Atipamezole-precipitated clonidine withdrawal induces c-Fos expression in rat central nervous system.
Atipamezole-precipitated clonidine withdrawal induces c-Fos expression in rat central nervous system.
复制标题
阿替美唑沉淀的可乐定戒断诱导大鼠中枢神经系统中的 c-Fos 表达。
DOI：
10.1016/s0006-8993(97)00424-1
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发表时间：
1997
期刊：
影响因子：
2.9
通讯作者：
Guyenet,PG
中科院分区：
文献类型：
--
作者：
Stornetta,RL;Grubb,MC;Guyenet,PG
我们试图通过研究单次注射特异性α2-肾上腺素能拮抗剂阿替美唑（1.5 mg/kg i. p.）α2-肾上腺素能激动剂可乐定（200 μg/kg/d，通过渗透微泵持续7-10天）长期治疗后。长期给予可乐定然后注射阿替美唑（可乐定-阿替美唑）的大鼠表现出显著的行为效应，包括摇晃、剧烈挖掘和全身痉挛样运动。对照组（生理盐水、可乐定-生理盐水和生理盐水-阿替美唑）在注射后未显示明显的异常行为效应。可乐定-阿替美唑组的脑显示出大量的c-Fos表达（尤其是在中脑和端脑中），而其他组显示出c-Fos免疫阳性细胞的背景水平（生理盐水-生理盐水和可乐定-生理盐水组）或在选定区域（生理盐水-阿替美唑组）中比背景略微增加。在每个处理组的五个代表性冠状面处生成c-Fos免疫标记细胞的图谱。C-Fos免疫阳性细胞计数在三个代表性的脑干结构（蓝斑，孤束核，延髓头端腹外侧（RVL））和三个区域的胸脊髓（背角，中间区和腹角）。在三种脑干结构中，可乐定-阿替美唑组的c-Fos阳性细胞数量比其他组增加8-10倍。其他处理组与生理盐水-生理盐水组无显著差异。与假手术阿替美唑注射组相比，可乐定-阿替美唑组胸脊髓背角和中间层中的c-Fos阳性神经元数量也增加。在可乐定-阿替美唑治疗（戒断）大鼠RVL中，59%的c-Fos阳性细胞含有α 2A肾上腺素能受体样免疫反应性。此外，三分之一的酪氨酸羟化酶（TH）免疫阳性细胞的RVL也c-Fos阳性可乐定戒断大鼠，没有TH阳性细胞也c-Fos阳性的RVL的对照组。单次注射可乐定（200 μg/kg，i. p.）不产生行为学效应，也不增加脑干c-Fos表达。注射阿片拮抗剂纳洛酮（100 mg/kg，i. p.）可乐定慢性给药未引起大鼠行为学改变，也未导致脑干c-Fos表达增加。总之，对长期接受α2-肾上腺素能激动剂可乐定治疗的大鼠给予选择性α2-拮抗剂阿替美唑可引发与c-Fos蛋白大量CNS表达相关的强烈戒断综合征。戒断综合征的强度表明长期暴露于α2-肾上腺素能受体激动剂产生强烈的依赖性。
We sought to identify a clonidine withdrawal syndrome in conscious rats by investigating the effects of a single injection of the specific α2-adrenergic antagonist atipamezole (1.5 mg/kg i.p.) after chronic treatment with the α2-adrenergic agonist clonidine (200 μg/kg per day via osmotic mini-pump for 7–10 days). Rats treated chronically with clonidine followed by atipamezole injection (clonidine–atipamezole) demonstrated dramatic behavioral effects including shaking, vigorous digging, and whole-body seizure-like movements. Control groups (saline–saline, clonidine–saline and saline–atipamezole) showed no overt unusual behavioral effects following injection. The brains of the clonidine–atipamezole group showed massive c-Fos expression (especially in di- and telencephalon) while the other groups showed either background levels of c-Fos-immunopositive cells (saline–saline and clonidine–saline groups) or a slight increase over background in selected areas (saline–atipamezole group). Maps of c-Fos-immunolabeled cells were generated at five representative coronal planes for each treatment group. C-Fos-immunopositive cells were counted in three representative brainstem structures (locus coeruleus, nucleus of the solitary tract, rostral ventrolateral medulla (RVL)) and in three regions of the thoracic spinal cord (dorsal horn, intermediate zone and ventral horn). In the three brainstem structures the number of c-Fos-positive cells was elevated 8–10-fold in the clonidine–atipamezole group compared to the other groups. No other treatment group was significantly different from the saline–saline group. An increased number of c-Fos-positive neurons was also noted in the dorsal horn and intermediate layers of the thoracic spinal cord in the clonidine–atipamezole group compared to a sham-operated atipamezole-injected group. In the RVL, 59% of c-Fos-positive cells contained α2A-adrenergic receptor-like immunoreactivity in clonidine–atipamezole treated (withdrawing) rats. In addition, one-third of the tyrosine hydroxylase (TH)-immunopositive cells in RVL were also c-Fos-positive in clonidine withdrawing rats where no TH-positive cells were also c-Fos-positive in RVL of control groups. Atipamezole injected 10 min after a single injection of clonidine (200 μg/kg, i.p.) produced no behavioral effect and did not increase c-Fos expression in brainstem. Injection of the opiate antagonist naltrexone (100 mg/kg, i.p.) in rats chronically treated with clonidine did not elicit behavioral effects or result in increased c-Fos expression in brainstem. In conclusion, administration of the selective α2-antagonist atipamezole to rats chronically treated with the α2-adrenergic agonist clonidine triggers a powerful withdrawal syndrome associated with massive CNS expression of c-Fos protein. The intensity of the withdrawal syndrome indicates that chronic exposure to α2-adrenergic receptor agonists produces strong dependence.