CHARACTERIZATION OF THE TRANSLOCATION OF PROTEIN-KINASE-C (PKC) BY 3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA ECSTASY) IN SYNAPTOSOMES - EVIDENCE FOR A PRESYNAPTIC LOCALIZATION INVOLVING THE SEROTONIN TRANSPORTER(SERT)/
Hk. Kramer et al., CHARACTERIZATION OF THE TRANSLOCATION OF PROTEIN-KINASE-C (PKC) BY 3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA ECSTASY) IN SYNAPTOSOMES - EVIDENCE FOR A PRESYNAPTIC LOCALIZATION INVOLVING THE SEROTONIN TRANSPORTER(SERT)/, Neuropsychopharmacology, 19(4), 1998, pp. 265-277
3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) is a substituted a
mphetamine whose acute and long-term effects on the serotonin system a
re dependent on an interaction with the 5-HT uptake transporter (SEAT)
. Although much of the work dedicated to the study of this compound ha
s focused on its ability to release monoamines, this drug has many imp
ortant metabolic consequences on neurons and glial cells. The identifi
cation of these physiological responses will help to bridge the gap th
at exists in the information between the acute and neurotoxic effects
of amphetamines. Substituted amphetamines have the ability to produce
a long-term translocation of protein kinase C (PKC) in vivo, and this
action may be crucial to the development of serotonergic neurotoxicity
. Our earlier results suggested that PKC activation occurred through p
re- and Postsynaptic mechanisms. Because the primary site of action of
these drugs is the 5-HT transporter, we now expand on our previous re
sults and attempt to characterize MDMA's ability to translocate PKC wi
thin cortical 5-HT nerve terminals. In synaptosomes, MDMA produced a c
oncentration-dependent increase in membrane-bound PKC (as measured by
H-3-phorbol 12, 13 dibutyrate, H-3-PDBu) bindings sites. This response
was abolished by cotreatment with the specific serotonin reuptake inh
ibitor (SSRI), fluoxetine, but not by the 5-HT2A/2C antagonist, ketans
erin. In contrast, full agonists to 5-HT1A and 5-HT2 receptors did not
produce significant PKC translocation. MDMA-mediated PKC translocatio
n also requires the presence of extracellular calcium ions. Using assa
y conditions where extracellular calcium was absent prevented the in v
itro activation of PKC by MDMA. Prolonged PKC translocation has been h
ypothesized to contribute to the calcium-dependent neurotoxicity produ
ced by substituted amphetamines. In addition, many physiological proce
sses within 5-HT nerve terminals, including 5-HT reuptake and vesicula
r serotonin release, ave susceptible to modification by PKC-dependent
protein phosphorylation. Our results suggest that prolonged activation
of PKC within the 5-HT nerve terminal may contribute to lasting chang
es in the homeostatic function of 5-HT neurons, leading to the degener
ation of specific cellular elements after repeated MDMA exposure. (C)
1998 American College of Neuropsychopharmacology. Published by Elsevie
r Science Inc.