PT  - JOURNAL ARTICLE
AU  - M. Foster Olive
AU  - Andrew J. Mcgeehan
AU  - Jennifer R. Kinder
AU  - Thomas McMahon
AU  - Clyde W. Hodge
AU  - Patricia H. Janak
AU  - Robert O. Messing
TI  - The mGluR5 Antagonist 6-Methyl-2-(phenylethynyl)pyridine Decreases Ethanol Consumption via a Protein Kinase Cϵ-Dependent Mechanism
AID  - 10.1124/mol.104.003319
DP  - 2005 Feb 01
TA  - Molecular Pharmacology
PG  - 349--355
VI  - 67
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/67/2/349.short
4100  - http://molpharm.aspetjournals.org/content/67/2/349.full
SO  - Mol Pharmacol2005 Feb 01; 67
AB  - 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 PKCϵ 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.