The mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine decreases ethanol consumption via a protein kinase C epsilon-dependent mechanism.
paper
Cited
Public
Unavailable
- Authors
- Olive, M Foster; McGeehan, Andrew J; Kinder, Jennifer R; McMahon, Thomas; Hodge, Clyde W; Janak, Patricia H; Messing, Robert O
- Year
- 2005
- Journal
- Molecular pharmacology
- PMID
- 15548766
- DOI
- 10.1124/mol.104.003319
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 (PKCepsilon) in mice reduces ethanol self-administration, we investigated whether there is a functional link between mGluR5 and PKCepsilon. Here, we show that acute administration of the mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine to mice increases phosphorylation of PKCepsilon in its activation loop (T566) as well as in its C-terminal region (S729). Increases in phospho-PKCepsilon 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 PKCepsilon at S729. We also show that MPEP dose dependently reduced ethanol consumption in wild-type but not in PKCepsilon-null mice, suggesting that PKCepsilon is an important signaling target for modulation of ethanol consumption by mGluR5 antagonists. Radioligand binding experiments using [(3)H]MPEP revealed that these genotypic differences in response to MPEP were not a result of altered mGluR5 levels or binding in PKCepsilon-null mice. Our data indicate that mGluR5 is coupled to PKCepsilon via a PI3K-dependent pathway and that PKCepsilon is required for the ability of the mGluR5 antagonist MPEP to reduce ethanol consumption.
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