Department of Experimental and Clinical Pharmacology, University of Catania Medical School, Viale A. Doria 6, 95125, Catania, Italy.
Eur Neuropsychopharmacol. 2010 Oct;20(10):704-13. doi: 10.1016/j.euroneuro.2010.04.006. Epub 2010 May 26.
These experiments were made to study the mechanisms underlying the antidepressant-like effects of the beta(3) adrenoceptor agonist amibegron (SR58611A). To this purpose, the expression levels of the hippocampal cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), B-cell lymphoma-2 (Bcl-2) and Bax proteins were assessed, by using western blot analysis, in rats tested in the forced swim test (FST). Under basal conditions (no previous exposure to stressors), different groups of male Wistar rats received acutely or repeatedly (once/day for 7days) intraperitoneal (i.p.) injections of amibegron (1, 5 and 10mg/kg), the tricyclic antidepressant (TCA) clomipramine (50mg/kg), the selective serotonin reuptake inhibitor (SSRI) citalopram (15mg/kg) or their vehicles. The influence of stress-related conditions was studied in rats subjected to acute (4h) or repeated (4h/day for 7days) restraint stress, applied prior to the FST procedure. Compared to the control groups, both stressor procedures increased the immobility time in the FST and reduced hippocampal BDNF and Bcl-2/Bax ratio proteins expression, which were counteracted by amibegron (5 and 10mg/kg) treatment. Opposite effects were found in the CREB expression, since it was lower after acute and higher after repeated stress procedure, respectively. Again, these effects were reversed by amibegron treatment. Different results were obtained in animals treated with clomipramine or citalopram. Hence, it is likely that the observed behavioral effects of amibegron could be due, at least in part, to its action on hippocampal expression of neurotrophic and/or anti-apoptotic factors, supporting the hypothesis that beta(3) adrenoceptors may be a therapeutic target for the treatment of stress-related disorders.
这些实验旨在研究β3 肾上腺素能受体激动剂阿米贝隆（SR58611A）产生抗抑郁样作用的机制。为此，通过 Western blot 分析评估了海马环磷酸腺苷（cAMP）反应元件结合蛋白（CREB）、脑源性神经营养因子（BDNF）、B 细胞淋巴瘤-2（Bcl-2）和 Bax 蛋白在强迫游泳试验（FST）中测试的大鼠中的表达水平。在基础条件下（无先前暴露于应激源），不同组别的雄性 Wistar 大鼠接受单次或重复（每天一次，共 7 天）腹膜内（i.p.）注射阿米贝隆（1、5 和 10mg/kg）、三环抗抑郁药（TCA）氯米帕明（50mg/kg）、选择性 5-羟色胺再摄取抑制剂（SSRI）西酞普兰（15mg/kg）或其载体。研究了应激相关条件对急性（4h）或重复（4h/天，共 7 天）束缚应激大鼠的影响，该应激在 FST 程序之前进行。与对照组相比，两种应激程序均增加了 FST 中的不动时间，并降低了海马 BDNF 和 Bcl-2/Bax 比值蛋白的表达，而阿米贝隆（5 和 10mg/kg）治疗则逆转了这种作用。在 CREB 表达中发现了相反的作用，因为急性应激后降低，重复应激后升高。再次，阿米贝隆治疗逆转了这些作用。用氯米帕明或西酞普兰治疗的动物得到了不同的结果。因此，阿米贝隆观察到的行为作用可能至少部分归因于其对海马神经营养和/或抗细胞凋亡因子表达的作用，支持β3 肾上腺素能受体可能是治疗应激相关疾病的治疗靶点的假说。
