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The mGluR5 Antagonist 6-Methyl-2-(phenylethynyl)pyridine Decreases Ethanol Consumption via a Protein Kinase C-Dependent Mechanism

Ernest Gallo Clinic and Research Center, Department of Neurology, University of California at San Francisco, Emeryville, California (M.F.O., A.J.M., J.R.K., T.M., P.H.J., R.O.M.); and Bowles Center for Alcohol Studies, Departments of Psychiatry and Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (C.W.H.)

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 (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 (R,S)-2-chloro-5-hydroxyphenylglycine to mice increases phosphorylation of PKC in its activation loop (T566) as well as in its C-terminal region (S729). Increases in phospho-PKC 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 wild-type 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.

Received for publication May 28, 2004.

Accepted for publication November 5, 2004.

Address correspondence to: Dr. M. Foster Olive, Ernest Gallo Clinic and Research Center, Department of Neurology, University of California at San Francisco, 5858 Horton St., Suite 200, Emeryville, CA 94608. E-mail: folive{at}itsa.ucsf.edu

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