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GABA A receptor regulation of voluntary ethanol drinking requires PKCϵ
Author(s) -
Besheer Joyce,
Lepoutre Veronique,
Mole Beth,
Hodge Clyde W.
Publication year - 2006
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20314
Subject(s) - flumazenil , zolpidem , protein kinase c , chemistry , agonist , pharmacology , gabaa receptor , diazepam , inverse agonist , gabaergic , receptor , ethanol , medicine , endocrinology , biology , biochemistry , signal transduction , insomnia
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 ε‐isoform of PKC (PKCε) 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 PKCε in GABA A receptor regulation of voluntary ethanol drinking. To address this question, PKCε 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 α1 agonist), L‐655,708 (BZ‐sensitive GABA A α5 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 PKCε 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 PKCε null mice. Thus, results of the present study show that PKCε 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 PKCε may be required for GABA A receptor regulation of chronic ethanol drinking. Synapse 60:411–419, 2006. © 2006 Wiley‐Liss, Inc.