![]() |
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
-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
This article has been cited by other articles:
![]() |
M.-H. Kang-Park, B. L. Kieffer, A. J. Roberts, G. R. Siggins, and S. D. Moore Presynaptic {delta} Opioid Receptors Regulate Ethanol Actions in Central Amygdala J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 917 - 925. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. Sanchis-Segura, T. Borchardt, V. Vengeliene, T. Zghoul, D. Bachteler, P. Gass, R. Sprengel, and R. Spanagel Involvement of the AMPA Receptor GluR-C Subunit in Alcohol-Seeking Behavior and Relapse J. Neurosci., January 25, 2006; 26(4): 1231 - 1238. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Ron and R. Jurd The "Ups and Downs" of Signaling Cascades in Addiction Sci. Signal., November 8, 2005; 2005(309): re14 - re14. [Abstract] [Full Text] [PDF] |
||||