Activation of protein kinase C (PKC) by 3,4-methylenedioxymethamphetamine (MDMA) occurs through the stimulation of serotonin receptors and transporter.
H K Kramer, Jose C Poblete, Efrain C. Azmitia
Neuropsychopharmacology September 1997 DOI: 10.1016/s0893-133x(97)00026-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | MDMA p-chloroamphetamine fluoxetine cocaine DOB ketanserin |
| Dose | MDMA 20 mg/kg |
| Measures | PKC binding sites measured by 3H-phorbol 12,13-dibutyrate (PDBu) binding |
| Topics | MDMA Serotonin |
| Key findings | A single MDMA injection increased PKC density in rat cortex and hippocampus for up to 24 hours, an effect mimicked by p-chloroamphetamine but not by fluoxetine, cocaine, or DOB. Fluoxetine and ketanserin attenuated MDMA-induced PKC translocation but completely prevented loss of serotonin uptake sites after multiple doses, suggesting MDMA acts via both the serotonin transporter and 5-HT2A/2C receptors. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 4
- Small Changes in Ambient Temperature Cause Large Changes in 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonin Neurotoxicity and Core Body Temperature in the Rat Journal of Neuroscience July 1, 1998
- Neuronal Nicotinic Receptors as New Targets for Amphetamine-Induced Oxidative Damage and Neurotoxicity Pharmaceuticals June 15, 2011
- Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview Molecular Neurobiology June 1, 2009
- (+/-)3,4-Methylenedioxyamphetamine elicits action potential bursts in a central snail neuron. Experimental Neurology February 2007
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