Deficits in amygdaloid cAMP-responsive element-binding protein signaling play a role in genetic predisposition to anxiety and alcoholism
Deficits in amygdaloid cAMP-responsive element-binding protein signaling play a role in genetic predisposition to anxiety and alcoholism
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DOI：
10.1172/jci24381
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发表时间：
2005-10-01
影响因子：
15.9
通讯作者：
Xu, TJ
中科院分区：
文献类型：
--
作者：
Pandey, SC;Zhang, HB;Xu, TJ
我们利用嗜酒(P)和非嗜酒(NP)大鼠研究了cAMP反应元件结合蛋白(CREB)在焦虑和饮酒行为遗传易感性中的作用。杏仁中央核(CEA)和杏仁内侧核CREB、磷酸化CREB和神经肽Y(NPY)水平先天较低。与正常大鼠相比，P组大鼠杏仁基底外侧核(BLA)的MEA明显减少，而杏仁基底外侧核(BLA)无明显变化。与NP大鼠相比，P大鼠表现出更高的基线焦虑样行为和更高的饮酒量。酒精注射或自愿摄入降低了P大鼠较高的焦虑水平。乙醇还能增加P大鼠CEA和MeA的CREB功能，但不能增加BLA的CREB功能。将PKA激活剂Sp-cAMP或NPY注入CEA可减少P大鼠的酒精摄入量和焦虑样行为。注射PKA激活剂还可增加P大鼠CEA的CREB功能。另一方面，酒精注射或自愿摄入对NP大鼠的焦虑水平和杏仁核结构的CREB功能没有任何影响。有趣的是，将PKA抑制剂RP-cAMP注入CEA可引起NP大鼠的焦虑样行为并增加酒精摄入量。PKA抑制剂降低了NP大鼠CEA的CREB功能。这些新的结果首次证明了CEA中CREB功能的降低可能在维持P大鼠的高焦虑和过度饮酒行为中起作用。
We investigated the role of cAMP-responsive element-binding protein (CREB) in genetic predisposition to anxiety and alcohol-drinking behaviors using alcohol-preferring (P) and -nonpreferring (NP) rats. The levels of CREB, phosphorylated CREB, and neuropeptide Y (NPY) were innately lower in the central amygdala (CeA) and medial amygdala. (MeA), but not in the basolateral amygdala (BLA), of P rats compared with NP rats. P rats displayed higher baseline anxiety-like behaviors and consumed higher amounts of alcohol compared with NP rats. Ethanol injection or voluntary intake reduced the higher anxiety levels in P rats. Ethanol also increased CREB function in the CeA and MeA, but not in the BLA, of P rats. Infusion of the PKA activator Sp-cAMP or NPY into the CeA decreased the alcohol intake and anxiety-like behaviors of P rats. PKA activator infusion also increased CREB function in the CeA of P rats. On the other hand, ethanol injection or voluntary intake did not produce any changes either in anxiety levels or on CREB function in the amygdaloid structures of NP rats. Interestingly, infusion of the PKA inhibitor Rp-cAMP into the CeA provoked anxiety-like behaviors and increased alcohol intake in NP rats. PKA inhibitor decreased CREB function in the CeA of NP rats. These novel results provide the first evidence to our knowledge that decreased CREB function in the CeA may be operative in maintaining the high anxiety and excessive alcohol-drinking behaviors of P rats.