Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 110, Issue 7, Pages 1003-1010Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200215903
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Funding
- NIAAA NIH HHS [AA-09981, AA-08117, R01 AA009981] Funding Source: Medline
- NIA NIH HHS [AG-20079] Funding Source: Medline
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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.
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