Furthermore, MA-induced increases in the dopamine turnover rate and decreases in tyrosine hydroxylase (TH) activity and the expression of TH, dopamine transporter, and vesicular monoamine transporter 2 were not significantly observed in rottlerin-treated or PKCδ(−/−) mice. Our results suggest that PKCδ gene expression is a key mediator of oxidative stress and dopaminergic damage induced by MA. Thus, inhibition of PKCδ may be a useful target for protection against MA-induced neurotoxicity.