Synergistic effect of 5-HT_<1A> and σ_1 receptor activation on prefrontal dopaminergic transmission under circulating steroid deficiency
Synergistic effect of 5-HT_<1A> and σ_1 receptor activation on prefrontal dopaminergic transmission under circulating steroid deficiency
复制标题
循环类固醇缺乏下5-HT_<1A>和σ_1受体激活对前额叶多巴胺能传递的协同作用
DOI：
10.1016/j.neuropharm.2013.06.026
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发表时间：
2013
影响因子：
4.7
通讯作者：
松田 敏夫
中科院分区：
文献类型：
--
作者：
平松 直樹;吾郷 由希夫;長谷 部茂;西村 明;森 和也;田熊 一敞;松田 敏夫
5-羟色胺（5-HT）1A和σ 1受体与精神疾病有关。我们以前发现，在缺乏循环类固醇激素的肾上腺切除/去势小鼠中，联合5-HT再摄取抑制和σ 1受体激活对前额叶多巴胺能传递具有协同作用。在本研究中，我们研究了这种神经化学协同作用的机制。全身给予氟伏沙明（一种选择性5-HT再摄取抑制剂，对σ 1受体具有激动活性）可增加前额叶多巴胺（DA）水平，肾上腺切除/去势可加强氟伏沙明诱导的DA增加，WAY 100635可阻断这种DA释放的增强作用对5-HT_（1A）受体拮抗剂利坦色林（ritanserin）、阿扎司琼（azasetron）和SB_269970（5-HT_（17）受体拮抗剂）均无明显作用。单独使用osemozotan（一种5-HT 1A受体激动剂）和（+）-SKF-10，047（一种σ 1受体激动剂）对肾上腺切除/去势小鼠和假手术小鼠的前额叶单胺水平没有不同的影响。与此相反，这些药物的共同管理增加前额DA水平在更大程度上在肾上腺切除/去势小鼠比假手术动物。此外，共同给予osemozotan和（+）-SKF-10，047增加了肾上腺切除/去势小鼠腹侧被盖区神经元活性标记物c-Fos的表达，但在假手术动物中没有。提示5-HT_（1A）和σ_（1A）受体的联合激活对循环类固醇缺乏时的前额叶多巴胺能传递具有协同作用，这种相互作用可能在前额叶DA系统的调节中起重要作用。
Serotonin (5-HT)1Aand σ1receptors have been implicated in psychiatric disorders. We previously found that combined 5-HT reuptake inhibition and σ1receptor activation has a synergistic effect on prefrontal dopaminergic transmission in adrenalectomized/castrated mice lacking circulating steroid hormones. In the present study, we examined the mechanisms underlying this neurochemical synergism. Systemic administration of fluvoxamine, a selective 5-HT reuptake inhibitor with agonistic activity towards the σ1receptor, increased prefrontal dopamine (DA) levels, and adrenalectomy/castration potentiated this fluvoxamine-induced increase in DA. This enhancement of DA release was blocked by WAY100635 (a 5-HT1Areceptor antagonist), but not by ritanserin (a 5-HT2receptor antagonist), azasetron (a 5-HT3receptor antagonist) or SB269970 (a 5-HT7receptor antagonist). Individually, osemozotan (a 5-HT1Areceptor agonist) and (+)-SKF-10,047 (a σ1receptor agonist) did not alter prefrontal monoamine levels in adrenalectomized/castrated and sham-operated mice differentially. In contrast, co-administration of these drugs increased prefrontal DA levels to a greater extent in adrenalectomized/castrated mice than in sham-operated animals. Furthermore, co-administration of osemozotan and (+)-SKF-10,047 increased expression of the neuronal activity marker c-Fos in the ventral tegmental area of adrenalectomized/castrated mice, but not in sham-operated animals. These findings suggest that combined activation of 5-HT1Aand σ1receptors has a synergistic effect on prefrontal dopaminergic transmission under circulating steroid deficiency, and that this interaction may play an important role in the regulation of the prefrontal DA system.