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 of the psychotropic amphetamine derivative, 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"), on the activity of second messenger-dependent kinases. Previous work has demonstrated that two injections of MDMA (20 mg/kg) elicits a prolonged translocation of the calcium and phospholipid-dependent enzyme, protein kinase C ( PKC) in rats. However, because MDMA has actions at the 5-HT transporter and 5-HT2A/2C receptors, our experiments were directed at uncovering which of these many sites may be involved in this second messenger dependent response. A single injection of MDMA produced a time- and dose-dependent increase in the density of cortical and hippocampal PKC (as measured by 3H-phorbol 12,13-dibutyrate (PDBu) binding sites. MDMA-mediated PKC translocation was long-lasting and remained above control (saline-treated rats) for up to 24 h after injection. This effect was mimicked by another substituted amphetamine, p-chloroamphetamine (pCA), but with a temporal-response curve that was to the left of MDMA's. However, pure uptake inhibitors like fluoxetine, cocaine, and the selective 5-HT2A/2C agonist, DOB, were unable to produce a long-lasting translocation of PKC binding sites in rat cortex. Fluoxetine, a selective serotonin uptake inhibitor (SSRI) and ketanserin a 5-HT2A antagonist, attenuated PKC translocation by MDMA with differing efficacies; however, both compounds completely prevented the loss of 5-HT uptake sties after multiple doses of MDMA. These results suggest that MDMA increases PKC translocation by two interrelated mechanisms that involve 5-HT2A/2C receptors and the 5-HT transporter. This pathway appears to include: (1) the drug binding to the 5-HT transporter, (2) the release of cytosolic 5-HT stores into the extracellular space, and (3) the activation of post-synaptic 5-HT2A/2C receptors linked to G-protein-mediated phospholipid hydrolysis.[1]References
- Activation of protein kinase C (PKC) by 3,4-methylenedioxymethamphetamine (MDMA) occurs through the stimulation of serotonin receptors and transporter. Kramer, H.K., Poblete, J.C., Azmitia, E.C. Neuropsychopharmacology (1997) [Pubmed]
Annotations and hyperlinks in this abstract are from individual authors of WikiGenes or automatically generated by the WikiGenes Data Mining Engine. The abstract is from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.About WikiGenesOpen Access LicencePrivacy PolicyTerms of Useapsburg
