Polymorphism in the corticotropin-releasing factor receptor 1 (CRF1-R) gene plays a role in shaping the high anxious phenotype of Marchigian Sardinian alcohol-preferring (msP) rats
Polymorphism in the corticotropin-releasing factor receptor 1 (CRF1-R) gene plays a role in shaping the high anxious phenotype of Marchigian Sardinian alcohol-preferring (msP) rats
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DOI：
10.1007/s00213-014-3743-7
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发表时间：
2015-03-01
影响因子：
3.4
通讯作者：
Ciccocioppo, Roberto
中科院分区：
文献类型：
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作者：
Cippitelli, Andrea;Ayanwuyi, Lydia O.;Ciccocioppo, Roberto
Marchigian撒丁岛酒精偏好(MSP)大鼠表现出天生的酒精偏好以及焦虑的表型。在这些动物中，发现了CRF1-R转录本第一起始密码子-1,836和-2,097处的两个单核苷酸多态。在这里，我们检查了这些点突变是否与MSP大鼠焦虑样行为和应激反应的增强有关。我们对MSP大鼠进行了重组，获得了两个不同的株系，分别携带野生型(GG)和点突变(AA)。CRF1-R基因表达分析显示，AA大鼠杏仁核延伸区存在明显的系统失调。在行为水平上，使用高架+迷宫，我们发现AA和GG系大鼠比Wistar大鼠有更高的基础焦虑。在防御性埋葬试验中，AA大鼠的埋葬行为比GG和未选择的Wistar品系有所减少。冷冻/不动在AA和GG之间没有差异，但高于Wistars。选择性CRF1-R拮抗剂antalarmin(0、10和20 mg/kg)可减少Wistar动物的埋葬行为。然而，在MSP品系中测试时，安塔拉明(10 mg/kg)倾向于增加而不是减少这种行为，这种效果在GG比AA品系更明显。目前的数据表明，具有MSP遗传背景的大鼠比Wistars更焦虑，对压力和CRF1-R阻断的敏感性不同。CRF1-R基因点突变似乎并不影响基础焦虑，而似乎影响对压力的积极反应。
Marchigian Sardinian alcohol-preferring (msP) rats exhibit innate preference for alcohol along with anxious phenotype. In these animals, two single-nucleotide polymorphisms in position -1,836 and -2,097 from the first start codon of the CRF1-R transcript have been found.Here, we examined whether these point mutations account for the heightened anxiety-like behavior and stress responsiveness of msP rats. We rederived the msP rats to obtain two distinct lines carrying the wild-type (GG) and point mutations (AA), respectively.CRF1-R gene expression analysis revealed significant dysregulation of the system in the extended amygdala of AA rats. At the behavioral level, using the elevated plus maze, we found that both AA and GG lines had higher basal anxiety compared to Wistar rats. In the defensive burying test, AA rats showed decreased burying behavior compared to the GG and the unselected Wistar lines. Freezing/immobility did not differ among AA and GG but was higher than that of Wistars. The selective CRF1-R antagonist antalarmin (0, 10, and 20 mg/kg) reduced burying behavior in Wistar animals. However, antalarmin (10 mg/kg) tended to increase rather than reducing this behavior when tested in the msP lines, an effect that appeared more marked in the GG as compared to the AA line.The present data suggest that rats with msP genetic background are more anxious and show different sensitivity to stress and CRF1-R blockade than Wistars. The point mutations occurring in the CRF1-R gene do not seem to influence basal anxiety while they appear to affect active responses to stress.