Acute functional tolerance to ethanol mediated by protein kinase C epsilon

A low level of response to ethanol is associated with increased risk of alcoholism. A major determinant of the level of response is the capacity to develop acute functional tolerance (AFT) to ethanol during a single drinking session. Mice lacking protein kinase C epsilon (PKC epsilon) show increased signs of ethanol intoxication and reduced ethanol self-administration. Here, we report that AFT to the motor-impairing effects of ethanol is reduced in PKC epsilon (-/-) mice when compared with wild-type littermates. In wild-type mice, in vivo ethanol exposure produced AFT that was accompanied by increased phosphorylation of PKC epsilon and resistance of GABA(A) receptors to ethanol. In contrast, in PKC epsilon (-/-) mice, GABAA receptor sensitivity to ethanol was unaltered by acute in vivo ethanol exposure. Both PKCe (-/-) and PKC epsilon (+/+) mice developed robust chronic tolerance to ethanol, but the presence of chronic tolerance did not change ethanol preference drinking. These findings suggest that ethanol activates a PKC epsilon signaling pathway that contributes to GABA(A) receptor resistance to ethanol and to AFT. AFT can be genetically dissociated from chronic tolerance, which is not regulated by PKC epsilon and does not alter PKC epsilon modulation of ethanol preference.