Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cε
Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cε
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DOI：
10.1172/jci200215903
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发表时间：
2002-10-01
影响因子：
15.9
通讯作者：
Messing, RO
中科院分区：
文献类型：
--
作者：
Hodge, CW;Raber, J;Messing, RO
缺乏蛋白激酶Cepsilon(PKCepsilon)的小鼠对γ-氨基丁酸酯A型(GABA(A))受体的正变构调节剂高度敏感。由于这些化合物中的许多都是抗焦虑的，我们检查了这些小鼠的焦虑样行为是否发生了改变。PKCepsilon缺失的小鼠表现出类似焦虑的行为减少，应激激素皮质酮和促肾上腺皮质激素(ACTH)水平降低。这与对GABA(A)受体的神经类固醇调节剂的敏感性增加有关。用GABA(A)受体拮抗剂荷包牡丹碱治疗PKCepsilon缺失的小鼠，皮质酮水平和焦虑样行为恢复到野生型水平。这些结果表明，GABA(A)受体对神经类固醇的敏感性增加有助于减少PKCepsilon缺失小鼠的焦虑样行为和应激激素反应。这些发现还表明，PKCepsilon可能是开发抗焦虑药物的治疗靶点。
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.