The interaction of the Chrna5 D398N variant with developmental nicotine exposure.
The interaction of the Chrna5 D398N variant with developmental nicotine exposure.
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Chrna5 D398N 变体与发育期尼古丁暴露的相互作用。
DOI：
10.1111/gbb.12474
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Stitzel,JA
中科院分区：
文献类型：
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作者：
O'Neill,HC;Wageman,CR;Sherman,SE;Grady,SR;Marks,MJ;Stitzel,JA
CHRNA 5中的单核苷酸多态性（SNP）（rs 16969968，人α5烟碱乙酰胆碱受体亚基第398位天冬氨酸[D]变为天冬酰胺[N]）与尼古丁依赖风险增加相关。因此，风险变体的携带者可能处于子宫内尼古丁暴露的高风险中。为了评估这种基因-环境相互作用是否可能影响发育中尼古丁暴露后代的尼古丁摄入量，我们使用了表达这种人类SNP的小鼠。从配种前30天至后代断奶，D和N母鼠饮用含尼古丁（100 μg/mL）的0.2%糖精水或仅含0.2%糖精水（溶剂）作为其唯一液体来源。暴露于尼古丁（D Nic，N Nic）或溶剂（D Veh，N Veh）的后代在出生后30 - 46天之间进行2瓶选择试验。与所有其他组相比，N Nic后代在最高浓度（400 μg/mL）下消耗的尼古丁最多。相比之下，D Nic后代在所有测试浓度下摄入的尼古丁量最少。从纹状体突触体测量的尼古丁刺激的多巴胺（DA）释放在D Nic后代中增加，而相对于其基因型匹配的对照，N Nic后代中减少。这些数据表明，α5变体影响发育尼古丁暴露对暴露后代尼古丁摄入量的影响。纹状体DA释放的这种基因-环境相互作用可能为N Nic后代增加尼古丁寻求和D Nic后代减少尼古丁消耗提供了动力。
A single nucleotide polymorphism (SNP) inCHRNA5(rs16969968, change from an aspartic acid [D] to asparagine [N] at position 398 of the human α5 nicotinic acetylcholine receptor subunit) has been associated with increased risk for nicotine dependence. Consequently, carriers of the risk variant may be at elevated risk for in utero nicotine exposure. To assess whether this gene‐environment interaction might impact nicotine intake in developmental nicotine‐exposed offspring, we utilized a mouse expressing this human SNP. D and N dams drank nicotine (100 μg/mL) in 0.2% saccharin water or 0.2% saccharin water alone (vehicle) as their sole source of fluid from 30 days prior to breeding until weaning of offspring. The nicotine (D Nic, N Nic) or vehicle (D Veh, N Veh) exposed offspring underwent a 2‐bottle choice test between postnatal ages of 30 to 46 days. N Nic offspring consumed the most nicotine at the highest concentration (400 μg/mL) compared with all other groups. In contrast, D Nic offspring drank the least amount of nicotine at all concentrations tested. Nicotine‐stimulated dopamine (DA) release measured from striatal synaptosomes was increased in D Nic offspring, while decreased in N Nic offspring relative to their genotype‐matched controls. These data suggest that the α5 variant influences the effect of developmental nicotine exposure on nicotine intake of exposed offspring. This gene‐environment interaction on striatal DA release may provide motivation for increased nicotine seeking in N Nic offspring and reduced consumption in D Nic offspring.