3,4-methylenedioxymethamphetamine ('Ecstasy') promotes the translocation of protein kinase C (PKC): requirement of viable serotonin nerve terminals

The metabolic effects of the neurotoxic, ring-substituted amphetamine 3,4-methylenedioxy-methamphetamine (MDMA or 'Ecstasy') were examined in vivo. In this study, we focused on the ability of MDMA to induce a translocation of the calcium and phospholipid-dependent protein kinase C (PKC) from cytosol to the cortical plasma membrane. Two injections of MDMA (20 mg/kg; 10 h apart; s.c.) increased the density of membrane bound PKC sites by 48.0% over saline treated animals without mediating a significant change in ligand ([³H]phorbol 12,13 dibutyrate; [³H]PDBu) affinity. Longer drug treatments (8 × 20 mg/kg) induced a lasting (up to 5 days post-treatment) increase in the density of membrane-bound PKC. Prior destruction of cortical 5-HT nerve terminals with p-chloroamphetamine (PCA) prevents this effect and suggests that viable 5-HT uptake sites are essential for MDMA-induced PKC translocation. These results demonstrate that MDMA-induced PKC translocation to mediated by viable cortical 5-HT nerve terminals, and that prolonged kinase activation may contribute to MDMA-induced serotonergic neurotoxicity.