title: GABAA receptor regulation of voluntary ethanol drinking requires PKCepsilon.
abstract: Protein kinase C (PKC) regulates a variety of neural functions, including ion channel activity, neurotransmitter release, receptor desensitization and differentiation. We have shown previously that mice lacking the epsilon-isoform of PKC (PKCepsilon) self-administer 75% less ethanol and exhibit supersensitivity to acute ethanol and allosteric positive modulators of GABA(A) receptors when compared with wild-type controls. The purpose of the present study was to examine involvement of PKCepsilon in GABA(A) receptor regulation of voluntary ethanol drinking. To address this question, PKCepsilon null-mutant and wild-type control mice were allowed to drink ethanol (10% v/v) vs. water on a two-bottle continuous access protocol. The effects of diazepam (nonselective GABA(A) BZ positive modulator), zolpidem (GABA(A) alpha1 agonist), L-655,708 (BZ-sensitive GABA(A) alpha5 inverse agonist), and flumazenil (BZ antagonist) were then tested on ethanol drinking. Ethanol intake (grams/kg/day) by wild-type mice decreased significantly after diazepam or zolpidem but increased after L-655,708 administration. Flumazenil antagonized diazepam-induced reductions in ethanol drinking in wild-type mice. However, ethanol intake by PKCepsilon null mice was not altered by any of the GABAergic compounds even though effects were seen on water drinking in these mice. Increased acute sensitivity to ethanol and diazepam, which was previously reported, was confirmed in PKCepsilon null mice. Thus, results of the present study show that PKCepsilon null mice do not respond to doses of GABA(A) BZ receptor ligands that regulate ethanol drinking by wild-type control mice. This suggests that PKCepsilon may be required for GABA(A) receptor regulation of chronic ethanol drinking.
authors.affiliation: Department of Psychiatry, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, 27599, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Besheer
authors.forename: Veronique
authors.initials: V
authors.lastname: Lepoutre
authors.forename: Beth
authors.initials: B
authors.lastname: Mole
authors.forename: Clyde W
authors.initials: CW
authors.lastname: Hodge
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics*; D000818:Animals; D003975:Diazepam / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology*; D000077334:Zolpidem
chemical_list: D018755:GABA Agonists; D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D011725:Pyridines; D011963:Receptors, GABA-A; D005442:Flumazenil; D000077334:Zolpidem; D051744:Protein Kinase C-epsilon; D003975:Diazepam