GABAA receptor regulation of voluntary ethanol drinking requires PKCε

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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 ε‐isoform of PKC (PKCε) self‐administer 75% less ethanol and exhibit supersensitivity to acute ethanol and allosteric positive modulators of GABAA receptors when compared with wild‐type controls. The purpose of the present study was to examine involvement of PKCε in GABAA 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 GABAA BZ positive modulator), zolpidem (GABAA α1 agonist), L‐655,708 (BZ‐sensitive GABAA 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 GABAA BZ receptor ligands that regulate ethanol drinking by wild‐type control mice. This suggests that PKCε may be required for GABAA receptor regulation of chronic ethanol drinking. Synapse 60:411–419, 2006.

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