Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis
Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis
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DOI：
10.1210/en.2004-0638
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发表时间：
2004-12-01
期刊：
影响因子：
4.8
通讯作者：
Hillard, CJ
中科院分区：
文献类型：
--
作者：
Patel, S;Roelke, CT;Hillard, CJ
下丘脑-垂体-肾上腺（HPA）轴的激活对于动物暴露于应激刺激后的适应和生存至关重要，数据表明内源性大麻素（eCB）信号传导调节神经内分泌功能。我们已经探索了eCB信号在应激诱导的HPA轴激活的调制中的作用。雄性小鼠接受CB 1受体拮抗剂/反向激动剂SR 141716（0.01、0.1、1和5 mg/kg，ip）给药后，血清皮质酮（CORT）浓度出现小幅剂量依赖性增加。尽管存在这种效应，但通过Fos蛋白诱导测定，最高剂量的SR 141716并未显著增加下丘脑室旁核内的神经元活动。同样，小鼠暴露于30分钟的约束增加血清CORT浓度，但并没有产生一致的，统计学上显着的增加，在PVN内的Fos表达。然而，在束缚应激前用SR 141716预处理小鼠强烈增强了束缚诱导的CORT释放和PVN内的Fos表达。用CB 1受体激动剂CP 55940、eCB转运抑制剂AM404或脂肪酸酰胺水解酶抑制剂URB 597对小鼠进行预处理显著降低或消除了限制诱导的CORT释放。暴露于急性束缚后，下丘脑2-花生四烯酸甘油含量与对照值相比降低;然而，5 d的束缚暴露（导致CORT反应减弱）后，下丘脑2-花生四烯酸甘油含量与对照值相比增加。这些数据表明，eCB信号负性调节HPA轴功能的上下文依赖性的方式，并表明，药理学增强eCB信号可以作为一种新的方法来治疗焦虑相关的疾病。
Activation of the hypothalamic-pituitary-adrenal (HPA) axis is critical for the adaptation and survival of animals upon exposure to stressful stimuli, and data suggest that endocannabinoid (eCB) signaling modulates neuroendocrine function. We have explored the role of eCB signaling in the modulation of stress-induced HPA axis activation. Administration of the CB1 receptor antagonist/inverse agonist SR141716 (0.01, 0.1, 1, and 5 mg/kg, ip) to male mice produced a small, dose-dependent increase in the serum corticosterone ( CORT) concentration. Despite this effect, the highest dose of SR141716 did not significantly increase neuronal activity within the paraventricular nucleus of the hypothalamus, as measured by the induction of Fos protein. Similarly, exposure of mice to 30 min of restraint increased serum CORT concentrations, but did not produce a consistent, statistically significant increase in Fos expression within the PVN. However, pretreatment of mice with SR141716 before restraint stress robustly potentiated restraint-induced CORT release and Fos expression within the PVN. Pretreatment of mice with either the CB1 receptor agonist CP55940, the eCB transport inhibitor AM404, or the fatty acid amide hydrolase inhibitor URB597 significantly decreased or eliminated restraint-induced CORT release. Upon exposure to acute restraint, hypothalamic 2-arachidonylglycerol content was reduced compared with the control value; however, after 5 d of restraint exposure ( which resulted in an attenuated CORT response), the hypothalamic 2-arachidonylglycerol content was increased compared with the control value. These data indicate that eCB signaling negatively modulates HPA axis function in a context-dependent manner and suggest that pharmacological augmentation of eCB signaling could serve as a novel approach to the treatment of anxiety-related disorders.