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首页> 美国卫生研究院文献>The Journal of Neuroscience >Reduction of Stress-Induced Behavior by Antagonism of Corticotropin-Releasing Hormone 2 (CRH2) Receptors in Lateral Septum or CRH1 Receptors in Amygdala
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Reduction of Stress-Induced Behavior by Antagonism of Corticotropin-Releasing Hormone 2 (CRH2) Receptors in Lateral Septum or CRH1 Receptors in Amygdala

机译：拮抗侧隔中促肾上腺皮质激素释放激素2（CRH2）受体或杏仁核中的CRH1受体的应激诱导的行为的减少。

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Although corticotropin-releasing hormone (CRH), a regulator of stress responses, acts through two receptors (CRH1 and CRH2), the role of CRH2 in stress responses remains unclear. Knock-out mice without the CRH2gene exhibit increased stress-like behaviors. This profile could result either directly from the absence of CRH2 receptors or indirectly from developmental adaptations. In the present study, CRH2 receptors were acutely blocked by α-helical CRH (αhCRH, CRH1/CRH2 antagonist; 0, 30, 100, and 300 ng) infusion into the lateral septum (LS), which abundantly expresses CRH2 but not CRH1receptors. Freezing, locomotor activity, and analgesia were tested after infusion. Intra-LS αhCRH blocked shock-induced freezing without affecting activity or pain responses; infusions into lateral ventricle or nucleus of the diagonal band had no effects. The same behavioral profile was obtained with d-Phe-CRH(12–41)(100 ng), another CRH1/CRH2 antagonist. A selective CRH1 antagonist (NBI27914), in doses that reduced freezing on intra-amygdala (central nucleus) infusion (0, 0.2, and 1.0 μg), did not affect freezing when infused into the LS.Ex vivo autoradiography revealed that binding of [125I]sauvagine, a mixed CRH1/CRH2 agonist, was prevented in the LS by previous intra-LS infusion of αhCRH but not NBI27914. In vitro studies demonstrated that [125I]sauvagine binding in the LS could be inhibited by a CRH1/CRH2 antagonist but not by the selective CRH1 receptor antagonist, confirming that in the LS, αhCRH antagonized exclusively CRH2receptors. Acute antagonism of CRH2 receptors in the LS thus produces a behaviorally, anatomically, and pharmacologically specific reduction in stress-induced behavior, in contrast to results of recent knock-out studies, which induced congenital and permanent CRH2 removal. CRH2 receptors may thus represent a potential target for the development of novel CRH system anxiolytics.
机译：尽管促肾上腺皮质激素释放激素（CRH）是应激反应的调节剂，它通过两个受体（CRH1和CRH2）起作用，但CRH2在应激反应中的作用仍不清楚。没有CRH2基因的基因敲除小鼠表现出增加的应激样行为。这种情况可能是由于缺乏CRH2受体而直接产生的，也可能是由于发育适应而间接产生的。在本研究中，CRH2受体被α-螺旋CRH（αhCRH，CRH1 / CRH2拮抗剂； 0、30、100和300 ng）输注到侧隔（LS）中而被急性阻断，该膜充分表达CRH2但不表达CRH1受体。输注后测试冷冻，自发活动和镇痛作用。 LS内αhCRH阻断了休克诱导的冰冻，而没有影响活动或疼痛反应；输注对侧脑室或对角带核不起作用。使用另一种CRH1 / CRH2拮抗剂d-Phe-CRH（12–41）（100 ng）也获得了相同的行为特征。选择性CRH1拮抗剂（NBI27914）的剂量能减少杏仁核内（中央核）输注（0、0.2和1.0μg）时的冻结，而注入LS时则不会影响冻结。离体放射自显影显示[先前通过LSh内αhCRH的输注预防了 125 I] sauvagine（一种混合的CRH1 / CRH2激动剂），但没有在NBI27914上进行过LS输注。体外研究表明，LSH中的[ 125 I] sauvagine结合可以被CRH 1 / CRH 2 拮抗剂抑制，但不能被CRH 1 / CRH 2 拮抗剂抑制。选择性CRH 1 受体拮抗剂，证实在LS中，αhCRH仅拮抗CRH 2 受体。因此，LS中CRH 2 受体的急性拮抗作用导致应激诱导行为的行为，解剖和药理学特异性降低，这与最近的敲除研究的结果相反，后者导致先天性和永久性CRH 2 删除。因此，CRH 2 受体可能代表了新型CRH系统抗焦虑药的潜在开发目标。

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