Received for publication June 3, 2004.
Revised October 15, 2004.
Accepted for publication November 5, 2004.

The mGluR5 antagonist MPEP decreases ethanol consumption via a PKC-dependent mechanism

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. Since mGluR5 is coupled to activation of protein kinase C (PKC), and targeted deletion of the epsilon isoform (PKC) in mice reduces ethanol self-administration, we investigated whether there is a functional link between mGluR5 and PKC. Here we show that acute administration of the mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) to mice increases phosphorylation of PKC in its activation loop (T566) as well as in its C-terminal region (S729). Increases in phosphoPKC 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 PKC at S729. We also show that MPEP dose-dependently reduced ethanol consumption in wildtype but not in PKC null mice, suggesting that PKC 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 PKC null mice. Our data indicate that mGluR5 is coupled to PKC via a PI3K-dependent pathway, and that PKC is required for the ability of the mGluR5 antagonist MPEP to reduce ethanol consumption.

Key words: Metabotropic glutamate, IP3/DAG, Protein Kinase C, Mutagenesis/Chimeric approaches, Receptor binding studies, Knockout, Alcohols