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)

H. Kenneth Kramer, Jose C. Poblete, Efrain C. Azmitia

Research output: Contribution to journalArticle

Abstract

3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) is a substituted amphetamine whose acute and long-term effects on the serotonin system are dependent on an interaction with the 5-HT uptake transporter (SERT). Although much of the work dedicated to the study of this compound has focused on its ability to release monoamines, this drug has many important metabolic consequences on neurons and glial cells. The identification of these physiological responses will help to bridge the gap that 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 pre- and postsynaptic mechanisms. Because the primary site of action of these drugs is the 5-HT transporter, we now expand on our previous results and attempt to characterize MDMA's ability to translocate PKC within cortical 5-HT nerve terminals. In synaptosomes, MDMA produced a concentration-dependent increase in membrane-bound PKC (as measured by 3H-phorbol 12, 13 dibutyrate, 3H-PDBu) bindings sites. This response was abolished by cotreatment with the specific serotonin reuptake inhibitor (SSRI), fluoxetine, but not by the 5-HT(2A/2C) antagonist, ketanserin. In contrast, full agonists to 5-HT(1A) and 5-HT2 receptors did not produce significant PKC translocation. MDMA-mediated PKC translocation also requires the presence of extracellular calcium ions. Using assay conditions where extracellular calcium was absent prevented the in vitro activation of PKC by MDMA. Prolonged PKC translocation has been hypothesized to contribute to the calcium-dependent neurotoxicity produced by substituted amphetamines. In addition, many physiological processes within 5-HT nerve terminals, including 5-HT reuptake and vesicular serotonin release, are 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 changes in the homeostatic function of 5-HT neurons, leading to the degeneration of specific cellular elements after repeated MDMA exposure. Copyright (C) 1998 American College of Neuropsychopharmacology.

Original languageEnglish (US)
Pages (from-to)265-277
Number of pages13
JournalNeuropsychopharmacology
Volume19
Issue number4
DOIs
StatePublished - Oct 1998

Keywords

  • Calcium
  • Ecstacy
  • Release
  • Reverse uptake
  • Second messenger

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Fingerprint Dive into the research topics of '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)'. Together they form a unique fingerprint.

  • Cite this