Thromboxane receptor activation enhances striatal dopamine release, leading to suppression of GABAergic transmission and enhanced sugar intake
Thromboxane receptor activation enhances striatal dopamine release, leading to suppression of GABAergic transmission and enhanced sugar intake
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DOI：
10.1111/j.1460-9568.2011.07774.x
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发表时间：
2011-08
影响因子：
3.4
通讯作者：
T. Mitsumori;T. Furuyashiki;T. Momiyama;A. Nishi;T. Shuto;Takashi Hayakawa;F. Ushikubi;S. Kitaoka;T. Aoki;H. Inoue;T. Matsuoka;S. Narumiya
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作者：
T. Mitsumori;T. Furuyashiki;T. Momiyama;A. Nishi;T. Shuto;Takashi Hayakawa;F. Ushikubi;S. Kitaoka;T. Aoki;H. Inoue;T. Matsuoka;S. Narumiya
细胞外多巴胺水平不仅受多巴胺神经元的突触输入调节，而且还受多巴胺能末梢周围的局部机制调节。然而，后一种机制仍有许多问题有待研究。血栓烷A2是花生四烯酸衍生的环氧合酶产物之一，作用于其同源G蛋白偶联受体[血栓烷受体（TP）]。我们在这里表明，TP在纹状体局部促进多巴胺溢出。纹状体内注射TP激动剂增加细胞外多巴胺水平在纹状体在体内微透析测量。TP刺激也增强了电诱发的多巴胺溢出纹状体切片。相反，TP缺乏减少纹状体切片中N-甲基-d-天冬氨酸（NMDA）和乙酰胆碱诱发的多巴胺溢出。TP免疫组化染色显示TP在血管内皮细胞中富集。一氧化氮（NO）合成的药理学阻断和内皮NO合酶（eNOS）的基因缺失抑制了NMDA/乙酰胆碱诱导的多巴胺溢出。在TP缺乏的切片中，NO的参与被消除，表明eNOS衍生的NO合成在TP介导的多巴胺溢出中的作用。作为TP介导的多巴胺增加的功能结果，TP激动剂通过D2样受体依赖性机制抑制中型棘神经元中的GABA能抑制性突触后电流。最后，TP参与蔗糖摄入，这是一种多巴胺依赖的动机行为。这些数据表明，TP刺激纹状体局部促进多巴胺溢出诱发的突触输入通过NO合成内皮细胞。
The extracellular dopamine level is regulated not only by synaptic inputs to dopamine neurons but also by local mechanisms surrounding dopaminergic terminals. However, much remains to be investigated for the latter mechanism. Thromboxane A2 is one of the cyclooxygenase products derived from arachidonic acid, and acts on its cognate G protein‐coupled receptor [thromboxane receptor (TP)]. We show here that TP in the striatum locally facilitates dopamine overflow. Intrastriatal injection of a TP agonist increased extracellular dopamine levels in the striatum as measured by in vivo microdialysis. TP stimulation also augmented electrically evoked dopamine overflow from striatal slices. Conversely, TP deficiency reduced dopamine overflow evoked by N‐methyl‐d‐aspartic acid (NMDA) and acetylcholine in striatal slices. TP immunostaining showed that TP is enriched in vascular endothelial cells. Pharmacological blockade of nitric oxide (NO) synthesis and genetic deletion of endothelial NO synthase (eNOS) suppressed NMDA/acetylcholine‐induced dopamine overflow. This involvement of NO was abolished in TP‐deficient slices, suggesting a role for eNOS‐derived NO synthesis in TP‐mediated dopamine overflow. As a functional consequence of TP‐mediated dopamine increase, a TP agonist suppressed GABAergic inhibitory postsynaptic currents in medium spiny neurons through a D2‐like receptor‐dependent mechanism. Finally, TP is involved in sucrose intake, a dopamine‐dependent motivational behavior. These data suggest that TP stimulation in the striatum locally facilitates dopamine overflow evoked by synaptic inputs via NO synthesis in endothelial cells.