Escalating evidences suggest that oxidative stress is involved in methamphetamine (MA)-induced neurotoxicity. In the present study, it was asked whether PKC-delta gene affects MA-induced dopaminergic neurotoxicity. Treatment with MA (8.0 mg/kg, Lp. x 4) resulted in the dopaminergic toxicity. Intrastriatal microinjection with rottlerin, a PKC-delta inhibitor, significantly attenuated MA-induced neurotoxicity. Consistently, these findings were more pronounced in PKC-delta (-/-) mice than PKC-delta (+/+) mice. The results suggest that PKC-delta gene may be an important mediator in MA-induced dopaminergic toxicity, and that PKC-delta gene is involved in the TH ser-40 phosphorylation and TH activity and ultimately inhibits DA synthesis.