Hk. Kramer et al., ACTIVATION OF PROTEIN-KINASE-C (PKC) BY 3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA) OCCURS THROUGH THE STIMULATION OF SEROTONIN RECEPTORS AND TRANSPORTER, Neuropsychopharmacology, 17(3), 1997, pp. 117-129
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.