Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response.
Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response.
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DOI：
10.1523/jneurosci.0496-11.2011
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发表时间：
2011-07-20
期刊：
影响因子：
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通讯作者：
Hillard CJ
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文献类型：
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作者：
Hill MN;McLaughlin RJ;Pan B;Fitzgerald ML;Roberts CJ;Lee TT;Karatsoreos IN;Mackie K;Viau V;Pickel VM;McEwen BS;Liu QS;Gorzalka BB;Hillard CJ
内侧前额叶皮层 (mPFC) 内糖皮质激素信号传导终止应激诱导的下丘脑 - 垂体 - 肾上腺 (HPA) 轴激活的能力的机制尚不清楚。我们报道，大鼠压力停止后，mPFC 内局部大麻素 CB1 受体的拮抗作用延长了皮质酮的分泌。缺乏 CB1 受体的小鼠表现出类似的对压力的长时间反应。大鼠暴露在压力下会导致 mPFC 内的内源性大麻素 2-花生四烯酰甘油升高，而用糖皮质激素受体拮抗剂 RU-486（20 mg/kg）预处理可逆转这一升高。电子显微镜和电生理学数据表明，抑制型末端存在 CB1 受体，撞击 mPFC 前边缘区域 V 层内的主要神经元。 1 小时后检查时，将皮质酮 (100 nM) 应用于前额皮质切片，抑制 GABA 释放到前边缘区域 V 层的主要神经元上，而使用 CB1 受体拮抗剂可以阻止这种情况。总的来说，这些数据表明，mPFC 内应激诱导的糖皮质激素信号传导终止 HPA 轴活性的能力是由内源性大麻素信号传导的局部募集介导的。 CB1 受体的内源性大麻素激活会减少 mPFC 内的 GABA 释放，可能会增加前边缘区域主要神经元的流出，从而有助于终止应激反应。这些数据支持一个模型，其中内源性大麻素信号传导将糖皮质激素受体的参与与抑制皮质酮分泌的皮质边缘继电器的激活联系起来。
The mechanisms subserving the ability of glucocorticoid signaling within the medial prefrontal cortex (mPFC) to terminate stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis are not well understood. We report that antagonism of the cannabinoid CB1 receptor locally within the mPFC prolonged corticosterone secretion following cessation of stress in rats. Mice lacking the CB1 receptor exhibited a similar prolonged response to stress. Exposure of rats to stress produced an elevation in the endocannabinoid 2-arachidonoylglycerol within the mPFC that was reversed by pretreatment with the glucocorticoid receptor antagonist RU-486 (20 mg/kg). Electron microscopic and electrophysiological data demonstrated the presence of CB1 receptors in inhibitory-type terminals impinging upon principal neurons within layer V of the prelimbic region of the mPFC. Bath application of corticosterone (100 nM) to prefrontal cortical slices suppressed GABA release onto principal neurons in layer V of the prelimbic region, when examined 1 h later, which was prevented by application of a CB1 receptor antagonist. Collectively, these data demonstrate that the ability of stress-induced glucocorticoid signaling within mPFC to terminate HPA axis activity is mediated by a local recruitment of endocannabinoid signaling. Endocannabinoid activation of CB1 receptors decreases GABA release within the mPFC, likely increasing the outflow of the principal neurons of the prelimbic region to contribute to termination of the stress response. These data support a model in which endocannabinoid signaling links glucocorticoid receptor engagement to activation of corticolimbic relays that inhibit corticosterone secretion.