1. ¹Ernest Gallo Clinic and Research Center, Emeryville, CA, USA
2. ²Graduate Program in Neuroscience, Department of Neurology, University of California at San Francisco, San Francisco, CA, USA

Correspondence: Dr RO Messing, Ernest Gallo Clinic and Research Center, 5858 Horton Avenue, Suite 200, Emeryville, CA 94608, USA. Tel: +1 510 985 3950; Fax: +1 510 985 3101; E-mail: romes@itsa.ucsf.edu

Received 18 August 2005; Revised 27 December 2005; Accepted 9 February 2006; Published online 15 March 2006.

Abstract

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) 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 (-/-) 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 and resistance of GABA_A receptors to ethanol. In contrast, in PKC (-/-) mice, GABA_A receptor sensitivity to ethanol was unaltered by acute in vivo ethanol exposure. Both PKC (-/-) and PKC (+/+) 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 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 and does not alter PKC modulation of ethanol preference.