Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cepsilon

J Clin Invest. 2002 Oct;110(7):1003-10. doi: 10.1172/JCI15903.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenocorticotropic Hormone / blood*
  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Anxiety / enzymology
  • Anxiety / prevention & control*
  • Corticosterone / blood*
  • Isoenzymes / deficiency*
  • Isoenzymes / physiology
  • Mice
  • Mice, Inbred C57BL
  • Pregnanolone / pharmacology*
  • Protein Kinase C / deficiency*
  • Protein Kinase C / physiology
  • Protein Kinase C-epsilon
  • Receptors, GABA-A / drug effects


  • Anti-Anxiety Agents
  • Isoenzymes
  • Receptors, GABA-A
  • Adrenocorticotropic Hormone
  • Pregnanolone
  • Prkce protein, mouse
  • Protein Kinase C
  • Protein Kinase C-epsilon
  • Corticosterone