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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.

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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