The mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine decreases ethanol consumption via a protein kinase Cε-dependent mechanism

M. Foster Olive, Andrew J. Mcgeehan, Jennifer R. Kinder, Thomas McMahon, Clyde W. Hodge, Patricia H. Janak, Robert O. Messing

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

Glutamatergic neurotransmission plays a critical role in addictive behaviors, and recent evidence indicates that genetic or pharmacological inactivation of the type 5 metabotropic glutamate receptor (mGluR5) reduces the self-administration of cocaine, nicotine, and alcohol. Because mGluR5 is coupled to activation of protein kinase C (PKC), and targeted deletion of the epsilon isoform (PKCε) in mice reduces ethanol self-administration, we investigated whether there is a functional link between mGluR5 and PKCε. Here, we show that acute administration of the mGluR5 agonist (R,S)-2-chloro-5- hydroxyphenylglycine to mice increases phosphorylation of PKCε in its activation loop (T566) as well as in its C-terminal region (S729). Increases in phospho-PKCε are dependent not only on mGluR5 stimulation but also on phosphatidylinositol-3 kinase (PI3K). In addition, the selective mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) reduced basal levels of phosphorylation of PKCε at S729. We also show that MPEP dose dependently reduced ethanol consumption in wild-type but not in PKCε-null mice, suggesting that PKCe is an important signaling target for modulation of ethanol consumption by mGluR5 antagonists. Radioligand binding experiments using [ 3H]MPEP revealed that these genotypic differences in response to MPEP were not a result of altered mGluR5 levels or binding in PKCε-null mice. Our data indicate that mGluR5 is coupled to PKCε via a PI3K-dependent pathway and that PKCε is required for the ability of the mGluR5 antagonist MPEP to reduce ethanol consumption.

Original languageEnglish (US)
Pages (from-to)349-355
Number of pages7
JournalMolecular Pharmacology
Volume67
Issue number2
DOIs
StatePublished - Feb 2005
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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