ACTIVATION OF PROTEIN-KINASE-C (PKC) BY 3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA) OCCURS THROUGH THE STIMULATION OF SEROTONIN RECEPTORS AND TRANSPORTER

This report further characterizes the intermediate metabolic effects o f the psychotropic amphetamine derivative, 3,4-methylenedioxymethamphe tamine (MDMA or ''ecstasy''), on the activity of second messenger-depe ndent kinases. Previous work has demonstrated that two injections of M DMA (20 mg/kg) elicits a prolonged translocation of the calcium and ph ospholipid-dependent enzyme, protein kinase C (PKC) in rats. However, because MDMA has actions at the 5-HT transporter and 5-HT2A/2C recepto rs, our experiments were directed at uncovering which of these many si tes may be involved in this second messenger-dependent response. A sin gle injection of MDMA produced a time- and dose-dependent increase in the density of cortical and hippocampal PKC (as measured by H-3-phorbo l 12,13-dibutyrate (PDBu)) binding sites. MDMA-mediated PKC translocat ion was long-lasting and remained above control (saline-treated rats) for up to 24 h after injection. This effect was mimicked by another su bstituted amphetamine, p-chloroamphetamine (pCA), but with a temporal- response curve that was to the left of MDMA's. However, pure uptake in hibitors like fluoxetine, cocaine, and the selective 5-HT2A/2C agonist , DOB, were unable to produce a long-lasting translocation of PKC bind ing sites in rat cortex. Fluoxetine, a selective serotonin uptake inhi bitor (SSRI) and ketanserin, a 5-HT2A antagonist, attenuated PKC trans location by MDMA with differing efficacies; however, both compounds co mpletely prevented the loss of 5-HT uptake sties after multiple doses of MDMA. These results suggest that MDMA increases PKC translocation b y two interrelated mechanisms that involve 5-HT2A/2C receptors and the 5-HT transporter. This pathway appears to include: (1) the drug bindi ng to the 5-HT transporter, (2) the release of cytosolic 5-HT stores i nto the extracellular space, and (3) the activation of post-synaptic 5 -HT2A/2C receptors linked to G-protein-mediated phospholipid hydrolysi s. (C) 1997 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.