| Because mGluR 5 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 mGluR 5 and PKCepsilon . ^^^ Here , we show that acute administration of the mGluR 5 agonist ( R , S ) 2 chloro 5 hydroxyphenylglycine to mice increases phosphorylation of PKCepsilon in its activation loop ( T 566 ) as well as in its C terminal region ( S 729 ) . ^^^ Increases in phospho PKCepsilon are dependent not only on mGluR 5 stimulation but also on phosphatidylinositol 3 kinase ( PI3K ) . ^^^ In addition , the selective mGluR 5 antagonist 6 methyl 2 ( phenylethynyl ) pyridine ( MPEP ) reduced basal levels of phosphorylation of PKCepsilon at S 729 . ^^^ 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 mGluR 5 antagonists . ^^^ |