Acute functional tolerance to ethanol mediated by protein kinase Cepsilon.
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 (PKCepsilon) 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 PKCepsilon (-/-) mice when compared with wild-type littermates. In wild-type mice, in vivo ethanol exposure produced AFT that was accompanied by increased phosphorylation of PKCepsilon and resistance of GABA(A) receptors to ethanol. In contrast, in PKCepsilon (-/-) mice, GABA(A) receptor sensitivity to ethanol was unaltered by acute in vivo ethanol exposure. Both PKCepsilon (-/-) and PKCepsilon (+/+) 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 PKCepsilon 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 PKCepsilon and does not alter PKCepsilon modulation of ethanol preference.
Ernest Gallo Clinic and Research Center, Emeryville, CA 94608, USA.
Melisa J
MJ
Wallace
Philip M
PM
Newton
Miho
M
Oyasu
Thomas
T
McMahon
Wen-Hai
WH
Chou
Jacklyn
J
Connolly
Robert O
RO
Messing
D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism; D000435:Alcoholic Intoxication / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D002531:Cerebellum / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects; D004361:Drug Tolerance / Q000235:genetics / Q000502:physiology*; D000431:Ethanol / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000172:deficiency / Q000502:physiology*; D011930:Reaction Time / Q000187:drug effects; D018079:Receptors, GABA / Q000187:drug effects / Q000502:physiology; D012018:Reflex / Q000187:drug effects; D045442:Rotarod Performance Test / Q000379:methods; D012646:Self Administration / Q000379:methods; D013997:Time Factors
D002492:Central Nervous System Depressants; D002712:Chlorides; D018079:Receptors, GABA; D000431:Ethanol; D051744:Protein Kinase C-epsilon