Inhibition of protein kinase ( PK ) C δ attenuates methamphetamine‐induced dopaminergic toxicity via upregulation of phosphorylation of tyrosine hydroxylase at S er 40 by modulation of protein phosphatase 2 A and PKA

Summary Recently, we proposed that inhibition of protein kinase ( PK ) C δ may be a useful target for protection against methamphetamine ( MA )‐induced dopaminergic toxicity. We demonstrated that treatment with MA resulted in a significant decrease in phosphorylation of tyrosine hydroxylase ( TH ) at S er 40 in the striatum, but not in the phosphorylation of TH at S er 31 . In the present study, treatment with rottlerin (1.5 or 3.0 μg, i.c.v, once a day for 5 days), a PKC δ inhibitor, or a PKC δ antisense oligonucleotide ( ASO ; 2.5 μg/μl, i.c.v., 3 times) significantly attenuated MA ‐induced reductions in the phosphorylation of TH at S er 40 and in the expression of PKA in the striatum of mice. This attenuation was significantly counteracted by H89 (10 or 30 ng, i.c.v., 1 h after the last MA administration), a PKA inhibitor. Treatment with rottlerin or ASO significantly attenuated the MA ‐induced increase in protein phosphatase ( PP ) 2 A activity. FTY 720 (1 or 5 mg/kg, i.p., 1 h after the last MA administration), a PP 2 A activator, significantly reversed the recovery in TH phosphorylation mediated by inhibition of PKC δ after MA treatment. Both H 89 and FTY 720 counteracted the recovery of MA ‐induced behavioural impairments induced by PKC δ inhibition. The effects, mediated by rottlerin or ASO in MA ‐treated wild‐type mice were comparable with those in MA ‐treated PKC δ −/− mice. However, neither inhibition of the mitogen‐activated protein kinase subfamily (extracellular signal‐regulated kinase, c‐ J un N ‐terminal kinase, p38) nor inhibition of calcium calmodulin kinase II significantly altered PKC δ inhibition‐mediated attenuation of MA ‐induced impairment of TH phosphorylation. The results suggest that genetic or pharmacological inhibition of PKC δ requires modulation of PKA expression and/or PP 2 A activity to attenuate the impairment of TH phosphorylation at S er 40 and behavioural activity induced by MA .