Supersensitivity to allosteric GABA(A) receptor modulators and alcohol in mice lacking PKCepsilon.
Several of the actions of ethanol are mediated by gamma-aminobutyrate type A (GABA(A)) receptors. Here we demonstrated that mutant mice lacking protein kinase C epsilon (PKCepsilon) were more sensitive than wild-type littermates to the acute behavioral effects of ethanol and other drugs that allosterically activate GABA(A) receptors. GABA(A) receptors in membranes isolated from the frontal cortex of PKCepsilon null mice were also supersensitive to allosteric activation by ethanol and flunitrazepam. In addition, these mutant mice showed markedly reduced ethanol self-administration. These findings indicate that inhibition of PKCepsilon increases sensitivity of GABA(A) receptors to ethanol and allosteric modulators. Pharmacological agents that inhibit PKCepsilon may be useful for treatment of alcoholism and may provide a non-sedating alternative for enhancing GABA(A) receptor function to treat other disorders such as anxiety and epilepsy.
Hodge
C W
CW
Department of Neurology and Ernest Gallo Clinic and Research Center, University of California, San Francisco 94110, USA. chodge@itsa.ucsf. edu
Mehmert
K K
KK
Kelley
S P
SP
McMahon
T
T
Haywood
A
A
Olive
M F
MF
Wang
D
D
Sanchez-Perez
A M
AM
Messing
R O
RO
D000494:Allosteric Regulation; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D005445:Flunitrazepam / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011493:Protein Kinase C / Q000235:genetics*; D051744:Protein Kinase C-epsilon; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000187:drug effects*; D012646:Self Administration
D018757:GABA Modulators; D007527:Isoenzymes; D011963:Receptors, GABA-A; D000431:Ethanol; D005445:Flunitrazepam; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon