O-2050 facilitates noradrenaline release and increases the CB1 receptor inverse agonistic effect of rimonabant in the guinea pig hippocampus
O-2050 facilitates noradrenaline release and increases the CB1 receptor inverse agonistic effect of rimonabant in the guinea pig hippocampus
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O-2050 促进去甲肾上腺素释放并增加利莫那班在豚鼠海马中的 CB1 受体反向激动作用
DOI：
10.1007/s00210-014-0991-3
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Schlicker E
中科院分区：
文献类型：
--
作者：
Jergas B;Schulte K;Bindila L;Lutz B;Schlicker E
豚鼠海马去肾上腺素能神经元上的大麻素cb1受体显示内源性内源性大麻素张力。这一结论是基于利莫那班的，利莫那班对去甲肾上腺素释放的促进作用可能是由于它的逆cb1受体激动作用和/或中断了内源性大麻素引起的强张性抑制。为了检验后一种机制，中性拮抗剂是合适的。因此，我们研究O-2050在豚鼠海马中是否是一种中性的cb1受体拮抗剂，以及它是否模仿利莫那班的促进作用。采用3h -利莫那班结合法，定量测定O-2050在脑皮质膜中的cb1受体亲和力。观察其cb1受体效价及对去甲肾上腺素释放的影响。利用35s - gtp - γ - s结合研究了其在海马膜上对cb1受体的内在活性。采用液相色谱-多反应监测法测定海马内源性大麻素水平。O-2050在cb1受体亲和力、效力和对去甲肾上腺素释放的促进作用上都比利莫那班低约10倍。虽然O-2050本身不影响35s - gtp - γ - s的结合，但它使cb1受体激动剂的浓度-反应曲线向右移动，而利莫那班的浓度-反应曲线向左移动。豚鼠海马中阿南达胺和2-花生四烯醇甘油的水平与小鼠海马相似。总之，我们对O-2050的研究结果证实了豚鼠海马去肾上腺素能神经元上的cb1受体表现出内源性张力。为了区分导致内源性紧张的两种机制，O-2050并不优于利莫那班，因为O-2050可能会增加内源性大麻素的拮抗作用。
The cannabinoid CB1receptors on the noradrenergic neurons in guinea pig hippocampal slices show an endogenous endocannabinoid tone. This conclusion is based on rimonabant, the facilitatory effect of which on noradrenaline release might be due to its inverse CB1receptor agonism and/or the interruption of a tonic inhibition elicited by endocannabinoids. To examine the latter mechanism, a neutral antagonist would be suitable. Therefore, we studied whether O-2050 is a neutral CB1receptor antagonist in the guinea pig hippocampus and whether it mimics the facilitatory effect of rimonabant. CB1receptor affinity of O-2050 was quantified in cerebrocortical membranes, using3H-rimonabant binding. Its CB1receptor potency and effect on3H-noradrenaline release were determined in superfused hippocampal slices. Its intrinsic activity at CB1receptors was studied in hippocampal membranes, using35S-GTPγS binding. Endocannabinoid levels in hippocampus were determined by liquid chromatography-multiple reaction monitoring. O-2050 was about ten times less potent than rimonabant in its CB1receptor affinity, potency and facilitatory effect on noradrenaline release. Although not affecting35S-GTPγS binding by itself, O-2050 shifted the concentration-response curve of a CB1receptor agonist to the right but that of rimonabant to the left. Levels of anandamide and 2-arachidonoyl glycerol in guinea pig hippocampus closely resembled those in mouse hippocampus. In conclusion, our results with O-2050 confirm that the CB1receptors on noradrenergic neurons of the guinea pig hippocampus show an endogenous tone. To differentiate between the two mechanisms leading to an endogenous tone, O-2050 is not superior to rimonabant since O-2050 may increase the inverse agonistic effect of endocannabinoids.
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