Tacr1 gene variation and neurokinin 1 receptor expression is associated with antagonist efficacy in genetically selected alcohol-preferring rats.
Tacr1 gene variation and neurokinin 1 receptor expression is associated with antagonist efficacy in genetically selected alcohol-preferring rats.
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DOI：
10.1016/j.biopsych.2012.12.027
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发表时间：
2013-04-15
影响因子：
10.6
通讯作者：
Heilig, Markus
中科院分区：
文献类型：
--
作者：
Schank, Jesse R.;Tapocik, Jenica D.;Barbier, Estelle;Damadzic, Ruslan;Eskay, Robert L.;Sun, Hui;Rowe, Kelly E.;King, Courtney E.;Yao, Mengdi;Flanigan, Meghan E.;Solomon, Matthew G.;Karlsson, Camilla;Cheng, Kejun;Rice, Kenner C.;Heilig, Markus
神经激肽1受体（NK 1 R）的基因缺失或拮抗作用减少了啮齿动物的酒精摄入量，酒精奖励和应激诱导的酒精复发，而TACR 1变异与人类的酒精中毒有关。我们使用了L 822429，一种对大鼠NK 1 R具有高亲和力的特异性拮抗剂，并检查了在嗜酒精（P）大鼠中对NK 1 R阻断的敏感性是否改变。在P-大鼠及其建立者Wistar系中分析了操作性酒精自我给药和累进比率反应。我们还分析了Tacr 1的表达和结合，并对两个品系的Tacr 1启动子进行了测序。全身性L 822429减少了P大鼠的酒精自我给药，但不影响Wistar大鼠的酒精自我给药率较低。Tacr 1在P-大鼠的前额叶皮层和杏仁核中的表达升高。在中央杏仁核中，Tacr 1表达升高伴随着NK 1 R结合升高。中央杏仁核（但不是前额叶皮层）输注L 822429复制了对P大鼠酒精自我给药的全身拮抗作用。所有的P-大鼠，但只有18%的创始人Wistar种群，是CC纯合子的− 1372 G/C单核苷酸多态性。计算机模拟分析表明，Tacr 1 −1372基因型可以调节转录因子加塔-2和E2 F-1的结合。电迁移率变化和荧光素酶报告基因分析表明，− 1372 C等位基因赋予转录因子结合和转录增加。Tacr 1基因座的遗传变异可能导致酒精自我给药率升高，同时增加对NK 1 R拮抗剂治疗的敏感性。
Genetic deletion or antagonism of the neurokinin 1 receptor (NK1R) decreases alcohol intake, alcohol reward, and stress-induced alcohol relapse in rodents, while TACR1 variation is associated with alcoholism in humans. We used L822429, a specific antagonist with high affinity for the rat NK1R, and examined whether sensitivity to NK1R blockade is altered in alcohol-preferring (P) rats. Operant alcohol self-administration and progressive ratio responding were analyzed in P-rats and their founder Wistar line. We also analyzed Tacr1 expression and binding and sequenced the Tacr1 promoter from both lines. Systemic L822429 decreased alcohol self-administration in P-rats but did not affect the lower rates of alcohol self-administration in Wistar rats. Tacr1 expression was elevated in the prefrontal cortex and the amygdala of P-rats. In central amygdala, elevated Tacr1 expression was accompanied by elevated NK1R binding. Central amygdala (but not prefrontal cortex) infusion of L822429 replicated the systemic antagonist effects on alcohol self-administration in P-rats. All P-rats, but only 18% of their founder Wistar population, were CC homozygous for a −1372G/C single nucleotide polymorphism. In silico analysis indicated that the Tacr1 −1372 genotype could modulate binding of the transcription factors GATA-2 and E2F-1. Electromobility shift and luciferase reporter assays suggested that the −1372C allele confers increased transcription factor binding and transcription. Genetic variation at the Tacr1 locus may contribute to elevated rates of alcohol self-administration, while at the same time increasing sensitivity to NK1R antagonist treatment.
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影响因子：
4.7
作者：
Singewald, Nicolas;Chicchi, Gary G.;Ebner, Karl
通讯作者：
Ebner, Karl
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