Activation of protein kinase C (PKC) by 3,4-methylenedioxymethamphetamine (MDMA) occurs through the stimulation of serotonin receptors and transporter

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

Research output: Contribution to journalArticle

Abstract

This report further characterize 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-HT(2A/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 hr 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-HT(2A/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-HT(2A) antagonist, attenuated PKC translocation by MDMA with differing efficacies; however, both compounds completely prevented the loss of 5-HT uptake sites after multiple doses of MDMA. These results suggest that MDMA increases PKC translocation by two interrelated mechanisms that involve 5-HT(2A/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-HT(2A/2C) receptors linked to G-protein-mediated phospholipid hydrolysis.

Original languageEnglish (US)
Pages (from-to)117-129
Number of pages13
JournalNeuropsychopharmacology
Volume17
Issue number3
DOIs
StatePublished - Sep 1997

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N-Methyl-3,4-methylenedioxyamphetamine
Serotonin Plasma Membrane Transport Proteins
Serotonin Receptors
Protein Kinase C
Serotonin
Receptor, Serotonin, 5-HT2C
Receptor, Serotonin, 5-HT2A
Fluoxetine
Second Messenger Systems
Amphetamine
Injections
p-Chloroamphetamine
Binding Sites
Phorbol 12,13-Dibutyrate
Ketanserin
Serotonin Antagonists
Serotonin Uptake Inhibitors
Extracellular Space
Cocaine
GTP-Binding Proteins

Keywords

  • Calcium
  • Second messenger
  • Serotonin
  • Serotonin(2A/2C)
  • Transporter

ASJC Scopus subject areas

  • Pharmacology

Cite this

Activation of protein kinase C (PKC) by 3,4-methylenedioxymethamphetamine (MDMA) occurs through the stimulation of serotonin receptors and transporter. / Kramer, H. Kenneth; Poblete, Jose C.; Azmitia, Efrain C.

In: Neuropsychopharmacology, Vol. 17, No. 3, 09.1997, p. 117-129.

Research output: Contribution to journalArticle

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abstract = "This report further characterize 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-HT(2A/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 hr 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-HT(2A/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-HT(2A) antagonist, attenuated PKC translocation by MDMA with differing efficacies; however, both compounds completely prevented the loss of 5-HT uptake sites after multiple doses of MDMA. These results suggest that MDMA increases PKC translocation by two interrelated mechanisms that involve 5-HT(2A/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-HT(2A/2C) receptors linked to G-protein-mediated phospholipid hydrolysis.",
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AB - This report further characterize 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-HT(2A/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 hr 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-HT(2A/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-HT(2A) antagonist, attenuated PKC translocation by MDMA with differing efficacies; however, both compounds completely prevented the loss of 5-HT uptake sites after multiple doses of MDMA. These results suggest that MDMA increases PKC translocation by two interrelated mechanisms that involve 5-HT(2A/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-HT(2A/2C) receptors linked to G-protein-mediated phospholipid hydrolysis.

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