Acute ethanol/cannabinoid-induced ataxia and its antagonism by oral/systemic/intracerebellar A1 adenosine receptor antisense in mice
Acute ethanol/cannabinoid-induced ataxia and its antagonism by oral/systemic/intracerebellar A1 adenosine receptor antisense in mice
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DOI：
10.1016/s0006-8993(02)03599-0
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发表时间：
2002-12-06
期刊：
影响因子：
2.9
通讯作者：
Mustafa, SJ
中科院分区：
文献类型：
--
作者：
Dar, MS;Mustafa, SJ
我们实验室以前的报告表明，乙醇和大麻素诱导的共济失调是由小脑腺苷 A(1) 受体调节的，因为小脑内 (i.c.b.) 腺苷 A(1) 激动剂会增强这些精神活性药物的共济失调，而 A(1) 拮抗剂会减弱这些精神活性药物的共济失调。在这项研究中，涉及通过多种途径用腺苷 A(1) 反义寡脱氧核苷酸进行预处理的新方法提供了小鼠小脑 A(1) 对乙醇和大麻素诱导的共济失调的调节的进一步直接证据。动物组通过口服 (p.o.)（3.12、6.25、12.5、50 杯/12 小时；总共 3 次治疗/每个剂量）、腹膜内（i.p.）（3.12、5、10、50 杯/12 小时；总共 3 次治疗/每个剂量）和 i.c.b. 预处理，使用 A(1) 反义及其错配。 （2 杯/12 小时；总共 3 次治疗）路线。根据我们的标准旋转杆测试，在最后一次反义治疗后 12 小时，观察到对乙醇（2 g/kg；腹腔注射）和 Delta(9)-THC（15 杯；i.c.b）诱导的共济失调的明显拮抗作用。 A(1) 受体错配预处理没有效果。全身（口服；腹膜内）反义预处理后的拮抗作用是剂量依赖性的。当用反义或其错配物随后用媒介物预处理动物时，没有观察到正常运动协调的变化。使用市售抗体和来自通过三种途径接受反义及其错配的不同动物组的小脑膜进行的蛋白质印迹结果证实，A(1) 腺苷受体蛋白显着减少。这些结果首次证明了 A(1) 反义药物对中枢神经系统中腺苷受体的口服和全身有效性。 (C) 2002 Elsevier Science B.V. 保留所有权利。
Previous reports from our laboratory have demonstrated that ethanol- and cannabinoid-induced ataxia is modulated by cerebellar adenosine A(1) receptor because intracerebellar (i.c.b.) adenosine A(1) agonists potentiated and A(1) antagonist attenuated ataxia by these psychoactive drugs. In this study, the novel approach involving pretreatment with adenosine A(1) antisense oligodeoxynucleotide via multiple routes provided further direct evidence of mouse cerebellar A(1) modulation of ethanol- and cannabinoid-induced ataxia. Animal groups were pretreated with A(1) antisense and its mismatch by oral (p.o.) (3.12, 6.25, 12.5, 50 mug/ 12 h; total three treatments/each dose), intraperitoneal (i.p.) (3.12, 5, 10, 50 mug/12 h; total three treatments/each dose), and i.c.b. (2 mug/12 h; total three treatments) routes. Based on our standard rotorod test, marked antagonism to ethanol (2 g/kg; i.p.) and Delta(9)-THC (15 mug; i.c.b)-induced ataxia was observed 12 h after the last antisense treatment. Pretreatment with A(1) receptor mismatch was without an effect. The antagonism following systemic (p.o.; i.p.) antisense pretreatment was dose-dependent. No change in the normal motor coordination was observed when the animals were pretreated with antisense or its mismatch followed by vehicle. Results of Western blotting using commercially available antibodies and cerebellar membranes from various animal groups which received antisense and its mismatch via three routes confirmed a significant decrease in the A(1) adenosine receptor protein. These results, for the first time, demonstrated an oral and systemic effectiveness of A(1) antisense towards adenosine receptors in the central nervous system. (C) 2002 Elsevier Science B.V. All rights reserved.