title: Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cepsilon.
abstract: 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.
authors.affiliation: Ernest Gallo Clinic and Research Center, Department of Neurology, University of California San Francisco, Emeryville, California 94608, USA.
authors.forename: Clyde W
authors.initials: CW
authors.lastname: Hodge
authors.forename: Jacob
authors.initials: J
authors.lastname: Raber
authors.forename: Thomas
authors.initials: T
authors.lastname: McMahon
authors.forename: Helen
authors.initials: H
authors.lastname: Walter
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Sanchez-Perez
authors.forename: M Foster
authors.initials: MF
authors.lastname: Olive
authors.forename: Kristin
authors.initials: K
authors.lastname: Mehmert
authors.forename: A Leslie
authors.initials: AL
authors.lastname: Morrow
authors.forename: Robert O
authors.initials: RO
authors.lastname: Messing
mesh_terms: 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
chemical_list: 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