PAC1 receptor antagonism in the bed nucleus of the stria terminalis (BNST) attenuates the endocrine and behavioral consequences of chronic stress.
PAC1 receptor antagonism in the bed nucleus of the stria terminalis (BNST) attenuates the endocrine and behavioral consequences of chronic stress.
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DOI：
10.1016/j.psyneuen.2014.05.014
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发表时间：
2014-09
影响因子：
3.7
通讯作者：
May, Victor
中科院分区：
文献类型：
--
作者：
Roman, Carolyn W.;Lezak, Kim R.;Hartsock, Matthew J.;Falls, William A.;Braas, Karen M.;Howard, Alan B.;Hammack, Sayamwong E.;May, Victor
关键词：
慢性或反复应激源暴露可导致一系列不适应的行为和生理后果，在边缘结构中，终纹床核(BNST)参与了应激反应的整合和解释。以往的工作表明，慢性变量应激(CVS)可增加BNST垂体腺苷环化酶激活多肽(PACAP，ADCYAP1)和PAC1受体(Adcyap1r1)的转录表达，急性注射BNST PACAP可刺激焦虑样行为。在这里，我们显示慢性应激选择性地增加PACAP在BNST背外侧椭圆形核的表达，其模式与促肾上腺皮质激素释放激素(CRH)的模式不同。在不同的受体亚型中，BNST PACAP通过PAC1受体传递的信号不仅可以增强不同行为参数的焦虑反应，还可以诱导类似厌食症的行为，以模拟应激的后果。相反，在CVS的一周内，通过持续输注PAC1受体拮抗剂PACAP(6-38)来慢性抑制BNST PACAP信号，可以减弱这些应激诱导的行为反应和体重增加的变化。BNST PACAP信号刺激下丘脑-垂体-肾上腺(HPA)轴，增加皮质酮的释放；在致敏应激模型中，BNST PACAP(6-38)可抑制皮质酮的释放。综上所述，最近PACAP/PAC1受体失调与包括创伤后应激障碍在内的应激反应的改变有关，这些数据表明，BNST PACAP/PAC1受体信号机制可能协调应激的行为和内分泌后果。
Chronic or repeated stressor exposure can induce a number of maladaptive behavioral and physiological consequences and among limbic structures, the bed nucleus of the stria terminalis (BNST) has been implicated in the integration and interpretation of stress responses. Previous work has demonstrated that chronic variate stress (CVS) exposure in rodents increases BNST pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) and PAC1 receptor (Adcyap1r1) transcript expression, and that acute BNST PACAP injections can stimulate anxiety-like behavior. Here we show that chronic stress increases PACAP expression selectively in the oval nucleus of the dorsolateral BNST in patterns distinct from those for corticotropin releasing hormone (CRH). Among receptor subtypes, BNST PACAP signaling through PAC1 receptors not only heightened anxiety responses as measured by different behavioral parameters but also induced anorexic-like behavior to mimic the consequences of stress. Conversely, chronic inhibition of BNST PACAP signaling by continuous infusion with the PAC1 receptor antagonist PACAP(6-38) during the week of CVS attenuated these stress-induced behavioral responses and changes in weight gain. BNST PACAP signaling stimulated the hypothalamic-pituitary-adrenal (HPA) axis and heightened corticosterone release; further, BNST PACAP(6-38) administration blocked corticosterone release in a sensitized stress model. In aggregate with recent associations of PACAP/PAC1 receptor dysregulation with altered stress responses including post-traumatic stress disorder, these data suggest that BNST PACAP/PAC1 receptor signaling mechanisms may coordinate the behavioral and endocrine consequences of stress.
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