Continuous administration of a selective alpha7 nicotinic partial agonist, DMXBA, improves sensory inhibition without causing tachyphylaxis or receptor upregulation in DBA/2 mice.
Continuous administration of a selective alpha7 nicotinic partial agonist, DMXBA, improves sensory inhibition without causing tachyphylaxis or receptor upregulation in DBA/2 mice.
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连续施用选择性 α7 烟碱部分激动剂 DMXBA 可改善 DBA/2 小鼠的感觉抑制，而不会引起快速耐受或受体上调。
DOI：
10.1016/j.brainres.2010.06.063
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发表时间：
2010
期刊：
影响因子：
2.9
通讯作者：
Kem,WilliamR
中科院分区：
文献类型：
--
作者：
Stevens,KarenE;Cornejo,Brandon;Adams,CatherineE;Zheng,Lijun;Yonchek,Joan;Hoffman,KeithL;Christians,Uwe;Kem,WilliamR
刺激烟碱受体，特别是 α7 亚型，可以改善受体缺陷的人类和啮齿动物的感觉抑制和认知功能。然而，用完全激动剂（例如尼古丁）刺激会产生 P20N40 测量的感觉抑制过程的快速耐受。 3-(2,4-二甲氧基苄基) anabaseine (DMXBA，也称为 GTS-21) 选择性激活 α7 烟碱受体，在急性给药研究中，重复给药已证明可以改善人类和啮齿动物的感觉抑制缺陷。与尼古丁不同，这种部分激动剂不会引起快速耐受。在这里，我们评估了 DMXBA 通过皮下植入的渗透微型泵连续给药 7 天后改善 DBA/2 小鼠感觉抑制的能力。在第 8 天进行评估时，接受盐水的小鼠表现出未治疗的 DBA/2 小鼠所见的特征性感觉抑制缺陷。 25 mg/ml 和 50 mg/ml 输注浓度（而非 100 mg/ml）的 DMXBA 显着改善了小鼠的感觉抑制，完全是通过测试幅度的降低。没有浓度显着上调海马α7受体水平。在 3 个输注浓度中的 2 个浓度下，大脑中的 DMXBA 水平高于血浆。这些数据表明，在这些相对较低的脑浓度下，持续暴露于 DMXBA 不会显着影响感觉抑制途径对这种部分激动剂的潜在反应性，也不会导致受体上调。 DMXBA 在恒定给药条件下保持其有效性的能力可能是由于能够在低浓度下激活 α7 受体，因此该同聚受体上五个可能的结合位点的占有率较低。
Stimulation of nicotinic receptors, specifically the α7 subtype, improves sensory inhibition and cognitive function in receptor deficient humans and rodents. However, stimulation with a full agonist, such as nicotine, produces rapid tachyphylaxis of the P20N40-measured sensory inhibition process. 3-(2,4-dimethoxybenzylidine) anabaseine (DMXBA, also GTS-21) selectively activates the α7 nicotinic receptor, and in acute administration studies, has been shown to improve deficient sensory inhibition in both humans and rodents with repeated dosing. Unlike nicotine, this partial agonist acted without inducing tachyphylaxis. Here, we assessed the ability of DMXBA to improve sensory inhibition in DBA/2 mice after 7days of continuous administration via a subcutaneously implanted osmotic minipump. When assessed on day 8, mice receiving saline showed the characteristic deficient sensory inhibition seen with untreated DBA/2 mice. The 25- and 50-mg/ml infusion concentrations of DMXBA, but not the 100-mg/ml, produced significantly improved sensory inhibition in the mice, exclusively through a decrease in test amplitude. No concentration significantly upregulated hippocampal α7 receptor levels. DMXBA levels in the brain were higher than plasma at 2 of the 3 concentrations infused. These data suggest that continuous exposure to DMXBA does not significantly affect the underlying responsiveness of the sensory inhibition pathway to this partial agonist, nor cause receptor upregulation, at these relatively low brain concentrations. The ability of DMXBA to maintain its effectiveness during constant administration conditions may be due to an ability to activate α7 receptors at low concentrations, and consequently low fractional occupancy of the five possible binding sites on this homomeric receptor.