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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism.
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Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism.

机译：通过下丘脑中的内源性大麻素释放抑制非基因组糖皮质激素：一种快速反馈机制。

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摘要

Glucocorticoid negative feedback in the brain controls stress, feeding, and neural-immune interactions by regulating the hypothalamic-pituitary-adrenal axis, but the mechanisms of inhibition of hypothalamic neurosecretory cells have never been elucidated. Using whole-cell patch-clamp recordings in an acute hypothalamic slice preparation, we demonstrate a rapid suppression of excitatory glutamatergic synaptic inputs to parvocellular neurosecretory neurons of the hypothalamic paraventricular nucleus (PVN) by the glucocorticoids dexamethasone and corticosterone. The effect was maintained with dexamethasone conjugated to bovine serum albumin and was not seen with direct intracellular glucocorticoid perfusion via the patch pipette, suggesting actions at a membrane receptor. The presynaptic inhibition of glutamate release by glucocorticoids was blocked by postsynaptic inhibition of G-protein activity with intracellular GDP-beta-S application, implicating a postsynaptic G-protein-coupled receptor and the release of a retrograde messenger. The glucocorticoid effect was not blocked by the nitric oxide synthesis antagonist N(G)-nitro-L-arginine methyl ester hydrochloride or by hemoglobin but was blocked completely by the CB1 cannabinoid receptor antagonists AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-py razole-3-carboxamide] and AM281 [1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyraz ole-3-carboxamide] and mimicked and occluded by the cannabinoid receptor agonist WIN55,212-2 [(beta)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de] -1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate], indicating that it was mediated by retrograde endocannabinoid release. Several peptidergic subtypes of parvocellular neuron, identified by single-cell reverse transcripton-PCR analysis, were subject to rapid inhibitory glucocorticoid regulation, including corticotropin-releasing hormone-, thyrotropin-releasing hormone-, vasopressin-, and oxytocin-expressing neurons. Therefore, our findings reveal a mechanism of rapid glucocorticoid feedback inhibition of hypothalamic hormone secretion via endocannabinoid release in the PVN and provide a link between the actions of glucocorticoids and cannabinoids in the hypothalamus that regulate stress and energy homeostasis.
机译：大脑中糖皮质激素的负反馈通过调节下丘脑-垂体-肾上腺轴来控制压力，进食和神经-免疫相互作用，但从未阐明抑制下丘脑神经分泌细胞的机制。在急性下丘脑切片制备中使用全细胞膜片钳记录，我们证明了糖皮质激素地塞米松和皮质酮可迅速抑制下丘脑室旁核（PVN）的小细胞神经分泌神经元的兴奋性谷氨酸能突触输入。地塞米松与牛血清白蛋白结合后可维持该作用，而通过补片吸管直接向细胞内进行糖皮质激素灌注则未见效果，提示其作用于膜受体。糖皮质激素对突触后谷氨酸释放的抑制被细胞内GDP-β-S的突触后抑制G蛋白活性所阻止，这牵涉到突触后G蛋白偶合受体和逆行信使的释放。糖皮质激素的作用并未被一氧化氮合成拮抗剂N（G）-硝基-L-精氨酸甲酯盐酸盐或血红蛋白所阻断，但被CB1大麻素受体拮抗剂AM251 [N-（piperidin-1-yl）- 5-（4-碘苯基）-1-（2,4-二氯苯基）-4-甲基-1H-吡唑-3-羧酰胺]和AM281 [1-（2,4-二氯苯基）-5-（4-碘苯基） ）-4-甲基-N-4-吗啉基-1H-吡唑ole-3-羧酰胺]并被大麻素受体激动剂WIN55,212-2 [β-（+）-[2,3-dihydro]模拟和封闭-5-甲基-3-（4-吗啉基甲基）吡咯并[1,2,3-de] -1,4-苯并恶嗪-6-基] -1-萘甲酮甲磺酸盐]，表明它是由逆向内源性大麻素释放介导的。通过单细胞逆转录-PCR分析鉴定出的几种小细胞神经元的肽能亚型受到了快速抑制性糖皮质激素的调节，包括促肾上腺皮质激素释放激素，促甲状腺激素释放激素，血管加压素和催产素表达神经元。因此，我们的发现揭示了通过PVN中的内源性大麻素释放，快速糖皮质激素反馈抑制下丘脑激素分泌的机制，并提供了下丘脑中糖皮质激素和大麻素的作用之间的联系，从而调节压力和能量稳态。

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