Antagonist-induced increase in 5-HT1A-receptor expression in adult rat hippocampus and cortex
Antagonist-induced increase in 5-HT1A-receptor expression in adult rat hippocampus and cortex
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DOI：
10.1002/syn.20399
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发表时间：
2007-07-01
期刊：
影响因子：
2.3
通讯作者：
Azmitia, Efrain C.
中科院分区：
文献类型：
--
作者：
Abbas, Syed Y.;Nogueira, Maria I.;Azmitia, Efrain C.
许多受体拮抗剂在信号转导途径中起反向激动剂的作用，但对这些药物调节受体表达的作用知之甚少。5-HT和无血清胎儿海马培养物中5-HT 1A（5-HT 1A）受体表达在特异性5-HT 1A受体拮抗剂N-（2-（4-（2-甲氧基苯基）-1-哌嗪基）乙基）-N-（2-吡啶基）环己烷甲酰胺（WAY 100635）存在下增加。为了研究在体内存在拮抗剂的情况下突触后5-HT 1A受体的可塑性，在3天内每天一次或两次腹膜内注射成年Sprague道利大鼠WAY 100635（3 mg/kg）。采用免疫细胞化学和光镜技术检测海马5-HT 1A受体的表达，并采用计算机辅助形态计量学方法对海马各亚区5-HT 1A受体的免疫反应性（IR）进行定量分析。每天注射WAY 100635后，记录到海马神经元中5-HT 1A受体标记的显著增加。5-HT 1A受体表达的这种显著增加，发生在单次注射WAY 100635后4小时内，在海马和皮层V层神经元的胞体膜和树突状突起上是明显的。相比之下，以低剂量（1 mg/kg）每日多次注射WAY 100635后，未观察到5-HT 1A受体-IR增加。我们的研究表明，每天一次或多次注射WAY 100635可导致5-HT 1A受体-IR的增加。这种标记的增加与受体蛋白的表达增强一致。这种“反向激动剂”的作用可能在5-HT 1A受体水平不足的疾病如抑郁症、癫痫和阿尔茨海默病中具有临床重要性。
Many receptor antagonists function as reverse agonists on the signaling transduction pathway, but little is known about, the action of these drugs on the regulation of receptor expression. Serotonin 1A (5-HT1A) receptor expression in 5-HT and serum-free fetal hippocampal cultures is increased in the presence of a specific 5HT1A-receptor antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635). To study the plasticity of postsynaptic 5-HT1A receptors in the presence of antagonist in vivo, adult Sprague Dawley rats were injected i.p. either once or twice daily with a dose of WAY 100635 (3 mg/kg) over a period of 3 days. The 5-HT1A receptor expression was detected by immunocytochemistry and light microscopy, and the receptor immunoreactivity (IR) in hippocampus subregions was quantitatively assessed by using a comparative computer-assisted morphometric analysis. Following the daily injections of WAY 100635, a significant increase in 5-HT1A receptor labeling in hippocampal neurons was recorded. This marked increase in 5-HT1A receptor expression, which occurred within 4 h after a single injection of WAY 100635, is evident on the somata membrane and dendritic processes of hippocampal and cortex layer V neurons. By contrast, no increase in 5-HT1A receptor-IR was observed after multiple daily injections at a low dose (1 mg/kg) of WAY 100635. Our study shows that a single or multiple daily injections of WAY 100635 can result in an increase in 5-HT1A receptor-IR. This increase in labeling is consistent with an enhanced expression of the receptor protein. The action of this "inverse agonist" may have clinical importance in disorders such as depression, epilepsy, and Alzheimer's disease in which 5-HT1A receptor levels are deficient.