Protein Kinase Cδ Regulates Ethanol Intoxication and Enhancement of GABA-Stimulated Tonic Current

Ethanol alters the distribution and abundance of PKCδ in neural cell lines. Here we investigated whether PKCδ also regulates behavioral responses to ethanol. PKCδ −/− mice showed reduced intoxication when administered ethanol and reduced ataxia when administered the nonselective GABA A receptor agonists pentobarbital and pregnanolone. However, their response to flunitrazepam was not altered, suggesting that PKCδ regulates benzodiazepine-insensitive GABA A receptors, most of which contain δ subunits and mediate tonic inhibitory currents in neurons. Indeed, the distribution of PKCδ overlapped with GABA A δ subunits in thalamus and hippocampus, and ethanol failed to enhance tonic GABA currents in PKCδ −/− thalamic and hippocampal neurons. Moreover, using an ATP analog-sensitive PKCδ mutant in mouse L(tk − ) fibroblasts that express α4β3δ GABA A receptors, we found that ethanol enhancement of GABA currents was PKCδ-dependent. Thus, PKCδ enhances ethanol intoxication partly through regulation of GABA A receptors that contain δ subunits and mediate tonic inhibitory currents. These findings indicate that PKCδ contributes to a high level of behavioral response to ethanol, which is negatively associated with risk of developing an alcohol use disorder in humans.