Tandospirone, a 5-HT1A agonist, ameliorates movement disorder via non-dopaminergic systems in rats with unilateral 6-hydroxydopamine-generated lesions
Tandospirone, a 5-HT1A agonist, ameliorates movement disorder via non-dopaminergic systems in rats with unilateral 6-hydroxydopamine-generated lesions
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DOI：
10.1016/j.brainres.2006.07.003
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发表时间：
2006-09-27
期刊：
影响因子：
2.9
通讯作者：
Shiono, Hiroshi
中科院分区：
文献类型：
--
作者：
Matsubara, Kazuo;Shimizu, Keiko;Shiono, Hiroshi
5-羟色胺1A（5-HT 1A）受体分布在整个大脑中，在额叶皮质、丘脑底核和脚内核以及中缝背核和正中核中浓度最高。越来越多的证据表明，5-HT 1A受体激动剂在重度抑郁症患者中具有抗抑郁作用。坦度螺酮是一种高效、选择性的5-HT 1A受体激动剂，在日本和中国临床上用作抗抑郁药，近年来的临床研究表明它可能是一种抗帕金森病药物。在本研究中，我们研究了坦度螺酮对单侧偏侧帕金森病大鼠模型中对侧旋转行为的影响，该模型由6-羟基多巴胺（6-OHDA）产生。坦度螺酮以及8-羟基-2-（二正丙基氨基）四氢化萘（8-OHDPAT）以剂量依赖性方式（0.5-10 mg/kg）显著增加对侧转向。坦度螺酮也显著增强阿扑吗啡0.025 mg/kg引起的对侧翻转。5-HT 1A受体拮抗剂WAY-10063 S预处理几乎完全阻断坦度螺酮和8-OHDPAT诱发的对侧翻转行为，但对阿扑吗啡无影响。选择性多巴胺D1受体拮抗剂SCH-23390不影响坦度螺酮诱导的旋转行为。提示坦度螺酮可作用于突触后5-HT 1A受体，调节基底节兴奋性氨基酸通路。因此，坦度螺酮可以通过调节非多巴胺能通路的神经元活性来治疗帕金森病。(c)2006 Elsevier B. V.保留所有权利。
Serotonin 1A (5-HT1A) receptors are distributed throughout the brain with their highest concentrations in the frontal cortex, subthalamic nucleus and entopeduncular nucleus as well as the dorsal and median raphe nucleus. There is growing evidence that 5-HT1A receptor agonists have an antidepressant effect in individuals with major depressive disorders. Recent clinical studies suggest that tandospirone, a highly potent and selective 5-HT1A receptor agonist used clinically as an antidepressant in Japan and China, may act as an antiparkinsonian drug. In the present study, we investigated the effect of tandospirone on contralateral rotational behavior in a unilateral hemiparkinsonian rat model produced with 6-hydroxydopamine (6-OHDA). Tandospirone, as well as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), significantly increased contralateral turnings in a dose-dependent manner (0.5-10 mg/kg). Tandospirone also remarkably potentiated the contralateral turning induced by 0.025 mg/kg of apomorphine. Pretreatment with WAY-10063S, a 5-HT1A receptor antagonist, almost completely blocked the contralateral turning behavior evoked by tandospirone and 8-OHDPAT, but not that by apomorphine. SCH-23390, a selective dopamine D1 receptor antagonist, did not affect on the tandospirone-induced rotational behavior. These results suggested that tandospirone could act on postsynaptic 5-HT1A receptors and modulate excitatory amino acid pathways in the basal ganglia. Thus, tandospirone could have therapeutic potential for the treatment of Parkinson's disease by modulating neuronal activities of non-dopaminergic pathways. (c) 2006 Elsevier B.V. All rights reserved.