Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cepsilon.
Mice lacking protein kinase Cepsilon (PKCepsilon) are supersensitive to positive allosteric modulators of gamma aminobutyrate type A (GABA(A)) receptors. Since many of these compounds are anxiolytic, we examined whether anxiety-like behavior is altered in these mice. PKCepsilon-null mice showed reduced anxiety-like behavior and reduced levels of the stress hormones corticosterone and adrenocorticotrophic hormone (ACTH). This was associated with increased sensitivity to neurosteroid modulators of GABA(A) receptors. Treatment of PKCepsilon-null mice with the GABA(A) receptor antagonist bicuculline restored corticosterone levels and anxiety-like behavior to wild-type levels. These results suggest that increased GABA(A) receptor sensitivity to neurosteroids contributes to reduced anxiety-like behavior and stress hormone responses in PKCepsilon-null mice. The findings also suggest PKCepsilon as a possible therapeutic target for development of anxiolytics.
Hodge
Clyde W
CW
Ernest Gallo Clinic and Research Center, Department of Neurology, University of California San Francisco, Emeryville, California 94608, USA.
Raber
Jacob
J
McMahon
Thomas
T
Walter
Helen
H
Sanchez-Perez
Ana Maria
AM
Olive
M Foster
MF
Mehmert
Kristin
K
Morrow
A Leslie
AL
Messing
Robert O
RO
D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000201:enzymology / Q000517:prevention & control*; D003345:Corticosterone / Q000097:blood*; D007527:Isoenzymes / Q000172:deficiency* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011280:Pregnanolone / Q000494:pharmacology*; D011493:Protein Kinase C / Q000172:deficiency* / Q000502:physiology; D051744:Protein Kinase C-epsilon; D011963:Receptors, GABA-A / Q000187:drug effects
D014151:Anti-Anxiety Agents; D007527:Isoenzymes; D011963:Receptors, GABA-A; D000324:Adrenocorticotropic Hormone; D011280:Pregnanolone; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D003345:Corticosterone