Evidence implicates the endocannabinoid (eCB) system as a negative modulator of neural and endocrine responses to acute stressors. Recently, eCB signaling was also reported to contribute to habituation of hypothalamo-pituitary-adrenal (HPA) axis responses to repeated homotypic stress. The present studies were initiated to distinguish a potential role of eCB signaling in the expression vs. the acquisition of habituation of the HPA axis response to repeated stress. In each of three experiments, adult male Sprague Dawley rats were exposed to daily, 30-minute sessions of loud white noise (95 dB), which resulted in a progressive decrease in HPA axis response over successive days. Cannabinoid receptor 1 (CB1) antagonist AM251 (0.5, 1.0 or 2.0 mg/kg, i.p.) was used to examine the role of eCB signaling in homotypic stressor habituation and heterotypic (novel) stressor cross-sensitization of neuroendocrine activity. Pretreatment with high dose (2.0 mg/kg) AM251 before each of 7 consecutive, daily loud noise exposures (acquisition of habituation) resulted in potentiation of stress-induced HPA axis activation and disruption of habituation. After an 8th loud noise exposure without AM251 pretreatment, the same group of rats displayed a habituated plasma corticosterone (CORT) level similar to that of controls, indicating that CB1 receptor antagonist pretreatments did not disrupt the acquisition of habituation. In two additional experiments, rats acquired habituation to loud noise drug free, then lower doses of AM251 (0.5 and 1.0 mg.kg) were administered before a final exposure (expression of habituation) to the homotypic stressor and/or a novel heterotypic stressor. CB1 receptor antagonism disrupted the expression of CORT response habituation and some of the c-fos mRNA reduction associated with it and facilitated novel stressor sensitization in doses that did not potentiate acute responses to these stressors. Collectively, these data suggest a progressive intensification of neural eCB signaling at CB1 receptors with repeated stress exposures.

中文翻译：

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内源性大麻素信号作为介导成年雄性成年鼠的花花公子大鼠反复应激暴露的适应性反应的电路的内在成分。

有证据表明，大麻素（eCB）系统是神经和内分泌对急性应激源反应的负调节剂。最近，也有报道称eCB信号有助于下丘脑-垂体-肾上腺（HPA）轴对重复的同型应激的反应的适应。启动本研究以区分eCB信号在表达中的潜在作用与对重复应力的HPA轴反应习惯的习性的获得。在这三个实验中的每一个实验中，成年雄性Sprague Dawley大鼠每天都暴露于30分钟的大声白噪声（95 dB）中，导致连续几天HPA轴反应逐渐降低。大麻素受体1（CB1）拮抗剂AM251（0.5、1.0或2.0 mg / kg，ip ）被用来检验eCB信号在同型应激源适应性和异型（新）应激源交叉内分泌对神经内分泌活性的作用。在每天连续7次每天大声暴露（习惯化）之前，均应使用高剂量（2.0 mg / kg）AM251进行预处理，从而增强了压力诱导的HPA轴激活并破坏了习惯性。在未进行AM251预处理的第8次大声噪音暴露之后，同一组大鼠显示出与对照组相似的习惯血浆皮质酮（CORT）水平，表明CB1受体拮抗剂预处理不会破坏习性的获得。在另外两个实验中，大鼠习惯了无大噪音药物的习惯，然后降低了AM251的剂量（0.5和1.0 mg。在最后暴露于同型应激源和/或新型异型应激源之前，先给予（kg）。CB1受体拮抗作用破坏了CORT反应习性的表达和与其相关的一些c-fos mRNA的降低，并在不增强对这些应激源急性反应的剂量下促进了新型应激源敏化。总的来说，这些数据表明，随着反复的压力暴露，CB1受体的神经eCB信号逐渐增强。